I was just going to mention that the use of L-methylfolate could be another approach to the management of post-influenza hemostatic effects, given that L-methylfolate and other reduced folates appear to be active as cofactors for tetrahydrobiopterin (BH4)-dependent enzymes. It's something that researchers could investigate and that one would want to discuss with one's doctor. I think it might primarily be useful, conceivably, after the acute illness has abated, in part because BH4 is a cofactor for inducible nitric oxide synthase (iNOS) enzymes and not just eNOS. I think the higher dosage range of L-methylfolate might be useful under certain circumstances, such as in the "aftermath" of a viral illness and the oxidative stress that is associated with viral illnesses. Oxidative stress would tend to increase the rate of degradation of BH4 and to potentially increase the neopterin/biopterin ratio, thereby potentially leading to further, functional inhibition of either the formation of BH4 or of BH4-dependent enzymes (eNOS, tyrosine hydroxylase, and tryptophan hydroxylase). For example, Mittermayer et al. (2005) [Mittermayer et al., 2005: (http://ajpheart.physiology.org/cgi/reprint/289/4/H1752.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/15964928?dopt=Abstract)] found that the intra-arterial administration of BH4 counteracted the detrimental effects of intravenous endotoxin on eNOS activity, basically (or it might have acted as an antioxidant, without enhancing eNOS activity). There's a large amount of research on BH4 in humans, now, and most of it shows that BH4 does increase eNOS-dependent blood flow responses (http://scholar.google.com/scholar?q=tetrahydrobiopterin+oral+OR+orally+OR+peroral+OR+supplement&hl=en&as_sdt=2001&as_sdtp=on). It's being tested in trials in the treatment of peripheral arterial disease, and maybe it'll be covered by insurance then. It's been approved to treat phenylketonuria, but I checked the out-of-pocket cost of it. It's prohibitively expensive. There's research showing it can pretty dramatically decrease blood pressure in people who are hypertensive. If only they'd started testing it 30 years ago, in 1981 or so, when some of the first research showing its biological effects was published. In the context of Alzheimer's disease, some researchers discussed the potential for an increase in BH4 availability to limit the uncoupling of eNOS activity (and nNOS and iNOS activities) to NO formation (or to uncouple the formation of citrulline, from arginine, from the formation of NO) and thereby decrease peroxynitrite formation [Foxton et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17191137)].
From the standpoint of the effects of methylfolate or BH4 on the brain, I think that L-methylfolate could initially increase, for example, iNOS activity in astrocytes or microglia or even increase nNOS activity excessively and produce effects on mood or cognitive functioning that would initially but not "ultimately" be counterproductive. For example, the administration of L-arginine via microdialysis into the caudal ventrolateral medulla (CVLM) augmented the pressor response to muscle contractions, but the arginine produced the opposite effect when administered into the rostral ventrolateral medulla (RVLM) [Freda et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10320724)]. Those effects could be explained in terms of differences in the anatomical "localization" of nitrergic inputs to glutamatergic neurons that provide excitatory inputs to the preganglionic sympathetic neurons in the RVLM, but most of these articles don't provide many details on the anatomy [Zanzinger et al., 1998: (http://ajpregu.physiology.org/cgi/reprint/275/1/R33.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9688957?dopt=Abstract)]. Another article found a pressor effect of arginine in the CVLM [Rampin and Giuliano, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10899272)] (I just glanced over part of that and thought that was on cardiovascular reflexes only). But the general idea is that nNOS-derived NO tends to be excitatory and to bind directly to NMDA receptors or to otherwise increase glutamatergic transmission, such as by amplifying the excitatory effects of NMDA receptor activation. But that's not really the way BH4 behaves in models of hypoxia or ischemia. There's some research showing that it worsens the damage, but a lot of it shows neutral or beneficial effects. Those parts of the medulla are mainly involved in cardiovascular reflexes, but the same type of concept applies to the nitrergic regulation of the firing rates of noradrenergic neurons in the locus ceruleus or of dopaminergic neurons, etc. BH4 or methylfolate could enhance nNOS activity and, by that mechanism and its function as a cofactor of tyrosine hydroxylase, exert an excitatory influence on dopaminergic and noradrenergic transmission (and serotonergic transmission), but there could be an initial enhancement of nNOS (and eNOS and iNOS) activity/activities and then a subsequent "normalization" of the nitrergic transmission. The increases in NO release, induced by BH4 or methylfolate, could, relatively rapidly, lead to a kind of new, equilibrium state and restore the normal extent to which nNOS-derived (and iNOS-derived) NO produces autoinhibition of nNOS and iNOS activities. For example, these authors [Galijasevic et al., 2003: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=299800)(http://www.ncbi.nlm.nih.gov/pubmed/14657339)] found that the presence of myeloperoxidase, a heme-containing enzyme present in neutrophils and other cell types, could function as a nitric oxide scavenger but paradoxically disinhibit iNOS activity by relieving the constitutive, autoinhibitory influence that iNOS-derived NO exerts on iNOS activity and that is thought to be largely responsible for the maintenance of iNOS activity at between 20 and 30 percent of its maximal rate (Galijasevic et al., 2003). The autoinhibition phenomena is a real phenomenon and isn't just a theoretical mechanism. I actually observed that type of phenomenon (in my opinion) when I took significant dosages of methylcobalamin during infectious mono, and it was mainly apparent when I increased the dosage (these were reasonable but sort of large dosages, as in 10 mg/d, even though there are 15 mg dosage forms of methylcobalamin now) and took it on an empty stomach. It always took 2 hours+ to be absorbed on an empty stomach (apparently because it's all bound to B12 binding proteins or forms some sorts of insoluble complexes?), and it behaved, initially, like a nitric oxide donor but then rapidly ceased to produce that type of effect (the migrating myoelectric complexes that drive gastric motility in the fasted state occur every 1.5 to 2 hours, incidentally, and "reset" upon the ingestion of small amounts of food, meaning it would take about 2 hours for the small amount of food to begin entering the small intestine, assuming it was part of a molecule too large to be transported into the small intestine in solution, by solvent drag or whatever, between the cells). It was possible to tell these things because of all the upregulation of iNOS activity, in response to the viral illness, etc. The point is that nitrergic effects, in response to something like methylfolate, seem to exhibit a kind of tachyphylaxis, and that's consistent with the transience of the inhibitory effects of high dosages of nitrate-derived NO on platelet function. There's an initial inhibition of platelet activation and platelet functions, but there's rapid adaptation/tolerance to the effect. But there still is a nitrergic effect of higher dosages of methylfolate, in the longer term, that's less pronounced than the effects that occur in the short term, in my opinion. In this article on the use of BH4 in the treatment of depression [Curtius et al., 1983: (http://www.ncbi.nlm.nih.gov/pubmed/6131342)], there was a delay of a couple of days until the maximal mood-elevating effect emerged, and the dosage regimes used in the articles on the use of BH4 itself, in treating depression, are bizarre. The authors (Curtius et al., 1983) used a dose that was probably excessively-high (1 g once and then a 100 mg/d maintenance dosage) and that could have compromised the efficacy of the BH4, in my view, given the potentially counterproductive effects that excesses of NO can have on glutamatergic and monoaminergic transmission, etc., in relation to mood or cognitive functioning. But the authors also were using tyrosine at a high dosage, and tyrosine has the potential to worsen depression, in my opinion, particularly at the high dosages that can allow for the autoinhibition of tyrosine hydroxylase activity by tyrosine itself to become significant. But the point is that the 100 mg/d dosage (used in other case reports, also) is similar to the highest dosage (90 mg/d) of methylfolate that's been used in small trials, in the treatment of depression. And the timecourse with which the changes in mood (or, by extension, in something like blood flow, etc.) emerged are consistent with some sort of adaptation to a change in nitrergic transmission. I generally haven't found that Rx L-methylfolate produces any more benefits at dosages above ~50 mg/day, but this hasn't always been the case. I just think that one has to work with one's doctor and try to individualize the dosage in a way that's appropriate for oneself, as an individual. In other words, there may be a significant need to individualize the dosage, and an awareness of some of the mechanisms by which BH4 acts, in the brain, may be useful in...the individualization of the dosage, etc.
No comments:
Post a Comment