This article [Berson et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8964414)] discusses the capacity of tacrine to produce uncoupling in mitochondria and to increase respiration, and I was noticing the crude structural similarity between tacrine and some of the tricylic antidepressants (http://scholar.google.com/scholar?q=tacrine+imipramine+tricyclic&hl=en&safe=off&num=100&um=1&ie=UTF-8&oi=scholart). Tacrine is sort of an extreme example, in my opinion, but some tricyclics also can produce some slight uncoupling effects in mitochondria (i.e. of redox reactions from oxidative phosphorylation) [see, for example, references in Wong et al., 2004: (http://149.142.238.229/pgxlab/docs/Wong-SJW-2004-MP.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/14743185)], and hypericin (which is a planar molecule that, in the sense that a planar ring system is one structural feature of some uncouplers, is structurally "similar," in a very general sense, to tricyclics), for example, can either facilitate or inhibit uncoupling in mitochondria (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=hypericin+mitochondrial+respiration). Some of the articles on uncoupling that I've cited in past postings provide better discussions of planar, "heterocyclic" ring systems being a structural feature of uncouplers, but here are some references (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=planar+uncoupling+mitochondria+orbital). I'm having trouble getting full texts of these types of articles, but I think the tricyclics can either assume planar or stacked-planar conformations that may explain their uncoupling effect [Maxwell et al., 1970: (http://jpet.aspetjournals.org/cgi/content/abstract/173/1/158)]. I forget what the conformational flexibility of that type of heterocyclic ring system, with the seven-carbon ring, is like. (In any case, it's not even really relevant to the discussion.)
Uncoupling is not always bad and is thought to be protective under many sets of circumstances. For example, uncoupling can protect against the generation of reactive oxygen species. I wonder if mild uncoupling contributes to the antidepressant effects of some tricyclics or to the St. John's Wort (SJW) extract. People may well have discussed this possibility in some articles, and I haven't really looked into it. The main problem some people have with SJW extract, which has considerable evidence to support its effects or usefulness or whatever, as an adjunctive antidepressant approach, is the photosensitivity. And I should mention that extended, planar ring systems, in compounds, are thought to mediate the photosensitizing effects of many compounds. There's actually a surprising amount of evidence suggesting that rutin, which I think is not photosensitizing and is sold separately, may contribute to the supposed antidepressant effects of SJW extracts (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=rutin+antidepressant). That research on rutin actually looks kind of questionable to me, and I'm inclined to doubt it does actually contribute to the effects of SJW. But that's just my opinion, and I put these types of things on the blog (as I come across them). I have no idea about that.
But Wong et al. (2004) note that, in animals, tricyclics have sometimes been shown to initially (within the first 7 days) increase glucose uptake or oxidation in the brain initially, consistent with a stimulation of respiration/oxygen uptake, resulting from a mild uncoupling effect. Subsequently, after 28 days, the rate of glucose oxidation was decreased, in response or as an adaptation to the presence or higher concentration of the tricyclic (reference 49, discussed on page 11). I wonder if that might partly explain the delay in the onset of the effects of tricyclics, etc.
These are crude thoughts, but the initial effect of an uncoupler on ATP production tends to be sort of neutral, from what I can tell. For example, the research on the apparent and mild uncoupling effects of beta-hydroxybutyrate or acetoacetate or sodium butyrate infusions in humans or animals, discussed in a fairly recent posting, shows that there can be a slight, initial decrease in the rate of ATP production in response to the presence of an uncoupler (in response to the proton cycling by the protonated form of the short-chain fatty acid, although it's not clear that ketones or short-chain fatty acids produce true uncoupling--they appear to produce something similar to it or may produce it indirectly). Then, there is a stimulation of respiration, in response to that initial effect, and an increase in oxygen uptake (producing the thermal effect, or thermogenic effect that is observed in response to i.v. beta-hydroxybutyrate infusion, etc.) that tends to offset some of the pH changes (at least in response to ketone infusion) and other initial effects of the mild uncoupling. That's thought to account for the increase in glucose utilization. Maybe there's some sort of adaptation that contributes to antidepressant effects. Creatine, for example, stimulates respiration, although it's not really an uncoupler, as far as I know. It's sort of the opposite. But maybe it's not so much about uncoupling vs. the inhibition of uncoupling. Maybe there needs to be some sort of shock to the status quo, in terms of state III vs. state IV respiration, such that drugs or compounds can produce opposite effects initially but lead to the same net, adaptive increase or decrease in respiration (the animal research seems to suggest that tricyclics can produce some adaptive decrease in respiration, almost in a way that's reminiscent of the effects of an increase in ketone oxidation by neurons or astrocytes). Tianeptine, for example, actually increases serotonin reuptake and has been used as an antidepressant (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=tianeptine+%22serotonin+reuptake%22), and the serotonin reuptake inhibitors are obviously one class of antidepressants. That's not much of an argument and is not evidence of much of anything, for many reasons, but the point is that one can, in some instances, arrive at the same net effect (among different individuals or even in the same individual) by administering either two treatments or compounds that have more or less opposite effects, etc.
In any case, an increase in noradrenergic transmission, such as would occur in response to tricyclics, also tends to stimulate oxidative metabolism in astrocytes [this is a really crude search: (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=noradrenergic+glycogen+astrocyte+respiration+OR+oxidation)]. So the effects of uncoupling could work in concert with the supposed astrocyte-glycogenolytic (and subsequent rebound increase in glycogen formation, as a phenomenon that displays a crude similarity to glycogen supercompensation) effect of an increase noradrenergic transmission, and the uncoupling effect and noradrenergic mechanisms would not be mutually exclusive. There's actually some evidence to suggest that there is a kind of glycogen supercompensation in the brain, in astrocytes, in response to glycogen depletion (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22glycogen+supercompensation%22+brain). In any case, creatine can increase glycogen storage/supercompensation in skeletal muscles (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=creatine+glycogen) and has been shown to produce antidepressant effects at low dosages (i.e. 3 grams/day or less) in three small studies (discussed in previous postings). In this search, one can see additional studies in which creatine's effects on "mood" were evaluated in a sort of informal or subjective way (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=creatine+monohydrate+antidepressant+OR+mood). There are other lines of evidence, but some of those articles are interesting.
No comments:
Post a Comment