The authors of these articles [Bliss, 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15293038); Al-Mosawi, 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12042902)] and similar articles have discussed the therapeutic effects that some soluble fibers, such as gum acacia or guar gum, have produced in people with chronic kidney disease that hasn't been life-threatening or in people with liver disease. Those types of very-high-molecular-weight polysaccharides can't be hydrolyzed by human enzymes but can be by the enzymes of bacteria in the colon, primarily, that use the breakdown products as substrates for the energy production that drives the cell division of the bacteria, etc. The oral administration of guar gum or gum acacia, among other soluble fibers, have reduced serum urea, serum phosphate/phosphorus, and serum creatinine in people with kidney disease, and the explanation has been that the bacteria use nitrogen-containing compounds for their cellular functions and proliferation. The effects on some of these parameters are not small or minor, really, in many of the articles, and, in my view, the research has validity. The idea has been that the soluble fibers provide the "fuel source" and cause, as a consequence, the bacteria to incorporate more of the nitrogen-containing compounds in the intestinal luminal fluid into their cellular processes.
Before I write the rest of this, I should mention that I think inulin, as a "probiotic," has the potential to be very problematic, and one of the reasons is that inulin can cross the intestinal barrier in the jejunum of the rat, apparently by passive diffusion in between the epithelial cells [Ma et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/2035637)]. That "paracellular" ("alongside" the cells) mode of absorption is not uncommon, and inulin has a very low molecular weight (it's ~5000 or so (Ma et al., 1995)). The colon is also permeable to inulin [Ma et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7806033)], and Ma et al. (1995) discussed the fact that the colon had generally been thought to be impermeable to compounds more than 6 angstroms in diameter. The "cross-sectional diameter" of inulin is 15 angstroms, and so inulin "broke the rule," so to speak. Yeah, this is a really, really serious issue, in part because of the way inulin behaves in vivo. I discussed some of my concerns in past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/disturbing-articles-on-inulin.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/note-on-inulin.html)]. Another reason the inclusion of inulin in more and more products, all over the place, is worrisome is that gamma-inulin, apparently a conformational isomer of inulin, is an immune adjuvant that's been researched for use in potentiating anticancer treatments (http://scholar.google.com/scholar?hl=en&q=cancer+gamma+inulin&as_sdt=2000&as_ylo=&as_vis=0). [Cooper, 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7551236)], and oral inulin or pectin or oligofructose reduced the growths of tumors at sites outside of the intestinal tract [Taper and Roberfroid, 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10395627); (http://jn.nutrition.org/cgi/reprint/129/7/1488S)]. One could make the argument that the inulin served as an adjuvant and activated dendritic cells, which are antigen-presenting cells in the intestinal tract that are in contact with the luminal fluid, exclusively in the intestinal tract, leading to some kind of 'totally safe,' indiscriminate activation of the immune system or to antigen-specific, pathological T-cell responses to epithelial antigens in the colon (thereby leading to some sort of cross-reactive anti-tumor immune response), etc. Even if inulin were confined to the luminal fluid, that effect would be pathological, in my opinion. But it seems possible, to me at least, that inulin was simply absorbed into the extracellular fluid or portal venous blood or reached the mesenteric lymph nodes, etc. It's interesting that the molecular weights of some components of pectin are as low as 300-400 Daltons [Fishman et al., 1991: (http://cat.inist.fr/?aModele=afficheN&cpsidt=5472774)], and others are less than 7,000 Daltons, etc. I'd be very wary, personally, of any soluble fiber that is of those types of low molecular weights and that could conceivably cross the intestinal barrier. It sounds really bad to me.
In any case, my point is that the effects of guar gum, for example, and perhaps some of the other high-MW polysaccharides (the MW of guar gum is between 2 and 20 million Daltons or something like that) have these effects, such as on bile acid reabsorption and probably on the enterohepatic circulation of unconjugated bilirubin, on liver function that could explain their beneficial effects on renal function. Researchers have found that guar gum, for example, increased the reabsorption of bile acids in the small intestine, after their entry, in the bile from the liver, into the duodenum via the common bile duct, also increased the amounts of bile acids entering the large intestine, and nonetheless led to a net loss of sterols via the large intestine [Moundras et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9187619)(http://jn.nutrition.org/cgi/reprint/127/6/1068.pdf); Favier et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9307936)]. Those articles show similar effects. One way of looking at their effects might be to say that they act as cosurfactants/surfactants in the small intestine (gums, such as guar gum and gum arabic, have been used as surfactants in emulsions), thereby enhancing the reabsorption of bile acids in the ileum by reducing the interfacial energy and promoting their binding to the ileal transporters (or something like that), and probiotic "fuel sources" in the large intestine. I don't have time to go through more articles, but increases in the reabsorption of bile acids in the ileum can tend to reduce the enterohepatic circulation of unconjugated bilirubin. If some of the different bile acids remain in the large intestine "too long," they can solubilize unconjugated bilirubin, a hydrophobic or fat-soluble molecule, usually (in the absence of visible or UVA light, for example), and allow for its reabsorption, with potentially damaging consequences for the liver, given the cytotoxic and respiratory-inhibitory effects that very high concentrations of bilirubin can have. Also, the loss of bacteria in the colon was shown to produce major increases in the serum bilirubin concentrations of rats (from mean values of 186 to 289 uM) [Vitek et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/15664250)], and the idea with that is that there's a decrease in the rate of consumption of unconjugated bilirubin by the bacteria (because the bacterial counts are very low). So more bilirubin is available for reabsorption in the ileum or along all parts of the intestinal tract, as it turns out, and for ongoing enterohepatic recycling. Excess concentrations of bilirubin can promote portal endotoxemia by interfering with the sequestration of endotoxin by bile acids or something like that (http://scholar.google.com/scholar?hl=en&q=bilirubin+portal+endotoxemia&as_sdt=2000&as_ylo=&as_vis=0). I forget, but another element is that bile acids can be cytotoxic to bacteria in the colon. So there can be this vicious cycle of deteriorating liver function, increases in the enterohepatic recycling of bilirubin, loss of bacteria in the colon due to pathologically-increased levels of cytotoxic bile acids in the luminal fluid of the intestine, due in part to impairments in the ileal reabsorption of bile acids, and so on. It's obviously much more complex than this, and increases in the availabilities of some bile acids to the liver can be cytotoxic to hepatocytes and cholangiocytes and other liver cells, etc. There's also the impact that the activities of glucuronidase enzymes in bacteria and enterocytes might have on bilirubin recycling. One might say that the "extra" bacteria would deconjugate conjugated bilirubin and increase the amounts of unconjugated bilirubin that would be available for ileal reabsorption. The glucuronide conjugates of bilirubin are hydrophilic (water-soluble), and I'm forgetting why this is normally not an issue, if I'm remembering correctly that it isn't an issue. I'll have to read some stuff on that.
Another issues is the fact that some guar gum preparations can be of low quality. Guar gum shouldn't form a "rubber cement" type of "epoxy-resin-like" material as soon as it comes in contact with water, in my opinion. It should be somewhat dispersible and shouldn't just form these pieces of hard @#$&#@# plastic in a glass of water. But hey, that's just my opinion. I'm joking, but that's "not the way it was meant to be." Additionally, xanthan gum has the potential to be problematic, in my view, and can form "rubber cement" types of aggregations almost instantly in water. Some animal research (a lot, I guess) has shown that xanthan gum is more or less the same as guar gum or the like, but it doesn't seem like they're very similar. Most of these are available as individual supplements. Hydrolyzed or modified gums could contain polysaccharides of relatively low molecular weights and might, conceivably, have more potential to be problematic. It's possible that the low-molecular weight components of something like pectin are not problematic or are present at very low concentrations. I don't know. At least pectin is present in foods, but I'd wonder about that type of issue with very low molecular weights. I'd personally be wary of it. Also, there are cases of esophageal obstructions (blockages in the esophagus) from guar gum, and there's one report of anaphylaxis from guar gum. There are many more reports of allergy from psyllium, incidentally, and there's only one report for guar gum, from what I can tell. If it's non-"rubber cement" guar gum, this esophageal obstruction business seems rather unlikely, in my view, but one is supposed to drink it with adequate water and discuss the issues with one's doctor.
Tuesday, December 29, 2009
Thursday, December 24, 2009
Summaries of Main Points from Blog Postings in 2009: Part II
More summaries of points from the blog in 2009 (between 12-2008 and 12-2009):
In my opinion, vitamin K supplementation is potentially very dangerous, and I'm actually doubting, at this point, if vitamin K is even essential. It doesn't behave at all like an essential nutrient, in my view, but that's just my opinion. There's research showing that geranylgeraniol, an intermediate in cholesterol biosynthesis, possesses vitamin K activity (see Ronden et al., 1997: (http://hardcorephysiologyfun.blogspot.com/2009/06/squalene-as-potential-cholesterol.html)], and I wonder if there isn't some endogenous ligand for the vitamin K-cycle enzymes. The whole business with squalene 2,3-epoxide being an intermediate in cholesterol biosynthesis and vitamin K epoxide being a vitamin K cycle intermediate seems like it might also suggest that endogenous compounds can be utilized for the gamma-carboxylation of glutamic acid residues on vitamin K dependent proteins. There's also research discussing the extremely low amounts of vitamin K that are required for humans to manufacture clotting factors, and, in fact, the amounts are so tiny as to make the notion of the essentiality of vitamin K more or less "not valid," in my opinion. I don't buy it anymore. The vitamin K nonsense in the literature has bothered me for a long time and defies all attempts to integrate it into anything resembling "nutritional" science. The facts that vitamin K decreases des-carboxyprothrombin levels and under-gamma-carboxylated osteocalcin aren't evidence of essentiality. In any case, vitamin K supplementation has the potential to not only exacerbate thrombotic conditions or lead to de novo thromboses by elevating levels of serum prothrombin and other clotting factors, in any number of disease states, but to also cause thrombogenic effects by exotic mechanisms, such as by inducing osteoclast precursor cell apoptosis, etc. Obviously, one would want to discuss these things with one's doctor, but there's all this research on vitamin K that looks good on paper but just becomes very bizarre on closer examination. Why would an essential nutrient cause osteoclast apoptosis or potentially cause such serious effects? In any case, I don't think it's essential, and this leads into another point. I should note that the vitamin K topics are not pleasant to write about.
In my opinion, coenzyme Q10 can exhibit vitamin K activity, and there's a lot of indirect evidence that it can. Riboflavin, or vitamin B2, can also enhance the activities of vitamin K dependent enzymes by providing the FAD cofactor for vitamin K reductase(s). There's evidence that quinone reductases or other cytosolic enzymes can utilize coenzyme Q10 and increase clotting factor biosynthesis. In my view, these facts seriously compromise the usefulness of CoQ10 or high-dose vitamin B2. I personally do not take coenzyme Q10 and only take a minimal dosage of vitamin B2, and the potential I see for problems with high doses of vitamin B3, vitamin B6, and vitamin B2 has caused me to not even be able to use a B-complex or multivitamin. In the case of multivitamins, all of the copper and zinc and manganese and vitamin A or beta-carotene are also reasons I don't use them. CoQ10 is also a benzoquinone, and benzoquinones are known to be highly reactive. One would want to discuss these things with one's doctor, but, in my view, there are plenty of energy substrates or other "agents" that could potentially substitute for CoQ10 as approaches to dealing with mitochondrial dysfunction in people who do not have mitochondrial disorders that require supplementation with CoQ10.
In my opinion, the large numbers of cases of intracranial hemorrhage in people taking some Ginkgo biloba extracts (GBEs) seriously compromises their usefulness, and there are, potentially, similar risks with high doses of supplemental omega-3 fatty acids. The numbers of case reports showing hemorrhages in people taking GBEs sort of speak for themselves, and there's no way of really evaluating the hemorrhagic risks of any degree of antagonism of platelet activating factor (PAF) receptors by GBE constituents, such as ginkgolide B and ginkgolides A and C and bilobalide. All of those are PAF receptor antagonists, and ginkgolide B is potent enough to be utilized as a pharmacological PAF receptor antagonist in in vitro research, etc. As far as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 fatty acids that are supplied in supplements, I don't know what the answer is. EPA and DHA are really reactive and have been shown to cause problems in animal models of fatty liver disease, but they're obviously essential and can have a lot of beneficial effects. One strategy might be to obtain small amounts of them in omega-3 egg yolk phospholipids, but I don't quite understand why hard-boiling eggs doesn't destroy all of the docosahexaenoyl- and eicosapentaenoyl-containing phospholipids. I also don't understand why egg yolk phospholipids, which supply choline in the form of sphingomyelin, more than phosphatidylcholine, do not cause depression, in my view, but supplemental phosphatidylcholine and other choline-containing compounds have been shown to cause severe depression in some humans. I think it might be that the sphingomyelin is utilized differently or that the elevations in plasma choline that result from egg-yolk phospholipid administration are not rapid enough to flood the brain with free choline and cause ATP depletion or inorganic phosphate sequestration, etc., thereby potentially causing depression. The omega-3 issues are really complex, and I don't really get into them much in my blog.
Wednesday, December 23, 2009
More of the Exploration of my "Thought" Processes
I was just going to add that, as far as blogging goes, I tend to use these blogs for different purposes at different times and to make not much effort to "map out" my purposes, if any, for writing any given thing. On one day, the blog can be an attempt to practice technical writing and to help myself learn a few new things or remember things I've read. On another day or posting or even part of the same posting, the blog(s) might be more like a kind of "talk therapy" that allows me to make wild, sweeping generalizations and to "rage against the machine" of society. If I do a posting and sound like a Jeckyl-and-Hyde, raving, rage-filled maniac, the reality is that I'm quietly typing as the "Zen master" and lamenting the way the world is set up, for the most part. I'm not someone who would ever hold onto seemingly hate-filled sentiments or anything, but I've noticed that blogging in a relative state of isolation can make me not as aware of these sorts of unconscious sentiments that can seem to be just filled with a vituperative ugliness. In reality, they're not intended to be that, and I'm not thinking that, at the time. But it's like they can sometimes end up being that way and seeming that way, to the extent that I or any other person might read the posting, later on, and feel that the posting doesn't show me at my finest hour. I think the entry of some vague, unconscious associations of some kind into blog postings may just be a result of the amount of writing that can go into a blog. I've sometimes read postings of mine and been shocked by the things that the posting might seem to be saying. In many cases, I wasn't really conscious of those potential implications. It's like writing for a blog causes one to have a sometimes-excessive amount of freedom of expression. But there can also be something about my writing style that can make it seem as if there's some organized, systematic "mayhem" or maniacal quality to the person writing the posting ("me"). The whole thing about blogging being like talk therapy can almost create an alternate persona at times, and I haven't seen much of any need to restrict the extent to which I can silently slip into this sort of altered state. Writing long postings on a blog and exploring lots of different topics can cause one to enter almost a trance or dream state, to a certain extent. I'm just saying that it opens up one's mind.
There are also some other aspects, such as the fact that many postings include this juxtaposition of precise, dispassionate language and discussions with random attempts at humor or wild generalizations that I haven't had much of a need to censor in my blogging. That can make it seem as if the wild statements are a reflection of an organized, inexplicable form of "madness" or something along those lines. In reality, I think I can just organize my sentences in ways that sound intense, when it comes to discussions of anything. I just haven't really had the energy to be extremely conscious of my tone, in some postings, because no one reads the blog and because the blog has always been more about organizing my thoughts on scientific topics and discussing any and every controversial topic that may come up. Another thing is that it has been really difficult to tell who my audience is or should be or needs to be or could conceivably be, etc. As a result, I tend to shut out attempts to shape my postings to specific audiences. I tend to jump around and may, when I try to think of some possible need to include a warning for such and such a reader who might, a year down the road, read the thing, include some statements that might be more of pure scientific interest and others that might be more about logistical or other details. The other thing I was going to mention is that I can sometimes end up communicating, in relation to some topics, like a person would in a debate. It's like I'll start with some vague or simple, generic sentiment and then allow the "debater-type" discussion to evolve or devolve into an argument that may be extreme and be a caricature of my true feelings about the matter. A lot of the complex discussions have always had a "hammed-up" quality on this blog, and that can be bad or good. The result can end up being a mixture of different things, etc. I've griped in generic ways about all sorts of topics on here. Nonetheless, when I see the ways I can end up allowing the less rational and superficially-angry facets of my thinking to mix with rational discussions, I don't, in a lot of these cases, like the things that I see, either in myself or in my postings. When I look closely and explore the issues and the extreme sides of some of the things I see in the world or in medicine, I sort of remember the ways things can just go on and on in the world (or, for example, in my life, in the past) and defy all reason and become devoid of hope, etc. I remember the way it feels and don't like remembering, and the result can be some sort of apparent tirade or seemingly-calculated expression of outrage that may just be mostly a journey into or exploration of some concept or concern. That's not to say that I don't have some thoughts and opinions that can seem extreme, but I haven't really made an attempt to carefully distinguish between statements that reflect my true feelings or perceived motivations (or, upon subsequent analysis, unconscious motivations) for saying things and statements that can constitute a "mixed bag," as discussed above. I generally have assumed that any one or any collection of statements that I've made have not been of much significance to anyone, and, even as that is likely to still be the case, that approach is not necessarily the best one and can lead to things that are troubling for me to see, to say the least.
Saturday, December 19, 2009
Potential Approaches to Addressing Complications or Sequelae of Influenza Infections
The stuff related to this (http://hardcorephysiologyfun.blogspot.com/2009/12/multiple-revisions-of-old-paper-of-mine.html) just got really complicated, but that's that. I got the intranasal H1N1 flu vaccine on Wednesday, and the people did do a good job conducting the clinic. It's like the mild symptoms from it are slightly worse than with the seasonal intranasal one but aren't much worse. I was going to mention some approaches to dealing with post-influenza issues or low-level, ongoing effects of influenza, I should say. I've discussed some of the pharmacological issues with antivirals' potential interactions with exogenous purines or sources of inorganic phosphate (via the organic anion transporters and multidrug resistance proteins, as in efflux transporters in hepatocytes and proximal tubule epithelial cells, etc.) (http://eahblog2.blogspot.com/2009/08/discussion-of-influenza.html). I think the use of even relatively low doses of oral purines could be useful in dealing with the kind of ongoing, low-level thrombogenicity that one would expect to see, following an influenza infection, from elevated anti-ganglioside autoantibody titers (or from elevated antiphospholipid autoantibody titers in general) and anti-hemagglutinin antibodies that one would expect to exert thrombogenic/hemostatic effects. There tends to be a perception that something like Guillain-Barre syndrome from influenza is an all-or-nothing event, and it is. But one would expect to see elevated anti-ganglioside autoantibody titers and immunity following influenza infections, and influenza vaccination has produced prolonged but asymptomatic elevations in antiphospholipid autoantibody titers in normal people (for 3-6 months or so). Here's a search that shows some articles discussing the issue in various contexts (http://scholar.google.com/scholar?q=antiphospholipid+influenza+vaccine+OR+vaccination&hl=en&as_sdt=2001&as_sdtp=on). This search (http://scholar.google.com/scholar?hl=en&q=ganglioside+autoantibodies+lipopolysaccharide+OR+antiphospholipid&as_sdt=2000&as_ylo=&as_vis=0) shows that anti-ganglioside antibodies can exhibit cross-reactive binding to lipopolysaccharide(s), which are bacterial endotoxins, and that fits in with this article showing that the injection of viral neuraminidase proteins from influenza viruses causes a rapidly-induced thrombocytopenic response in rodents [see (http://eahblog2.blogspot.com/2009/08/influenza-is-it-big-man-on-campus-is.html); Choi et al., 1972: (http://www.ncbi.nlm.nih.gov/pubmed/5060079)(http://www3.interscience.wiley.com/cgi-bin/fulltext/120727425/PDFSTART)]. That could be explained by some sort of rapid release of IgE from mast cells or something, but mast cells can participate in all sorts of different immune responses and can actually serve as antigen-presenting cells, etc., and all-around "loose-cannons" of the immune system. But it could be that the viral neuraminidase elicits an existing, established, anti-lipopolysaccharide antibody response or multifaceted response that causes cross-reactive, antibody-mediated clearance of platelets. Choi et al. (1972) found evidence that the platelets' membranes were damaged over that short time course. They were being degraded and damaged, and the platelets were being destroyed, if I remember correctly. It sounded like an anti-platelet glycoprotein or antiphospholipid autoreactivity or contact hypersensitivity type of response. Elevations in antiphospholipid autoantibodies generally cause thrombogenic symptoms, with or without bleeding, etc. Here's another search (http://scholar.google.com/scholar?hl=en&q=influenza+ganglioside+autoantibodies&as_sdt=2000&as_ylo=&as_vis=0), but the point is that influenza neuraminidase enzymes cleave sialyl (or disialyl, I think) residues on cell-surface proteins of human cells and allow influenza to enter cells (http://scholar.google.com/scholar?hl=en&q=influenza+neuraminidase+sialic+OR+acetylneuraminic+OR+ganglioside&as_sdt=2000&as_ylo=&as_vis=0). The viral neuraminidase is a sialidase enzyme, and humans have sialidase enzymes, of course. One would expect antibodies to the (anti-influenza) antibodies to the active site or associated residues of a viral neuraminidase enzyme to potentially bind to gangliosides or other phospholipids (and to potentially lead to anti-ganglioside or more generalized antiphospholipid autoreactivity). The viral hemagglutinin proteins agglutinate red blood cells, meaning the red blood cells clump together and produce hemostatic effects or microthrombi that constantly are reforming and being degraded in a dynamic manner. Then that can lead to a big mess of chaotic immune responses, etc.
The general idea, in my opinion, is that hemostatic conditions will inevitably lead to some problems with energy metabolism and that the elevated levels of pro-inflammatory cytokines in many different tissues, following the influenza-induced increases in mast-cell density just about everywhere, for example, will also disturb mitochondrial functioning. TNF-alpha and other cytokines rapidly and reliably impair mitochondrial functioning and induce oxidative stress. Antiphospholipid and anti-ganglioside autoantibodies would be expected to produce thrombogenic effects and, basically, low-level neuropathic effects, in my opinion. One approach would be to consider the potential effects of exogenous uridine or triacetyluridine, for their supposed, generalized anti-inflammatory effects and for their potential effects on glucose uptake and energy metabolism (pyrimidines' effects, I mean, on those processes, as discussed in past postings), and to potentially consider the utility of L-glutamine supplementation as a way of addressing the supposed, low-level neuropathy and adverse effects on energy metabolism. Anti-ganglioside autoantibodies would clearly compromise energy metabolism, and, in people without overt Guillain-Barre syndrome, glutamine might help to address a supposed, low-level conduction blockade from elevated anti-ganglioside antibody titers, etc. Glutamine can produce anti-inflammatory effects, and so can uridine, in a lot of different models of inflammation, and glutamine [see Amara, 2008, cited here, for a review of three trials on the use of glutamine in the prevention of chemotherapy-drug-induced neuropathy, implying that it acts as an energy substrate or has some other generic effects (it's likely to basically be acting as an energy substrate/precursor of TCA cycle intermediates, in my view): (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)] and uridine (PN401 = RG2133 = triacetyluridine: cited as ref 32 in Ashour et al., 1996(?); the research exists somewhere, maybe here, as shown: (http://scholar.google.com/scholar?hl=en&q=neuropathy+acetyluridine+OR+RG2133+OR+PN401&as_sdt=2000&as_ylo=&as_vis=0)] have both been used in the treatment of peripheral neuropathy, implying some generic usefulness in addressing neuropathy of inflammatory origins (). There might well be research specifically on glutamine in influenza infections [(http://scholar.google.com/scholar?hl=en&q=%22L-glutamine%22+influenza+supplement+OR+exogenous&as_sdt=2000&as_ylo=&as_vis=0)], but this article [Neu et al., 2002: (http://www.victusinc.com/VictusTecnical_files/Glutamine%20in%20Radioterphy/Docs/09.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/11790953)] cites some of the research showing anti-inflammatory effects of glutamine (elevations in interleukin-10 expression or release, etc.). I'm pretty sure there's research showing that glutamine protects against the adverse effects of lipopolysaccharide on energy metabolism or the cellular redox state. Yeah, there is (http://scholar.google.com/scholar?as_q=&num=100&btnG=Search+Scholar&as_epq=glutamine&as_oq=lipopolysaccharide+endotoxin&as_eq=&as_occt=title&as_sauthors=&as_publication=&as_ylo=&as_yhi=&as_sdt=1.&as_sdtp=on&as_sdts=5&hl=en). This article shows that lipopolysaccharide induces DNA damage and deficits in energy metabolism in macrophages [Zingarelli et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8598485?dopt=Abstract)]. Anyway, there are lots of articles on the anti-inflammatory effects of uridine and on its capacity to protect against neuronal loss or other effects of inhibitors of mitochondrial respiration, such as sodium azide, [see here for a lot of the articles showing protection against the effects of respiratory-chain enzyme inhibitors by triacetyluridine-derived uridine and other pyrimidines: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)]. Some other time, soon, I'll put the links to some of the articles that show anti-inflammatory effects of uridine, but these are some [Uppugunduri et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15251120); Tian et al., 2009 (protection against damage due to cerebral ischemia, meaning it would potentially be useful for the ischemia one would expect from compromised energy metabolism and thrombogenicity per se and all the other mess of influenza): (http://linkinghub.elsevier.com/retrieve/pii/S030439400901180X); Evaldsson et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17570319)]. The article by Evaldsson et al. (2007) showed anti-inflammatory effects of uridine in a model or models of lung inflammation. I haven't looked at the article in awhile and forget the details. Then there's the massive elevations in peroxynitrite formation from activated macrophages, during influenza, and purines (all purines, by more or less similar reactions, interestingly) are peroxynitrite scavengers. But then there's the issue of uric acid competing for efflux with active metabolites of neuraminidase inhibitors or even with M1 protein inhibitors that are excreted unchanged, as in adamantane derivatives. Magnesium would probably be useful, assuming a person can tolerate it, and I'm not finding any easy searches that would explain my reasoning. Magnesium is just depleted strongly by any physiological stress, even exercise, and it produces antithrombotic effects that are less likely to be accompanied by bleeding (just as purines' antithrombotic or anti-cell-adhesion effects are not too likely to be hemorrhagic, in my view), in my opinion, than other antithrombotic strategies. It's hard to convince people of the effects of magnesium. It's like the research is scattered and is so vast that it's hard to convey. Magnesium is really important, in my opinion, as discussed in...past postings. It has crucial effects on energy metabolism (partly as a result of its mild calcium-channel antagonistic effect, as is the case with its antithrombotic effects) and can reduce lipid peroxidation by blunting calcium influx, etc. Here's a hastily-done search that shows some articles on the anti-inflammatory effects associated with magnesium repletion (http://scholar.google.com/scholar?hl=en&q=allintitle%3A+magnesium+inflammatory+OR+inflammation&as_sdt=2000&as_ylo=&as_vis=0). There's a bonus article showing glutamine (or ammonia) can limit the replication of influenza virus replication [Eaton and Scala, 1961: (http://www.ncbi.nlm.nih.gov/pubmed/13725527)]. That's actually a sort of "Saturday-roadkill" type of article, and the effect of ammonia could just be a generalized toxic effect. But it could be that ammonia can serve as a pyrimidine precursor. Who knows.
The general idea, in my opinion, is that hemostatic conditions will inevitably lead to some problems with energy metabolism and that the elevated levels of pro-inflammatory cytokines in many different tissues, following the influenza-induced increases in mast-cell density just about everywhere, for example, will also disturb mitochondrial functioning. TNF-alpha and other cytokines rapidly and reliably impair mitochondrial functioning and induce oxidative stress. Antiphospholipid and anti-ganglioside autoantibodies would be expected to produce thrombogenic effects and, basically, low-level neuropathic effects, in my opinion. One approach would be to consider the potential effects of exogenous uridine or triacetyluridine, for their supposed, generalized anti-inflammatory effects and for their potential effects on glucose uptake and energy metabolism (pyrimidines' effects, I mean, on those processes, as discussed in past postings), and to potentially consider the utility of L-glutamine supplementation as a way of addressing the supposed, low-level neuropathy and adverse effects on energy metabolism. Anti-ganglioside autoantibodies would clearly compromise energy metabolism, and, in people without overt Guillain-Barre syndrome, glutamine might help to address a supposed, low-level conduction blockade from elevated anti-ganglioside antibody titers, etc. Glutamine can produce anti-inflammatory effects, and so can uridine, in a lot of different models of inflammation, and glutamine [see Amara, 2008, cited here, for a review of three trials on the use of glutamine in the prevention of chemotherapy-drug-induced neuropathy, implying that it acts as an energy substrate or has some other generic effects (it's likely to basically be acting as an energy substrate/precursor of TCA cycle intermediates, in my view): (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)] and uridine (PN401 = RG2133 = triacetyluridine: cited as ref 32 in Ashour et al., 1996(?); the research exists somewhere, maybe here, as shown: (http://scholar.google.com/scholar?hl=en&q=neuropathy+acetyluridine+OR+RG2133+OR+PN401&as_sdt=2000&as_ylo=&as_vis=0)] have both been used in the treatment of peripheral neuropathy, implying some generic usefulness in addressing neuropathy of inflammatory origins (). There might well be research specifically on glutamine in influenza infections [(http://scholar.google.com/scholar?hl=en&q=%22L-glutamine%22+influenza+supplement+OR+exogenous&as_sdt=2000&as_ylo=&as_vis=0)], but this article [Neu et al., 2002: (http://www.victusinc.com/VictusTecnical_files/Glutamine%20in%20Radioterphy/Docs/09.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/11790953)] cites some of the research showing anti-inflammatory effects of glutamine (elevations in interleukin-10 expression or release, etc.). I'm pretty sure there's research showing that glutamine protects against the adverse effects of lipopolysaccharide on energy metabolism or the cellular redox state. Yeah, there is (http://scholar.google.com/scholar?as_q=&num=100&btnG=Search+Scholar&as_epq=glutamine&as_oq=lipopolysaccharide+endotoxin&as_eq=&as_occt=title&as_sauthors=&as_publication=&as_ylo=&as_yhi=&as_sdt=1.&as_sdtp=on&as_sdts=5&hl=en). This article shows that lipopolysaccharide induces DNA damage and deficits in energy metabolism in macrophages [Zingarelli et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8598485?dopt=Abstract)]. Anyway, there are lots of articles on the anti-inflammatory effects of uridine and on its capacity to protect against neuronal loss or other effects of inhibitors of mitochondrial respiration, such as sodium azide, [see here for a lot of the articles showing protection against the effects of respiratory-chain enzyme inhibitors by triacetyluridine-derived uridine and other pyrimidines: (http://hardcorephysiologyfun.blogspot.com/2009/08/some-more-old-papers-of-mine.html)]. Some other time, soon, I'll put the links to some of the articles that show anti-inflammatory effects of uridine, but these are some [Uppugunduri et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15251120); Tian et al., 2009 (protection against damage due to cerebral ischemia, meaning it would potentially be useful for the ischemia one would expect from compromised energy metabolism and thrombogenicity per se and all the other mess of influenza): (http://linkinghub.elsevier.com/retrieve/pii/S030439400901180X); Evaldsson et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17570319)]. The article by Evaldsson et al. (2007) showed anti-inflammatory effects of uridine in a model or models of lung inflammation. I haven't looked at the article in awhile and forget the details. Then there's the massive elevations in peroxynitrite formation from activated macrophages, during influenza, and purines (all purines, by more or less similar reactions, interestingly) are peroxynitrite scavengers. But then there's the issue of uric acid competing for efflux with active metabolites of neuraminidase inhibitors or even with M1 protein inhibitors that are excreted unchanged, as in adamantane derivatives. Magnesium would probably be useful, assuming a person can tolerate it, and I'm not finding any easy searches that would explain my reasoning. Magnesium is just depleted strongly by any physiological stress, even exercise, and it produces antithrombotic effects that are less likely to be accompanied by bleeding (just as purines' antithrombotic or anti-cell-adhesion effects are not too likely to be hemorrhagic, in my view), in my opinion, than other antithrombotic strategies. It's hard to convince people of the effects of magnesium. It's like the research is scattered and is so vast that it's hard to convey. Magnesium is really important, in my opinion, as discussed in...past postings. It has crucial effects on energy metabolism (partly as a result of its mild calcium-channel antagonistic effect, as is the case with its antithrombotic effects) and can reduce lipid peroxidation by blunting calcium influx, etc. Here's a hastily-done search that shows some articles on the anti-inflammatory effects associated with magnesium repletion (http://scholar.google.com/scholar?hl=en&q=allintitle%3A+magnesium+inflammatory+OR+inflammation&as_sdt=2000&as_ylo=&as_vis=0). There's a bonus article showing glutamine (or ammonia) can limit the replication of influenza virus replication [Eaton and Scala, 1961: (http://www.ncbi.nlm.nih.gov/pubmed/13725527)]. That's actually a sort of "Saturday-roadkill" type of article, and the effect of ammonia could just be a generalized toxic effect. But it could be that ammonia can serve as a pyrimidine precursor. Who knows.
Friday, December 18, 2009
Brief Summaries of Main "Theses" from Past Groups of Postings: Part I
In the next few days or weeks, I'm going to try to summarize some of the main points from the postings I've made over the last year. In some cases, each summary encompasses hundreds of pages of writing and numbers of articles, articles and pages that I've explored in horrendous, "rock-and-roll-ice-storm" ways over the last year. Here are summaries of some of the groups of postings.
In my opinion, zinc and copper supplementation can be very problematic and inadvisable in many cases, in the absence of medical supervision. There are hundreds of reports of neurotoxicity visible on MRI and degeneration of the brain and spinal cord in humans who have taken excessive supplemental zinc, and the mechanisms that regulate the amount of neurotoxic free zinc and, also, copper are not very reliable, from a physiological standpoint. Copper transport in the blood and even in cells is messy and poorly-regulated, and many foods, including many breakfast cereals, have more than enough copper and also have enough zinc (as well as manganese, for example).
In my opinion, vitamin A or beta-carotene supplementation has the potential to cause serious neurotoxicity, and there are many reports of neurotoxicity or "pure" psychiatric disorders caused by vitamin A or beta-carotene supplementation. One important mechanism is, in my opinion, the toxic effects that retinoids, including vitamin A and beta-carotene as a precursor of vitamin A and retinoic acid, etc., exert on epithelial cells of the choroid plexuses that form cerebrospinal fluid and are crucial in the regulation of other brain functions, such as glutamate efflux, etc. Retinoids, including vitamin A and its precursors, can elevate the intracranial pressure by causing toxic effects on the choroid plexuses at extremely small dosages in some people, and those elevations in the intracranial pressure and associated venous ischemia or venous sinus thrombosis could be important causes of the psychiatric manifestations that vitamin A or beta-carotene supplementation have been associated with. In some cases, people who have done nothing but eat one of the relatively few foods high in preformed vitamin A (i.e., carrots or liver or fish, conceivably, as in fish liver, etc.) have developed severe psychiatric disorders that remitted upon discontinuation of the carrot-eating-induced psychosis or suicidality. The nutrition tables do not differentiate between beta-carotene and preformed vitamin A and only provide information about "retinol equivalents," but even eating a lot of beta-carotene in foods could conceivably produce adverse effects, given that an increase in beta-carotene intake can increase vitamin A (and that elevations in intracranial pressure have been shown to occur across miniscule increments in serum retinol, etc.).
In my opinion, all of the therapeutic effects of oral S-adenosylmethionine, in every disease state it has been used in, could be replicated by oral adenosine monophosphate or adenosine triphosphate. Both of those are sold, and each would be expected to exhibit much higher bioavailability (meaning entry into the brain or other extrahepatic tissues) than many oral SAM-e preparations would, in my view. These disease states include liver disease and osteoarthritis, etc. SAM-e has been researched heavily in many different contexts. The adenosine (and other purine metabolites from it) derived from the SAM-e is likely to be, in my opinion, the only significant mediator of the therapeutic effects of SAM-e. The extreme rapidity with which adenosine is utilized, by any of several pathways, precludes, in my view, a mass-action, inhibitory effect of the extra adenosine or other purines derived from it, on S-adenosylhomocysteine hydrolase activity. Nonetheless, the adenosine derived from SAM-e can increase the intracellular ATP and cAMP levels, and increases in ATP availability can be a determinant of the rate of formation of SAM-e. Increases in the cAMP/AMP ratio or in cAMP levels of cAMP in relation to other purines can influence the activity of S-adenosylhomocysteine hydrolase. One could use a methionine adenosyltransferase inhibitor in an experiment, but the use of that would not allow one to rule out, at all, the contribution of adenosine, derived from SAM-e, to the endogenously-produced SAM-e (via the utilization of adenosine for ATP formation, etc.). Adenosine has been used to treat liver disease in animal models and is thought to enhance hepatic blood flow and to maintain hepatocellular ATP levels and to ameliorate portal venous thrombosis (effects that could account for its therapeutic effects, especially along with pyrimidine nucleotides, in animal models of liver disease), and adenosine is thought to mediate the therapeutic effects of low-dose methotrexate, for example, in rheumatoid arthritis. Thus, there is reason to think that increases in purine availability, in response to exogenous adenosine nucleotides, could influence those conditions by the same mechanisms that SAM-e may influence the conditions. Adenosine could also influence DNA methylation by elevating SAM-e levels (via adenosine-induced increases in ATP levels), and exogenous SAM-e could influence DNA methylation not by increasing the ratio of SAM-e to S-adenosylhomocysteine but by increasing ATP levels (via the conversion of SAM-e to adenosine to AMP, ADP, and then ATP, which is a substrate of methionine adenosyltransferase) or by adenosine receptor signalling, etc.
In my opinion, L-methylfolate has a lot of potential usefulness as an adjunctive antidepressant and as a way of normalizing cognitive functioning or assisting in the treatment of circadian rhythm abnormalities, and its supposed effects in any of those disease states would probably be a result of its enhancement of noradrenergic and dopaminergic activity (via nitrergic mechanisms, secondary to its supposed effects as an analog of tetrahydrobiopterin (BH4), and by the "methylfolate-as-BH4-analog-dependent" increase in tyrosine hydroxylase activity). In my view, as discussed over maybe 150 postings or something, L-methylfolate and other reduced folates are likely to be not toxic or damaging, in theory, at the 30-50 mg/day range, or thereabouts, but I'd advise anyone to obviously use reduced folates under a doctor's supervision. The augmentation or counteracting of the effects of psychiatric medications could be dangerous in some people & could exacerbate the courses of psychiatric disorders. At high dosages, methylfolate and other reduced folates have generally been much safer than folic acid and less neurotoxic. In my view, L-methylfolate, which is available over-the-counter or by Rx, has less potential to produce adverse or unpredictable nitrergic side effects than, for example, L-arginine and is likely to produce more reliable or predictable or consistent effects than something like L-arginine, from the standpoint of effects on the brain.
In my view, creatine supplementation can be problematic at dosages higher than about 1.2 to 1.5 grams/day, over the long term, and low but not high dosages have been used as adjunctive approaches to treating depression in at least two trials (with other trials showing less clearly-defined effects on mood). Obviously, these are all just my opinions.
In my opinion, zinc and copper supplementation can be very problematic and inadvisable in many cases, in the absence of medical supervision. There are hundreds of reports of neurotoxicity visible on MRI and degeneration of the brain and spinal cord in humans who have taken excessive supplemental zinc, and the mechanisms that regulate the amount of neurotoxic free zinc and, also, copper are not very reliable, from a physiological standpoint. Copper transport in the blood and even in cells is messy and poorly-regulated, and many foods, including many breakfast cereals, have more than enough copper and also have enough zinc (as well as manganese, for example).
In my opinion, vitamin A or beta-carotene supplementation has the potential to cause serious neurotoxicity, and there are many reports of neurotoxicity or "pure" psychiatric disorders caused by vitamin A or beta-carotene supplementation. One important mechanism is, in my opinion, the toxic effects that retinoids, including vitamin A and beta-carotene as a precursor of vitamin A and retinoic acid, etc., exert on epithelial cells of the choroid plexuses that form cerebrospinal fluid and are crucial in the regulation of other brain functions, such as glutamate efflux, etc. Retinoids, including vitamin A and its precursors, can elevate the intracranial pressure by causing toxic effects on the choroid plexuses at extremely small dosages in some people, and those elevations in the intracranial pressure and associated venous ischemia or venous sinus thrombosis could be important causes of the psychiatric manifestations that vitamin A or beta-carotene supplementation have been associated with. In some cases, people who have done nothing but eat one of the relatively few foods high in preformed vitamin A (i.e., carrots or liver or fish, conceivably, as in fish liver, etc.) have developed severe psychiatric disorders that remitted upon discontinuation of the carrot-eating-induced psychosis or suicidality. The nutrition tables do not differentiate between beta-carotene and preformed vitamin A and only provide information about "retinol equivalents," but even eating a lot of beta-carotene in foods could conceivably produce adverse effects, given that an increase in beta-carotene intake can increase vitamin A (and that elevations in intracranial pressure have been shown to occur across miniscule increments in serum retinol, etc.).
In my opinion, all of the therapeutic effects of oral S-adenosylmethionine, in every disease state it has been used in, could be replicated by oral adenosine monophosphate or adenosine triphosphate. Both of those are sold, and each would be expected to exhibit much higher bioavailability (meaning entry into the brain or other extrahepatic tissues) than many oral SAM-e preparations would, in my view. These disease states include liver disease and osteoarthritis, etc. SAM-e has been researched heavily in many different contexts. The adenosine (and other purine metabolites from it) derived from the SAM-e is likely to be, in my opinion, the only significant mediator of the therapeutic effects of SAM-e. The extreme rapidity with which adenosine is utilized, by any of several pathways, precludes, in my view, a mass-action, inhibitory effect of the extra adenosine or other purines derived from it, on S-adenosylhomocysteine hydrolase activity. Nonetheless, the adenosine derived from SAM-e can increase the intracellular ATP and cAMP levels, and increases in ATP availability can be a determinant of the rate of formation of SAM-e. Increases in the cAMP/AMP ratio or in cAMP levels of cAMP in relation to other purines can influence the activity of S-adenosylhomocysteine hydrolase. One could use a methionine adenosyltransferase inhibitor in an experiment, but the use of that would not allow one to rule out, at all, the contribution of adenosine, derived from SAM-e, to the endogenously-produced SAM-e (via the utilization of adenosine for ATP formation, etc.). Adenosine has been used to treat liver disease in animal models and is thought to enhance hepatic blood flow and to maintain hepatocellular ATP levels and to ameliorate portal venous thrombosis (effects that could account for its therapeutic effects, especially along with pyrimidine nucleotides, in animal models of liver disease), and adenosine is thought to mediate the therapeutic effects of low-dose methotrexate, for example, in rheumatoid arthritis. Thus, there is reason to think that increases in purine availability, in response to exogenous adenosine nucleotides, could influence those conditions by the same mechanisms that SAM-e may influence the conditions. Adenosine could also influence DNA methylation by elevating SAM-e levels (via adenosine-induced increases in ATP levels), and exogenous SAM-e could influence DNA methylation not by increasing the ratio of SAM-e to S-adenosylhomocysteine but by increasing ATP levels (via the conversion of SAM-e to adenosine to AMP, ADP, and then ATP, which is a substrate of methionine adenosyltransferase) or by adenosine receptor signalling, etc.
In my opinion, L-methylfolate has a lot of potential usefulness as an adjunctive antidepressant and as a way of normalizing cognitive functioning or assisting in the treatment of circadian rhythm abnormalities, and its supposed effects in any of those disease states would probably be a result of its enhancement of noradrenergic and dopaminergic activity (via nitrergic mechanisms, secondary to its supposed effects as an analog of tetrahydrobiopterin (BH4), and by the "methylfolate-as-BH4-analog-dependent" increase in tyrosine hydroxylase activity). In my view, as discussed over maybe 150 postings or something, L-methylfolate and other reduced folates are likely to be not toxic or damaging, in theory, at the 30-50 mg/day range, or thereabouts, but I'd advise anyone to obviously use reduced folates under a doctor's supervision. The augmentation or counteracting of the effects of psychiatric medications could be dangerous in some people & could exacerbate the courses of psychiatric disorders. At high dosages, methylfolate and other reduced folates have generally been much safer than folic acid and less neurotoxic. In my view, L-methylfolate, which is available over-the-counter or by Rx, has less potential to produce adverse or unpredictable nitrergic side effects than, for example, L-arginine and is likely to produce more reliable or predictable or consistent effects than something like L-arginine, from the standpoint of effects on the brain.
In my view, creatine supplementation can be problematic at dosages higher than about 1.2 to 1.5 grams/day, over the long term, and low but not high dosages have been used as adjunctive approaches to treating depression in at least two trials (with other trials showing less clearly-defined effects on mood). Obviously, these are all just my opinions.
More Ramblings from Hardcore
The other thing I meant to add is that I've generally thought that it's probably for the best that not many people read the blog, to a large extent, and I make sort of a big effort to assume that people aren't reading it and to make my assessments as independently as possible. Even though I value tremendously my ability to speak independently, as far as the science goes, I'm always re-evaluating my thoughts on things and trying to think more carefully about the aspects of things that go beyond science. I can say I'm speaking objectively and independently about something and feel that I am, at any given time, but still end up being human and having my own silly sense of pride about things. The thought of being some kind of guru in any of these areas or having people trust my statements, without going to the science and looking it over themselves, is repugnant to me. It's like my thought is, "don't trust me a lot, or I might disappoint you the way I disappointed myself for the first ten or twelve years I read about physiological approaches, etc. And it's probably best that no one read the blog, given that the statements about the research will probably disappoint people, also." I feel like there's a strong, strong distinction between the science and the people who do the science. That's probably not realistic, but I'd be paralyzed and wouldn't be able to write on most topics if I didn't look at the science as being a separate thing, as much as possible. I have a tendency to take that too far, but I've just seen, in this disturbing way, how devastating the consequences of the dearth of critical expression and thought has been in just these few areas that I've written about on the blog. In a lot of cases, research can go on for thirty and forty years along these terrible avenues and can sort of just wither away, year after year. It's not exactly devastating in every area, but it can be kind of appalling to see. It may be the fact that I've been very near to death, for different reasons and in different "disease states," on a couple of occasions in my life that has shaped my view of things, too. It's like it changes you and makes you see the strings behind the puppet show or something. The human body just doesn't impress you, in a lot of ways, after seeing medicine fail you (me) in ways that were appalling to me, at the time, and it's like the models of diseases seem to cease to have any intrinsic validity. I'm not meaning to make any kind of big point in this posting or anything, but I thought I could sort of try to sum up my thought processes, in a not-too-effective way, on the anniversary, here. I just tend to think that it's possible to think and evaluate critically in a dynamic way, and I've re-evaluated my thoughts in a lot of different areas on the blog, as I've read more. For example, I used to think that vitamin B6 wouldn't cause peripheral neuropathy (or even autonomic neuropathy, given that it can cause that, too, at high dosages) at dosages below about 100 mg/day, but I now think it could, potentially, cause neuropathy in susceptible individuals at dosages as low as, say, 25-50 mg/day or less. Neuropathy can cause all sorts of different pathologies in just about any organ and can severely disturb bone remodeling, as in Charcot foot disease, or severely exacerbate liver disease, by shutting down the neurogenic regulation of gallbladder contractions, as in diabetic neuropathy, etc. It's not really possible to easily evaluate those potential manifestations of neuropathy in a person. Anyway, that's about all I can think of to talk about. I don't get very many page hits per day. I get an average of about 10 or so, I'd say, and I have no way of evaluating whatever numbers of people are using any of the hundreds of RSS readers to check or look over the blog. I doubt it's very many, though.
Wednesday, December 16, 2009
Summer & Fall; Perferryl Heme "States" and Ferryl Heme and General, Free-Flowing Discussion
I added a caption to the screen snapshot of that diagram of compound II, for this posting, as discussed below. My main point with those postings was that I didn't like the way the whole process with this work (http://hardcorephysiologyfun.blogspot.com/2009/12/multiple-revisions-of-old-paper-of-mine.html) went. I did the first two last summer and then made some more revisions again, within the last two weeks or so. But it got so that the focus on the content with that type of thing seemed to not matter, really. So it's like I couldn't communicate freely on this blog, and the amount of work or the degree of validity of the things I'd worked on seemed to be of little consequence. Anyway, the work on heme has been going well, and it tends to be the case that it takes time to be able to shorten and condense things that I've recently tried to get up to speed on. I can write about something but still sort of require time to digest the material and be able to separate the wheat from the chaff. When I learn new things in an area, I tend to write long things and then be able to shorten them. The content on heme is still too long and has been for the last month or so, but I'm sure I'll be able to finish shortening it, here, etc. My main reason for getting into the electron configuration content was to see how I could draw and keep track of structural diagrams of reactions involving heme. It's like the bookkeeping of electron transfers between inorganic and organic elements, in organometallic compounds, is sort of shrouded in mystery still, more from the standpoint of the theoretical framework of chemistry than the experimental data that's reported in chemistry journals, but it's been interesting to sort of scratch the surface of. All the diagrams might have a sort of rock-and-roll quality to them, but the chemistry is just really complex. I still don't have a good understanding of what the different factors are, besides the apparently-slow, proton-coupled electron transfer reactions that can drive radical migration within a protein, but it's like amino acid residues are being protonated and deprotonated dynamically, due to small pH gradients or something like that, and that helps to dictate, as a slow process of "equilibration," the progression of this continuous and rapid electron tunneling that nonetheless is able to slowly progress toward equilibrium and allow for the existence of long-lived tyrosyl radicals. The main, "big-picture" things I've gotten (things that may or may not be relevant or things to include) are that free perferryl heme can, according to at least four or five articles, exist and that the iron(IV) Fe=O moiety of heme with a protein radical is, itself, inclusive of the radical, perferryl heme. Iron(IV)-heme with a protein radical that's mobile is perferryl heme, and so is iron(IV)-heme with a pi-cation radical on the porphyrin ring. But iron(IV)-heme with a closed-shell, nonradical porphyrin ring and no protein radical is ferryl heme, and, even though the diagramming may tend to suggest that the Fe=O moieties are the same in ferryl and perferryl heme, ferryl heme's Fe=O moiety is less oxidized than the Fe=O moiety in either of those states of perferryl heme. And when the amino acid residue harboring the mobile radical is reduced by a reductant, the oxidation state of the Fe=O oxygen changes, and the whole path and potential path of the mobile radical, within the protein (the whole protein, in effect), acts like an extension of the porphyrin ring. There's a change in the electron configuration or distribution that's translated through one or more of the axial ligands of the protein-bound heme. That's one thing that took awhile to recognize (see de Montellano, 1987, cited in past postings, and other articles). It gets so it wasn't really possible for me to discuss the topic in a way that made sense to me and that would make sense to others, in the absence of that information. In some cases, there are descriptions of "ferryl heme" with a protein radical present, but that overall heme-bound protein is, itself, perferryl heme, given that the radical is delocalized across its entire path, in effect. That's my understanding of the way it works, and the oxene-type electron configuration of perferryl heme isn't the same as the one in ferryl heme. Anyway, I've done most of the content on here, related to heme, to allow me to be able to talk about things in a way that makes sense to me, etc.
Wednesday, December 9, 2009
Sailor-Boy Scavenger Suit
The efficiency with which I work tends to decrease as the semester progresses, but that's obviously not always a bad thing. I'm hoping that switching to the pharmacology class will work out, in part because the pharmacology department--and the people associated with it--at the U. is/are spectacular, obviously. I always feel like I don't need to say things and that the best way I'm likely to be able to communicate, personally, in some of these areas is to do the most thorough work that I can on things. This blog has always been like a recycling dump or landfill, basically, and I wade around in it and look for gems in the material that's being processed or is old or whatever. I don't show up to a landfill with a starched shirt--that's one way of looking at it. I'll stumble around a recycling plant, and I'm liable to swear like a @#$%&%$ sailor in a cracker-jack suit and gun the engine on the bobcat. Vrrrrrrroom...Vrrrroom-Vrroom. "Put it in first gear...I said, put the bobcat in first. I SAID, PUT THE @#$%*& thing in FIRST, OR IT'LL STALL when...SUM @#%&*'LL STALL WHEN...mmm-hmm...when you run it over the old piles and heaps." Anyway, that's basically the way I have to approach it, if I'm going to do a blog. And if I find a nice clean area, I might gun the bobcat and stir up some old junk and get the ball rolling in the clean spot. "Put that stuff over...OVER IN THE CLEAN AREA, I...said, YASSSS, THERE. Bec--Because it's...THAAA F$#@@!# thing--LIGE-THIZ...VRROOM, VROOM. I said, dump THAA JUNK on it....STIR tha-tuh-s#$%-tuh-up-uh." I don't know--a neat and tidy spot might be just the place to find some old gems that have been swept over and trampled over into a spick-n-span surface. Obviously, I'm exaggerating, but I'm liable to show up at the blog like Cracker Jack, and he's swaying around because he's toasted out of his mind. He can't walk a straight line, and, though I don't drink and run the bobcat, I won't think twice about wearing that toy sailor suit, given that it helps me stumble around rull good.
Tuesday, December 8, 2009
More Obnoxious Prattling About Influenza and Viral Transmission
The traffic was bad today, and the evening commute took 2.25 hours. I didn't get a live, attenuated flu vaccine, and the reason is basically that I decided not to try to sweet-talk my way into getting one. I'm not very good at that. The high-risk categories that the CDC has created are really problematic and have just really been defined in a nebulous way. The categories give the impression that a person needs to be quite ill to qualify, if one isn't 24 years old or younger. Of course, the "24-year-old" cut-off is totally arbitrary and has not a smidgen of credible evidence to support its validity. I think someone heard it in a folk song, passed down through the generations, as part of the oral storytelling tradition. The categories seem inclusive of a lot of sick people, but, as one looks at the illnesses included in the "high-risk" category, one realizes that a sick person is likely to be left wondering if he or she is actually sick enough to qualify. The person might think, "I have x disease, but I'm more or less healthy. Maybe I'm not sick enough. Maybe I should 'let a sick person have my vaccine,'" or some such thing. Of course, the sick person isn't going to get it, either. The people who thought up this type of approach seem to have no understanding of psychology, when one thinks about it. Who wants to think of himself or herself as being someone who's sick enough to get a complication from influenza? What doctor ever discusses the risks of influenza complications with his or her patients, especially those that are "sick" with those conditions? The person might think, "What am I going to have to tell the person, in order to establish that I'm sick enough to be at risk of complications? What's the actual procedure? Is the person going to flash the "shark eyes" at me, the blank stare? That's a little joke, but there are so many factors that are conspiring to decrease the likelihood that a person is going to get one of these early vaccines. If someone doesn't make the big decision to scrap this absurdly restrictive plan and hold a big press conference that no reporters may even attend, now that some of the decision-makers at the CDC have lost whatever credibility they might have initially had, then no one's going to get any vaccines this winter.
I was thinking about the educational system, and it's not even that the professors who teach science classes are not really good. The science professors I've had have been really articulate and terrific (although I've found that the professors in the humanities and rhetoric/writing classes surpass the science professors and are obviously superb), but the science textbooks and curricula are stuck in the 1950's or something, in terms of methodologies. It's almost as if it's the fact that the methods for teaching science haven't kept pace with the degree of complexity and vastness of the subject matter. One aspect of that problem is that one doesn't really learn much of anything, even when one gets an A or a B in a class. If one is told to memorize a fact, one can do it and answer questions about that fact. But, in most cases, one isn't going to remember it after the test is over, and the fact may, in actuality, be objectively incorrect, according to many of the different sets of standards by which one might evaluate the objective accuracy of the statement. For example, if I'm told to memorize that a hormone is usually released with such-and-such a serum-concentration-dependence, in response to x and y as stimuli for the hormone's release, I might remember that. But there may well be 500 articles calling that fact into question, and the sheer mass of information that contradicts that "textbook fact" will basically cause the statement in the textbook to be incorrect. There just isn't any purpose that's served by memorizing something, in the sciences, that's given such a superficial and lacking-in-subjective-nuance treatment in a textbook. It's like something out of 1920 or something. I'm exaggerating with that, but it gets to be upsetting to see. I always find writing to be a valuable use of my time, and it doesn't matter what things I'm writing, in many ways. It's always beneficial. But writing incorrect questions and answers on note cards, as a way of remembering material from a science textbook, is not beneficial and can...leave...a bad taste in one's mouth. If I were able to actually get a sense of the reality of the area of science, I...might "not get a bad taste" from the information. "Remember that, 'boy.' Now, go wash them @#%^&#$ hands, too, and don't take too long with the disinfectant, because I used to get sick and found that it helped warm my @#$%&$$ bones up in the wintertime--you hear--I say I sh-sh-sh-shivered me timbers, by jumpin' jehosaphat."
Anyway, the other point is that "virions" can be transferred, for example, from a contaminated surface to one's hands and then to another, non-contaminated surface and could, after "the transfer," conceivably survive for days and infect one with something like influenza. If one supposes that the "5-minute-survival" estimate [Collignon and Carnie (2006) mentioned that in the article I cited in a past posting: Collignon and Carnie, 2006: (https://www.mja.com.au/public/issues/185_10_201106/col10881_fm.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17115953)] is likely to not be written in stone and that the estimate may be incorrect by as large a factor as the "surivival-on-porous-surface" estimate was for influenza A [Collignon and Carnie (2006) estimated 6-12 hours for that, if I remember correctly, and Thomas et al. (2008) found the survival time, on a porous surface, of 17 days: (http://hardcorephysiologyfun.blogspot.com/2009/12/another-rambler-on-influenza.html)], then influenza might be able to live on one's hands for as long as [17/0.25 (as in the time of 6 hours that's the lower limit of the estimate for the survival on a porous surface) = 68, and 68 times 5 minutes = 340 minutes] 5.67 hours. That's about the length of time the rotavirus can survive and remain infectious for, I think. I would personally assume that influenza can survive for longer than 5 minutes on one's hands. But it doesn't really matter, as far as the issue of surface-to-hand-to-surface transfers go. Anyway, I just think this type of concept can be alien to a lot of people, and it doesn't hurt to practice thinking about these things. It's an "unreasonable" type of consideration, but I guess viruses have never been reasonable. It's easy to see that controlling some types of infections of patients in hospitals is unlikely to ever be possible, with all of these people running all over the place. I remember reading that the tv remotes (commonly, according to some research) in hospital rooms and stuffed animals passed out to patients can transmit the infectious particles that ultimately kill them, and that's sort of a concept that's almost "hostile" to human social interaction and is just hard for me and, presumably, a lot of other people to be cognizant of and also be a "reasonable" human. It basically seems like it would create something akin to cognitive dissonance, as if a person might think, unconsciously (I'm obviously exaggerating with this), "A good person wouldn't allow potentially lethal infections to be transmitted via a remote control or stuffed teddy bear, and a reasonable person wouldn't even think that that would be a reasonable possibility. The viruses couldn't do that and simultaneously be reasonable, but I know, from my readings, that viruses can be made to behave in reasonable ways, in the context of medicine. I need to think of myself as being a good person, and, therefore (here's the little "tweak" that fixes the dissonance), since I know I am a good person, the viruses must not be that unreasonable." I mean, that's the type of thought process that sometimes crosses my mind. "Now, let's see, here. I've got some crisp papers with information on pathology and horrors, and, over here, I've got some lethal viral infections and calculations of viral transmission. Alll right, now, this looks interesting..."
I was thinking about the educational system, and it's not even that the professors who teach science classes are not really good. The science professors I've had have been really articulate and terrific (although I've found that the professors in the humanities and rhetoric/writing classes surpass the science professors and are obviously superb), but the science textbooks and curricula are stuck in the 1950's or something, in terms of methodologies. It's almost as if it's the fact that the methods for teaching science haven't kept pace with the degree of complexity and vastness of the subject matter. One aspect of that problem is that one doesn't really learn much of anything, even when one gets an A or a B in a class. If one is told to memorize a fact, one can do it and answer questions about that fact. But, in most cases, one isn't going to remember it after the test is over, and the fact may, in actuality, be objectively incorrect, according to many of the different sets of standards by which one might evaluate the objective accuracy of the statement. For example, if I'm told to memorize that a hormone is usually released with such-and-such a serum-concentration-dependence, in response to x and y as stimuli for the hormone's release, I might remember that. But there may well be 500 articles calling that fact into question, and the sheer mass of information that contradicts that "textbook fact" will basically cause the statement in the textbook to be incorrect. There just isn't any purpose that's served by memorizing something, in the sciences, that's given such a superficial and lacking-in-subjective-nuance treatment in a textbook. It's like something out of 1920 or something. I'm exaggerating with that, but it gets to be upsetting to see. I always find writing to be a valuable use of my time, and it doesn't matter what things I'm writing, in many ways. It's always beneficial. But writing incorrect questions and answers on note cards, as a way of remembering material from a science textbook, is not beneficial and can...leave...a bad taste in one's mouth. If I were able to actually get a sense of the reality of the area of science, I...might "not get a bad taste" from the information. "Remember that, 'boy.' Now, go wash them @#%^&#$ hands, too, and don't take too long with the disinfectant, because I used to get sick and found that it helped warm my @#$%&$$ bones up in the wintertime--you hear--I say I sh-sh-sh-shivered me timbers, by jumpin' jehosaphat."
Anyway, the other point is that "virions" can be transferred, for example, from a contaminated surface to one's hands and then to another, non-contaminated surface and could, after "the transfer," conceivably survive for days and infect one with something like influenza. If one supposes that the "5-minute-survival" estimate [Collignon and Carnie (2006) mentioned that in the article I cited in a past posting: Collignon and Carnie, 2006: (https://www.mja.com.au/public/issues/185_10_201106/col10881_fm.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/17115953)] is likely to not be written in stone and that the estimate may be incorrect by as large a factor as the "surivival-on-porous-surface" estimate was for influenza A [Collignon and Carnie (2006) estimated 6-12 hours for that, if I remember correctly, and Thomas et al. (2008) found the survival time, on a porous surface, of 17 days: (http://hardcorephysiologyfun.blogspot.com/2009/12/another-rambler-on-influenza.html)], then influenza might be able to live on one's hands for as long as [17/0.25 (as in the time of 6 hours that's the lower limit of the estimate for the survival on a porous surface) = 68, and 68 times 5 minutes = 340 minutes] 5.67 hours. That's about the length of time the rotavirus can survive and remain infectious for, I think. I would personally assume that influenza can survive for longer than 5 minutes on one's hands. But it doesn't really matter, as far as the issue of surface-to-hand-to-surface transfers go. Anyway, I just think this type of concept can be alien to a lot of people, and it doesn't hurt to practice thinking about these things. It's an "unreasonable" type of consideration, but I guess viruses have never been reasonable. It's easy to see that controlling some types of infections of patients in hospitals is unlikely to ever be possible, with all of these people running all over the place. I remember reading that the tv remotes (commonly, according to some research) in hospital rooms and stuffed animals passed out to patients can transmit the infectious particles that ultimately kill them, and that's sort of a concept that's almost "hostile" to human social interaction and is just hard for me and, presumably, a lot of other people to be cognizant of and also be a "reasonable" human. It basically seems like it would create something akin to cognitive dissonance, as if a person might think, unconsciously (I'm obviously exaggerating with this), "A good person wouldn't allow potentially lethal infections to be transmitted via a remote control or stuffed teddy bear, and a reasonable person wouldn't even think that that would be a reasonable possibility. The viruses couldn't do that and simultaneously be reasonable, but I know, from my readings, that viruses can be made to behave in reasonable ways, in the context of medicine. I need to think of myself as being a good person, and, therefore (here's the little "tweak" that fixes the dissonance), since I know I am a good person, the viruses must not be that unreasonable." I mean, that's the type of thought process that sometimes crosses my mind. "Now, let's see, here. I've got some crisp papers with information on pathology and horrors, and, over here, I've got some lethal viral infections and calculations of viral transmission. Alll right, now, this looks interesting..."
Multiple Revisions of an Old Paper of Mine
I guess this is the end of this [(http://www.mediafire.com/?410jmzmrjjm); (http://hardcorephysiologyfun.blogspot.com/2009/06/folate-and-uvb-papers-in-pdf-format.html); (http://hardcorephysiologyfun.blogspot.com/2009/05/another-old-paper-of-mine.html); (http://hardcorephysiologyfun.blogspot.com/search/label/UVB)]. Maybe I'll try it elsewhere, at some point in the future. In any case, it wasn't really for my benefit that I did these, and it's not going to benefit me in the future. The dermatologists wouldn't like it, and the neurologists wouldn't like it, either. But the mechanisms are relevant to biology in general.
Multiple Sclerosis and Ultraviolet Radiation (UVR): Can UVR Exert Immunomodulatory Effects in the CNS Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?
Bains [1], in a recent and very interesting article, noted that excessively-direct exposure of the eyes to ultraviolet radiation (UVR) could cause optic neuritis and contribute to the development of multiple sclerosis (MS) in some people, and additional research lends credence to that hypothesis and sheds light on some mechanisms by which neurogenic effects of UVR could influence immunological processes in the brain. Cutaneous exposure to either ultraviolet B (UVB) or ultraviolet A (UVA) increases the concentrations of inflammatory mediators in the skin [2,3], and these mediators can then act on primary afferent neurons (PAN’s) innervating the skin and increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by direct or indirect, neurogenic mechanisms [6-13], and UVR could, by increasing the percentages of spontaneously-active PAN’s, either augment or suppress the immune and inflammatory responses of microglia and dendritic cells in the central nervous system (CNS).
UVR can increase the release of cytokines and neurotrophins and other mediators from keratinocytes and mast cells in the skin [14, 15], and these mediators can then depolarize and induce spontaneous action potentials (APs) in C-fibers [2,16,17] and A-fibers [16] innervating the exposed skin [2,16,17]. The APs are likely to be largely asynchronous [18], can begin as soon as 30 minutes after exposure [17] and persist for five days [2,16], and can occur at low frequencies of 0.8-1.25 Hz [2] or at comparable freqencies [16,17]. Thus, UVA-induced APs in trigeminal ganglion (TG) neurons may have contributed to the visual-evoked potentials measured in humans [19] and the rapid emergence of changes in the pineal gland [20] or suprachiasmatic nucleus [9] in hamsters or rats, respectively.
The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes [21-23] or dorsal root reflexes. In an axon reflex, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a dorsal root reflex, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24]. The complex, UVR-induced changes in the expression, formation, and release of CGRP and SP, in the DH, are likely to result from changes in the patterns of orthodromic and antidromic APs that PAN’s, in the dorsal root ganglia (DRG) or TG, exhibit following UVR [3-5,25].
TG and DRG neurons are likely to serve as the primary inputs for the apparently-polysynaptic pathways by which UVR can alter neuronal activity in the CNS. UVR can cause neurons in the DH to fire spontaneously [26,27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5,6,9,10,30-35] in animals or humans. The apparent effects of UVB or UVA on the brain [6,9,10,32,35] have sometimes been blocked by ciliary ganglionectomy [10], optic nerve (ON) transection [7] or denervation [8], hypophysectomy [8,10], or orbital enucleation [6,9]. Despite the evidence suggesting that UVR induces APs in ON fibers [6-9], ocular UVB is known to reliably induce Herpes simplex virus reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears [10,32] were likely to have been mediated by the activation of TG neurons, in the ophthalmic branch of the trigeminal nerve (V1), and also by neurons in the ciliary ganglion/ganglia (CG) [10], and, consistent with this, some neurons in the caudal trigeminal nucleus (Vc) project to the hypothalamus and receive monosynaptic inputs from TG neurons innervating the facial skin [37].
In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19,20], it is relevant that only ~ 2 percent of UVB reaches the lens in the intact eye and that almost all of the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [38]. Sliney et al. [38] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [39], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19,20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. Most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [38], and any prolonged exposure of the eyes to direct UVR could damage corneal C-fibers or A-fibers, impact neurotransmission in the brain by atypical mechanisms, or, as noted by Bains [1], contribute to the development of optic neuritis.
The axons of many neurons in the TG or CG or accessory CG, in rats [40] and some mice [41] and also humans [42], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [41], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6,8-10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [40], and many of the TG neurons pass through the CG without forming synapses [40].
The neurogenic release of CGRP in the skin contributes to UVB-induced systemic immunosuppression [25,43] and to visible-light-mediated immune privilege in the eyes [44], and the UVR-induced release of SP and CGRP in the CNS could act on microglia or dendritic cells and either promote tolerance to CNS-specific antigens, such as in people who do not have MS, or exacerbate the course of MS. Following UVR exposures to rodents, researchers could evaluate, with an eye to the relevance to MS, phenotypic changes in dendritic cells that migrate from the CNS to the cervical lymph nodes [45] or site-specific changes in microglial activation in the CNS.
References
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Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?
Recently, Brajac et al. [1] noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) [6-9], the ophthalmic branch of the trigeminal nerve (V1) [10], or by incompletely-defined mechanisms [11,12], potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides [13] or in the activities of PAN’s [11]. UVR could influence the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by increasing the percentages of spontaneously-active PAN’s and thereby altering the release of CGRP, SP, and glutamate at different sites in the CNS.
UVR can induce spontaneous action potentials (AP’s) in C-fibers [2,14,15] and A-fibers [14] innervating the exposed skin [2,14,15]. These sensory fibers (SF’s), which are the peripheral branches of PAN’s in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators [16] that are released from keratinocytes and mast cells [17] in UV-exposed skin. The AP’s in PAN’s can begin as soon as 30 minutes after exposure [15] and persist for five days [2,14] or longer. Spontaneous AP’s in SF’s are likely to be largely asynchronous [18], and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz [2] or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) [15] or 6-108 AP’s per minute (~0.1-1.8 Hz) [14]. Thus, UVA-induced AP’s in TG neurons may have contributed to the visual-evoked potentials measured in humans [19] and rapid emergence of changes in the pineal gland [20] and suprachiasmatic nucleus [7].
The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes (AXR) [21-23] or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24].
The AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats [25], and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s [3]. The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central branches of PAN’s, in response to the release of those neuropeptides [4,5]. Those increases in CGRP and SP may also result from adaptive decreases, over the long term [3] or short term [4], in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s [3,4]. For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.
TG and DRG neurons are likely to serve as the primary inputs for the polysynaptic pathways activated by UVR. UVR can cause neurons in the DH to fire spontaneously [26, 27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5-7, 10, 30-35] in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH [10, 32] or in IEG expression [6, 7] or pineal NAT activity [35], have sometimes been blocked by ciliary ganglionectomy [10], ON transection [8] or denervation [9], hypophysectomy [9, 10], or orbital enucleation [6, 7]. Despite the evidence suggesting that UVR induces AP’s in ON fibers [6-9], ocular UVB is known to reliably induce HSV reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) [10]. These effects were more pronounced after exposure to the eyes alone than after exposure to the ears alone [10, 32], and this could be explained by the exceptionally-dense trigeminal innervation of the corneas [37]. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc [38], and the UVR-induced increases in plasma ACTH [32] or -MSH [10] in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus [39] and receive monosynaptic inputs from TG neurons innervating the facial skin [39]. Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of some cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc [36].
In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19, 20], it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [40]. Sliney et al. [40] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [41], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19, 20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [40], and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.
The axons of many neurons in the TG or CG or accessory CG, in rats [42] and some mice [43] and also humans [44], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [43], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6, 7, 9, 10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [42], and many of the TG neurons pass through the CG without forming synapses [42].
UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans [34] or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.
References
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Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?
Recently, Brajac et al. (13) noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin (21,39) and also in the dorsal horn (DH) of the spinal cord (26, 46). The increases in the DH are likely to result from increases in the release of CGRP and SP from the central terminals of PAN’s (27,48). Similarly, exposure of the facial skin to UVR is likely to induce the release of CGRP, SP, and glutamate in the trigeminal nucleus caudalis (Vc), in the brainstem (51). Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) (1,2,30,33), the ophthalmic branch of the trigeminal nerve (V1) (31), or by incompletely-defined mechanisms (20,57), potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides (47) or in the activities of PAN’s (20). There is evidence that cutaneous UVR can influence peptidergic and glutamatergic transmission in the spinal cord (9,10,15,17,46,59,60,61) and brain (2,31) along polysynaptic pathways, and these effects are likely to result from prolonged increases in low-frequency, spontaneous action potentials (AP’s) induced in PAN’s, in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), innervating the UV-irradiated skin (3,21,56). Those mechanisms (3,21,26,27,29,30,31) imply that the neuroendocrinological effects (12,29,31), increases in immediate-early gene (IEG) expression in the suprachiasmatic nucleus (SCN) and other sites in the brain (1,2), or decreases in pineal melatonin content (12) or serotonin N-acetyltransferase (NAT) activity (65), induced by UVR exposure to only the eyes (1,2,29,30,31) or ears (29,31), could have resulted from increases in the percentages of spontaneously-active PAN’s, in the TG or cervical DRG, innervating the corneas or ears, respectively. UVR may influence, via PAN’s, the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by altering the release of CGRP, SP, and glutamate at different sites in the brain.
UVR can induce spontaneous AP’s in C-fibers (3,21,56) and A-fibers (3) innervating the exposed skin (3,21,56). These sensory fibers (SF’s) develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators (48), and the increases in the release of many of these mediators from keratinocytes (KC’s) and mast cells (54), in UV-exposed skin, are likely to produce the AP’s in SF’s (48). The UVR-induced AP’s in PAN’s can begin as soon as 30 minutes after exposure (56) and persist for up to five days (3,21), and the dermal concentrations of bradykinin, a neuropeptide that induces AP’s and not just sensitization in C-fibers (56), in human skin within 21 minutes of exposure (19). Spontaneous AP’s in SF’s are likely to be largely asynchronous (32), and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz (21) or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) (56) or 6-108 AP’s per minute (~0.1-1.8 Hz) (3). Thus, the visual-evoked potentials measured in UVA-exposed humans (11) and rapid emergence of changes in the pineal gland (12) and SCN (2) may, particularly given the use of high intensity UVA (11), have been partially a result of early, UVA-induced AP’s in TG neurons.
The UVR-induced release of neuropeptides into the skin is likely to occur through axon reflexes (AXR) (4,18,37) or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent, or orthodromic, AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent, or antidromic, direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber (64). In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber (64).
The UVR-induced afferent AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats (25), and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s (39). The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central terminals of DRG neurons, in response to the UVR-induced release of CGRP and SP from those terminals (26,46). Those increases in CGRP and SP may also result from adaptive decreases, over the long term (39) or short term (26), in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s (26,39). For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.
The apparent polysynaptic pathways by which UVR can produce changes in the CNS have not been precisely delineated, but TG and DRG neurons are likely to serve as the primary inputs for those changes. UVR can also cause neurons in the DH to fire spontaneously (15,61), to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission (10,15,60,61), and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS (1,2,9,17,29,31,46,50,65) in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH (29,31) or on IEG expression (1,2) or NAT activity (65) in parts of the brain, have sometimes been blocked by ciliary ganglionectomy (31), ON transection (30) or denervation (33), hypophysectomy (31,33), or orbital enucleation (1,2). Despite the evidence suggesting that UVR induces AP’s in ON fibers (1,2,30,33), ocular UVB is known to reliably induce HSV reactivation in the TG (52) and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. (31) suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) (31). The apparent effects of UVR on the CNS were more pronounced after exposure to the eyes alone than after exposure to the ears alone (29,31), and this could be explained by the exceptionally-dense trigeminal innervation of the corneas {{771}}. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc (6), and the UVR-induced increases in plasma ACTH (29) or -MSH (31) in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus (42) and receive monosynaptic inputs from TG neurons innervating the facial skin (42). Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc (52).
In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised (11,12), it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor (53). Sliney et al. (53) noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum (62), can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by the excised ocular tissues of nonprimate, mammalian species (11,12). The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses (11), but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules (53), and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.
The axons of many neurons in the TG or CG or accessory CG, in rats (38) and some mice (45) and also humans (44), extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON (45), and it is possible that the ON denervation or transection procedures (1,2,33) severed some axons of neurons whose cell bodies are in the CG, accessory CG, or TG. Most of the sensory neurons in the TG that innervate parts of the eye are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, and the nasociliary nerve is a subdivision of V1 (38). Many of the TG neurons that project to the corneas, within the ciliary nerves, pass through the CG without forming synapses (38). Despite the anatomical differences among mice, rats, and humans (38,44,45), the short or long ciliary nerves that contain corneal afferents from the TG also extend along sections of the ON, just posterior to the globe, in rats (38), mice (45), and also humans (44) and could have been damaged or severed during the ciliary ganglionectomy (31,33), ON transection (1,2,30) or denervation (31,33), or orbital enucleation (1,2) procedures.
UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans (50) or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.
References
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(22) Feldman SR, Liguori A, Kucenic M, et al. Ultraviolet exposure is a reinforcing stimulus in frequent indoor tanners. J Am Acad Dermatol 2004;51(1):45-51.
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(25) Gillardon F, Moll I, Michel S, Benrath J, Weihe E, Zimmermann M. Calcitonin gene-related peptide and nitric oxide are involved in ultraviolet radiation-induced immunosuppression. Eur J Pharmacol 1995;293(4):395-400.
(26) Gillardon F, Schrock H, Morano I, Zimmermann M. Long-term increase in CGRP levels in rat spinal dorsal horn following skin ultraviolet irradiation. A mechanism of sunburn pain? Ann N Y Acad Sci 1992;657:493-6.
(27) Gillardon F, Wiesner RJ, Zimmermann M. Expression of the junD proto-oncogene in the rat spinal cord and skin following noxious cutaneous ultraviolet irradiation. Neurosci Lett 1992;136(1):87-90.
(28) Gillardon F, Zimmermann M, Uhlmann E. Expression of c-Fos and c-Jun in the cornea, lens, and retina after ultraviolet irradiation of the rat eye and effects of topical antisense oligodeoxynucleotides. Br J Ophthalmol 1995;79(3):277-81.
(29) Hiramoto K. Ultraviolet A irradiation of the eye activates a nitric oxide-dependent hypothalamo-pituitary pro-opiomelanocortin pathway and modulates the functions of Langerhans cells. J Dermatol 2009;36(6):335-45.
(30) Hiramoto K, Mashita Y, Katada T, Konishi H, Sugiura M, Hayakawa R. Immunosuppression by ultraviolet B rays via eyes in mice. Arch Dermatol Res 1997;289(12):709-11.
(31) Hiramoto K, Yanagihara N, Sato EF, Inoue M. Ultraviolet B irradiation of the eye activates a nitric oxide-dependent hypothalamopituitary proopiomelanocortin pathway and modulates functions of alpha-melanocyte-stimulating hormone-responsive cells. J Invest Dermatol 2003;120(1):123-7.
(32) Ikeda H, Stark J, Fischer H, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 2006;312(5780):1659-62.
(33) Inoue M, Hiramoto K, Park A-M, Sato EF. UV-Irradiation down-regulates immune functions and causes fatigue by photo-optico-neuronal network: lessons from iNOS-knockout mice (Abstract). Neurochemical Research 2004;29(8):1582.
(34) Jalali MH, Ansarin H, Soltani-Arabshahi R. Broad-band ultraviolet B phototherapy in zoster patients may reduce the incidence and severity of postherpetic neuralgia. Photodermatol Photoimmunol Photomed 2006;22(5):232-7.
(35) Kaur M, Feldman SR, Liguori A, Fleischer AB, Jr. Indoor tanning relieves pain. Photodermatol Photoimmunol Photomed 2005;21(5):278.
(36) Klein T, Magerl W, Hopf HC, Sandkuhler J, Treede RD. Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 2004;24(4):964-71.
(37) Koppert W, Brueckl V, Weidner C, Schmelz M. Mechanically induced axon reflex and hyperalgesia in human UV-B burn are reduced by systemic lidocaine. Eur J Pain 2004;8(3):237-44.
(38) Kuchiiwa S, Kuchiiwa T, Suzuki T. Comparative anatomy of the accessory ciliary ganglion in mammals. Anat Embryol 1989;180(2):199-205.
(39) Legat FJ, Griesbacher T, Schicho R, et al. Repeated subinflammatory ultraviolet B irradiation increases substance P and calcitonin gene-related peptide content and augments mustard oil-induced neurogenic inflammation in the skin of rats. Neurosci Lett 2002;329(3):309-13.
(40) Lynn B and Shakhanbeh J. Neurogenic inflammation in the skin of the rabbit. Agents Actions 1988;25(3-4):228-30.
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(42) Malick A and Burstein R. Cells of origin of the trigeminohypothalamic tract in the rat. J Comp Neurol 1998;400(1):125-44.
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(45) Nowak E, Kuder T, Szczurkowski A, Kuchinka J. Anatomical and histological data on the ciliary ganglion in the Egyptian spiny mouse (Acomys cahirinus Desmarest). Folia Morphol 2004;63(3):267-72.
(46) Polgar E, Szucs P, Urban L, Nagy I. Alterations of substance P immunoreactivity in lumbar and thoracic segments of rat spinal cord in ultraviolet irradiation induced hyperalgesia of the hindpaw. Brain Res 1998;786(1-2):248-51.
(47) Rogers SC, Shuster S, Marks JM, Penny RJ, Thody AJ. The effects of photochemotherapy on endocrine secretion in patients with psoriasis. Acta Derm Venereol 1981;61(4):350-2.
(48) Saade NE, Farhat O, Rahal O, Safieh-Garabedian B, Le Bars D, Jabbur SJ. Ultraviolet-induced localized inflammatory hyperalgesia in awake rats and the role of sensory and sympathetic innervation of the skin. Brain Behav Immun 2008;22(2):245-56.
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(50) Seifert F, Jungfer I, Schmelz M, Maihofner C. Representation of UV-B-induced thermal and mechanical hyperalgesia in the human brain: a functional MRI study. Hum Brain Mapp 2008;29(12):1327-42.
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(55) Streilein JW, Okamoto S, Sano Y, Taylor AW. Neural control of ocular immune privilege. Ann N Y Acad Sci 2000;917:297-306.
(56) Szolcsanyi J. Selective responsiveness of polymodal nociceptors of the rabbit ear to capsaicin, bradykinin and ultra-violet irradiation. J Physiol 1987;388:9-23.
(57) Taylor SL, Kaur M, LoSicco K, et al. Pilot Study of the Effect of Ultraviolet Light on Pain and Mood in Fibromyalgia Syndrome. The Journal of Alternative and Complementary Medicine 2009;15(1):15-23.
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Multiple Sclerosis and Ultraviolet Radiation (UVR): Can UVR Exert Immunomodulatory Effects in the CNS Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?
Bains [1], in a recent and very interesting article, noted that excessively-direct exposure of the eyes to ultraviolet radiation (UVR) could cause optic neuritis and contribute to the development of multiple sclerosis (MS) in some people, and additional research lends credence to that hypothesis and sheds light on some mechanisms by which neurogenic effects of UVR could influence immunological processes in the brain. Cutaneous exposure to either ultraviolet B (UVB) or ultraviolet A (UVA) increases the concentrations of inflammatory mediators in the skin [2,3], and these mediators can then act on primary afferent neurons (PAN’s) innervating the skin and increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by direct or indirect, neurogenic mechanisms [6-13], and UVR could, by increasing the percentages of spontaneously-active PAN’s, either augment or suppress the immune and inflammatory responses of microglia and dendritic cells in the central nervous system (CNS).
UVR can increase the release of cytokines and neurotrophins and other mediators from keratinocytes and mast cells in the skin [14, 15], and these mediators can then depolarize and induce spontaneous action potentials (APs) in C-fibers [2,16,17] and A-fibers [16] innervating the exposed skin [2,16,17]. The APs are likely to be largely asynchronous [18], can begin as soon as 30 minutes after exposure [17] and persist for five days [2,16], and can occur at low frequencies of 0.8-1.25 Hz [2] or at comparable freqencies [16,17]. Thus, UVA-induced APs in trigeminal ganglion (TG) neurons may have contributed to the visual-evoked potentials measured in humans [19] and the rapid emergence of changes in the pineal gland [20] or suprachiasmatic nucleus [9] in hamsters or rats, respectively.
The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes [21-23] or dorsal root reflexes. In an axon reflex, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a dorsal root reflex, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24]. The complex, UVR-induced changes in the expression, formation, and release of CGRP and SP, in the DH, are likely to result from changes in the patterns of orthodromic and antidromic APs that PAN’s, in the dorsal root ganglia (DRG) or TG, exhibit following UVR [3-5,25].
TG and DRG neurons are likely to serve as the primary inputs for the apparently-polysynaptic pathways by which UVR can alter neuronal activity in the CNS. UVR can cause neurons in the DH to fire spontaneously [26,27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5,6,9,10,30-35] in animals or humans. The apparent effects of UVB or UVA on the brain [6,9,10,32,35] have sometimes been blocked by ciliary ganglionectomy [10], optic nerve (ON) transection [7] or denervation [8], hypophysectomy [8,10], or orbital enucleation [6,9]. Despite the evidence suggesting that UVR induces APs in ON fibers [6-9], ocular UVB is known to reliably induce Herpes simplex virus reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears [10,32] were likely to have been mediated by the activation of TG neurons, in the ophthalmic branch of the trigeminal nerve (V1), and also by neurons in the ciliary ganglion/ganglia (CG) [10], and, consistent with this, some neurons in the caudal trigeminal nucleus (Vc) project to the hypothalamus and receive monosynaptic inputs from TG neurons innervating the facial skin [37].
In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19,20], it is relevant that only ~ 2 percent of UVB reaches the lens in the intact eye and that almost all of the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [38]. Sliney et al. [38] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [39], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19,20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. Most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [38], and any prolonged exposure of the eyes to direct UVR could damage corneal C-fibers or A-fibers, impact neurotransmission in the brain by atypical mechanisms, or, as noted by Bains [1], contribute to the development of optic neuritis.
The axons of many neurons in the TG or CG or accessory CG, in rats [40] and some mice [41] and also humans [42], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [41], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6,8-10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [40], and many of the TG neurons pass through the CG without forming synapses [40].
The neurogenic release of CGRP in the skin contributes to UVB-induced systemic immunosuppression [25,43] and to visible-light-mediated immune privilege in the eyes [44], and the UVR-induced release of SP and CGRP in the CNS could act on microglia or dendritic cells and either promote tolerance to CNS-specific antigens, such as in people who do not have MS, or exacerbate the course of MS. Following UVR exposures to rodents, researchers could evaluate, with an eye to the relevance to MS, phenotypic changes in dendritic cells that migrate from the CNS to the cervical lymph nodes [45] or site-specific changes in microglial activation in the CNS.
References
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[27] Urban L, Perkins MN, Campbell E, Dray A. Activity of deep dorsal horn neurons in the anaesthetized rat during hyperalgesia of the hindpaw induced by ultraviolet irradiation. Neuroscience 1993;57(1):167-72.
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[30] Boxall SJ, Berthele A, Laurie DJ, et al. Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 1998;82(2):591-602.
[31] Davis CL, Naeem S, Phagoo SB, Campbell EA, Urban L, Burgess GM. B1 bradykinin receptors and sensory neurones. Br J Pharmacol 1996;118(6):1469-76.
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[33] Gillardon F, Wiesner RJ, Zimmermann M. Expression of the junD proto-oncogene in the rat spinal cord and skin following noxious cutaneous ultraviolet irradiation. Neurosci Lett 1992;136(1):87-90.
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[35] Zawilska JB, Rosiak J, Nowak JZ. Effects of near-ultraviolet light on the nocturnal serotonin N-acetyltransferase activity of rat pineal gland. Neurosci Lett 1998;243(1-3):49-52.
[36] Shimeld C, Easty DL, Hill TJ. Reactivation of herpes simplex virus type 1 in the mouse trigeminal ganglion: an in vivo study of virus antigen and cytokines. J Virol 1999;73(3):1767-73.
[37] Malick A and Burstein R. Cells of origin of the trigeminohypothalamic tract in the rat. J Comp Neurol 1998;400(1):125-44.
[38] Sliney D. Ultraviolet radiation effects upon the eye: Problems of dosimetry. Radiat Prot Dosimet 1997;72(3-4):197-206.
[39] Van den Berg TJ. Quantal and visual efficiency of fluorescence in the lens of the human eye. Invest Ophthalmol Vis Sci 1993;34(13):3566-73.
[40] Kuchiiwa S, Kuchiiwa T, Suzuki T. Comparative anatomy of the accessory ciliary ganglion in mammals. Anat Embryol 1989;180(2):199-205.
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Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?
Recently, Brajac et al. [1] noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin [2,3] and also in the dorsal horn (DH) of the spinal cord [4,5]. Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) [6-9], the ophthalmic branch of the trigeminal nerve (V1) [10], or by incompletely-defined mechanisms [11,12], potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides [13] or in the activities of PAN’s [11]. UVR could influence the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by increasing the percentages of spontaneously-active PAN’s and thereby altering the release of CGRP, SP, and glutamate at different sites in the CNS.
UVR can induce spontaneous action potentials (AP’s) in C-fibers [2,14,15] and A-fibers [14] innervating the exposed skin [2,14,15]. These sensory fibers (SF’s), which are the peripheral branches of PAN’s in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators [16] that are released from keratinocytes and mast cells [17] in UV-exposed skin. The AP’s in PAN’s can begin as soon as 30 minutes after exposure [15] and persist for five days [2,14] or longer. Spontaneous AP’s in SF’s are likely to be largely asynchronous [18], and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz [2] or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) [15] or 6-108 AP’s per minute (~0.1-1.8 Hz) [14]. Thus, UVA-induced AP’s in TG neurons may have contributed to the visual-evoked potentials measured in humans [19] and rapid emergence of changes in the pineal gland [20] and suprachiasmatic nucleus [7].
The release of neuropeptides into UVR-exposed skin is likely to occur through axon reflexes (AXR) [21-23] or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent (and, here, orthodromic) AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent (and, here, antidromic) direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber [24]. In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber [24].
The AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats [25], and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s [3]. The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central branches of PAN’s, in response to the release of those neuropeptides [4,5]. Those increases in CGRP and SP may also result from adaptive decreases, over the long term [3] or short term [4], in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s [3,4]. For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.
TG and DRG neurons are likely to serve as the primary inputs for the polysynaptic pathways activated by UVR. UVR can cause neurons in the DH to fire spontaneously [26, 27], to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission [26-29], and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS [5-7, 10, 30-35] in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH [10, 32] or in IEG expression [6, 7] or pineal NAT activity [35], have sometimes been blocked by ciliary ganglionectomy [10], ON transection [8] or denervation [9], hypophysectomy [9, 10], or orbital enucleation [6, 7]. Despite the evidence suggesting that UVR induces AP’s in ON fibers [6-9], ocular UVB is known to reliably induce HSV reactivation in the TG [36] and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. [10] suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) [10]. These effects were more pronounced after exposure to the eyes alone than after exposure to the ears alone [10, 32], and this could be explained by the exceptionally-dense trigeminal innervation of the corneas [37]. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc [38], and the UVR-induced increases in plasma ACTH [32] or -MSH [10] in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus [39] and receive monosynaptic inputs from TG neurons innervating the facial skin [39]. Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of some cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc [36].
In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised [19, 20], it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor [40]. Sliney et al. [40] noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum [41], can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by excised ocular tissues [19, 20]. The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses [19], but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules [40], and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.
The axons of many neurons in the TG or CG or accessory CG, in rats [42] and some mice [43] and also humans [44], extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON [43], just posterior to the globe, and it is possible that the ON denervation or transection or ciliary ganglionectomy procedures [6, 7, 9, 10] damaged some axons of neurons in the CG, accessory CG, or TG. Most of the TG neurons that innervate the corneas are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, a subdivision of V1 [42], and many of the TG neurons pass through the CG without forming synapses [42].
UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans [34] or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.
References
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(19) Brainard GC, Beacham S, Sanford BE, Hanifin JP, Streletz L, Sliney D. Near ultraviolet radiation elicits visual evoked potentials in children. Clin Neurophysiol 1999;110(3):379-83.
(20) Brainard GC, Podolin PL, Leivy SW, Rollag MD, Cole C, Barker FM. Near-ultraviolet radiation suppresses pineal melatonin content. Endocrinology 1986;119(5):2201-5.
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(22) Eisenbarth H, Rukwied R, Petersen M, Schmelz M. Sensitization to bradykinin B1 and B2 receptor activation in UV-B irradiated human skin. Pain 2004;110(1-2):197-204.
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Does Ultraviolet Radiation Regulate Brain Function and Circadian Neuroendocrine Rhythms Through its Capacity to Induce Action Potentials in Sensory Neurons Innervating the Skin?
Recently, Brajac et al. (13) noted that the sensory innervation of the skin may influence the development of psoriatic plaques and that stress-activated signalling in the central nervous system (CNS) may interact with melanocytes and with the disease process in psoriasis. The research on the effects of cutaneous exposure to ultraviolet B (UVB) or ultraviolet A (UVA) on primary afferent neurons (PAN’s) innervating the skin may shed light on the mechanisms by which changes in the skin could interact with processes in the CNS. Ultraviolet radiation (UVR) can increase the concentrations of sensory neuropeptides, including -calcitonin gene-related peptide (CGRP) and substance P (SP), in the skin (21,39) and also in the dorsal horn (DH) of the spinal cord (26, 46). The increases in the DH are likely to result from increases in the release of CGRP and SP from the central terminals of PAN’s (27,48). Similarly, exposure of the facial skin to UVR is likely to induce the release of CGRP, SP, and glutamate in the trigeminal nucleus caudalis (Vc), in the brainstem (51). Researchers have suggested that UVR may be able to modify brain function by altering neurotransmission in the optic nerve (ON) (1,2,30,33), the ophthalmic branch of the trigeminal nerve (V1) (31), or by incompletely-defined mechanisms (20,57), potentially related to changes in the levels of biogenic amine neurotransmitters or neuropeptides (47) or in the activities of PAN’s (20). There is evidence that cutaneous UVR can influence peptidergic and glutamatergic transmission in the spinal cord (9,10,15,17,46,59,60,61) and brain (2,31) along polysynaptic pathways, and these effects are likely to result from prolonged increases in low-frequency, spontaneous action potentials (AP’s) induced in PAN’s, in the dorsal root ganglion/ganglia (DRG) and trigeminal ganglion/ganglia (TG), innervating the UV-irradiated skin (3,21,56). Those mechanisms (3,21,26,27,29,30,31) imply that the neuroendocrinological effects (12,29,31), increases in immediate-early gene (IEG) expression in the suprachiasmatic nucleus (SCN) and other sites in the brain (1,2), or decreases in pineal melatonin content (12) or serotonin N-acetyltransferase (NAT) activity (65), induced by UVR exposure to only the eyes (1,2,29,30,31) or ears (29,31), could have resulted from increases in the percentages of spontaneously-active PAN’s, in the TG or cervical DRG, innervating the corneas or ears, respectively. UVR may influence, via PAN’s, the thermoregulatory and neuroendocrine aspects of circadian rhythms and influence other processes in the CNS, such as the immune responses of microglia and dendritic cells, by altering the release of CGRP, SP, and glutamate at different sites in the brain.
UVR can induce spontaneous AP’s in C-fibers (3,21,56) and A-fibers (3) innervating the exposed skin (3,21,56). These sensory fibers (SF’s) develop graded receptor potentials, which are analogous to excitatory postsynaptic potentials (EPSP’s), and AP’s in response to their rapid depolarization by cytokines and NGF and other mediators (48), and the increases in the release of many of these mediators from keratinocytes (KC’s) and mast cells (54), in UV-exposed skin, are likely to produce the AP’s in SF’s (48). The UVR-induced AP’s in PAN’s can begin as soon as 30 minutes after exposure (56) and persist for up to five days (3,21), and the dermal concentrations of bradykinin, a neuropeptide that induces AP’s and not just sensitization in C-fibers (56), in human skin within 21 minutes of exposure (19). Spontaneous AP’s in SF’s are likely to be largely asynchronous (32), and UVR-induced AP’s in SF’s have occurred at frequencies of 0.8-1.25 Hz (21) or 6.64 AP’s per minute (an arithmetic mean of 0.1 Hz) (56) or 6-108 AP’s per minute (~0.1-1.8 Hz) (3). Thus, the visual-evoked potentials measured in UVA-exposed humans (11) and rapid emergence of changes in the pineal gland (12) and SCN (2) may, particularly given the use of high intensity UVA (11), have been partially a result of early, UVA-induced AP’s in TG neurons.
The UVR-induced release of neuropeptides into the skin is likely to occur through axon reflexes (AXR) (4,18,37) or dorsal root reflexes (DRR’s). In an AXR, it is thought that an afferent, or orthodromic, AP propagates from an epidermal C-fiber terminal to the DH and also propagates in an efferent, or antidromic, direction, beginning at a branching point of the terminal arborization of a C-fiber, to one or more periarteriolar terminals of the same C-fiber (64). In a DRR, an afferent AP would propagate from the skin to the DH and cause, via the induction of an AP in an interneuron, an efferent AP to originate in the DH and propagate back to the skin in a second C-fiber or A-fiber (64).
The UVR-induced afferent AP’s in SF’s are likely to first deplete and subsequently increase the levels of CGRP and SP in both the skin and DH. UVR is thought to induce the release and depletion of CGRP and SP from cutaneous SF’s, during the first several hours after exposure in rats (25), and to then induce adaptive increases in the anterograde transport of those neuropeptides, from the cell bodies to the peripheral terminals of PAN’s, and in the formation of new CGRP and SP in PAN’s (39). The increases in CGRP and SP in the DH have also been attributed to adaptive increases in the formation and storage of CGRP and SP in the central terminals of DRG neurons, in response to the UVR-induced release of CGRP and SP from those terminals (26,46). Those increases in CGRP and SP may also result from adaptive decreases, over the long term (39) or short term (26), in the rates of release of CGRP and SP from the peripheral or central terminals, respectively, of PAN’s (26,39). For example, the UVR-induced increases in the firing rates of DH projection neurons could activate neurons in supraspinal sites that produce descending inhibition of nociceptive transmission in the DH.
The apparent polysynaptic pathways by which UVR can produce changes in the CNS have not been precisely delineated, but TG and DRG neurons are likely to serve as the primary inputs for those changes. UVR can also cause neurons in the DH to fire spontaneously (15,61), to become sensitized to stimulus-evoked peptidergic and glutamatergic transmission (10,15,60,61), and to exhibit other changes suggestive of central sensitization or polysynaptic transmission in the CNS (1,2,9,17,29,31,46,50,65) in animals or humans. The apparent effects of UVB or UVA on the brain, as indicated by increases in plasma ACTH or -MSH (29,31) or on IEG expression (1,2) or NAT activity (65) in parts of the brain, have sometimes been blocked by ciliary ganglionectomy (31), ON transection (30) or denervation (33), hypophysectomy (31,33), or orbital enucleation (1,2). Despite the evidence suggesting that UVR induces AP’s in ON fibers (1,2,30,33), ocular UVB is known to reliably induce HSV reactivation in the TG (52) and is likely to exert prominent effects on the trigeminal system. Hiramoto et al. (31) suggested that the neuroendocrine effects of UVB exposure to only the eyes or ears were likely to have been mediated by the activation of TG neurons, in V1, and also by neurons in the ciliary ganglion/ganglia (CG) (31). The apparent effects of UVR on the CNS were more pronounced after exposure to the eyes alone than after exposure to the ears alone (29,31), and this could be explained by the exceptionally-dense trigeminal innervation of the corneas {{771}}. Additionally, corneal inflammation can increase plasma ACTH by inducing the SP-mediated activation of neurons in the Vc (6), and the UVR-induced increases in plasma ACTH (29) or -MSH (31) in mice could be explained in terms of UVR-induced changes in the firing rates or firing patterns of neurons in the Vc. Some Vc neurons project to the hypothalamus (42) and receive monosynaptic inputs from TG neurons innervating the facial skin (42). Ocular UVB exposure, in mice that had not been infected with HSV-1, also increased the concentrations of cytokines in satellite cells in the TG and in cells in the dorsal root entry zone of the Vc (52).
In contrast to the transmittance of UVR by individual, ocular tissues, such as lenses or corneas, that have been excised (11,12), it is also relevant that, in the intact eye, only ~ 2 percent of UVB reaches the lens and that the ~ 2 percent of UVA that is transmitted past the lens is likely to be absorbed by the vitreous humor (53). Sliney et al. (53) noted that fluorescence in the lens, in which tryptophan and other fluorophores can absorb UV wavelengths but emit wavelengths in the visible spectrum (62), can spuriously elevate the apparent transmittance of UVA wavelengths by the lens, and that could account for the apparent transmittance of UVA by the excised ocular tissues of nonprimate, mammalian species (11,12). The emission of light at visible wavelengths by fluorophores in the lens might have contributed to the evoked potentials observed in humans, in response to ocular UVA pulses (11), but neither UVA nor UVB is likely to act directly on cells in the retina. It should be noted that most UVR that reaches the eyes is diffuse UVR that has been heavily scattered by atmospheric gas molecules (53), and any prolonged exposure of the eyes to direct UVR could damage corneal SF’s and impact neurotransmission in the brain by atypical mechanisms.
The axons of many neurons in the TG or CG or accessory CG, in rats (38) and some mice (45) and also humans (44), extend toward the eye, within the short and long ciliary nerves, along sections of the surface of the ON (45), and it is possible that the ON denervation or transection procedures (1,2,33) severed some axons of neurons whose cell bodies are in the CG, accessory CG, or TG. Most of the sensory neurons in the TG that innervate parts of the eye are contained within the short ciliary nerves and long ciliary nerves, which are subdivisions of the nasociliary nerve, and the nasociliary nerve is a subdivision of V1 (38). Many of the TG neurons that project to the corneas, within the ciliary nerves, pass through the CG without forming synapses (38). Despite the anatomical differences among mice, rats, and humans (38,44,45), the short or long ciliary nerves that contain corneal afferents from the TG also extend along sections of the ON, just posterior to the globe, in rats (38), mice (45), and also humans (44) and could have been damaged or severed during the ciliary ganglionectomy (31,33), ON transection (1,2,30) or denervation (31,33), or orbital enucleation (1,2) procedures.
UVR exposure could influence circadian neuroendocrine rhythms and other processes in the brain, including immune privilege, by inducing low-frequency AP’s in TG and DRG neurons and thereby inducing changes in the firing patterns of neurons in the Vc or DH, and these mechanisms could be relevant to the interpretation of research suggesting that changes in sun exposure may influence the risk of developing multiple sclerosis or various cancers. Researchers could expand upon the fMRI research in UVR-exposed humans (50) or examine the changes in the CNS, in rodents, in more detail and over longer periods of time.
References
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(2) Amir S and Robinson B. Ultraviolet light entrains rodent suprachiasmatic nucleus pacemaker. Neuroscience 1995;69(4):1005-11.
(3) Andreev N, Urban L, Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 1994;58(4):793-8.
(4) Benrath J, Gillardon F, Zimmermann M. Differential time courses of skin blood flow and hyperalgesia in the human sunburn reaction following ultraviolet irradiation of the skin. Eur J Pain 2001;5(2):155-67.
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(8) Bishop T, Hewson DW, Yip PK, et al. Characterisation of ultraviolet-B-induced inflammation as a model of hyperalgesia in the rat. Pain 2007;131(1-2):70-82.
(9) Boxall SJ, Berthele A, Laurie DJ, et al. Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 1998;82(2):591-602.
(10) Boxall SJ, Berthele A, Tolle TR, Zieglgansberger W, Urban L. mGluR activation reveals a tonic NMDA component in inflammatory hyperalgesia. Neuroreport 1998;9(6):1201-3.
(11) Brainard GC, Beacham S, Sanford BE, Hanifin JP, Streletz L, Sliney D. Near ultraviolet radiation elicits visual evoked potentials in children. Clin Neurophysiol 1999;110(3):379-83.
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