This is a fringe topic that I wouldn't expect much from, in the way of therapeutic effects in any disease state, but I find it mildly interesting. There are these puzzling articles showing that oral gamma-aminobutyric acid (GABA), a neurotransmitter or "signalling molecule" [if one wants to cling to the notion, as some people apparently do, that it doesn't always act as a neurotransmitter--in fact, the reverse transport/uptake of GABA, from the cytosol to the extracellular fluid, can occur, given that a cytosolic pool, in neurons, is separate from the vesicular pool and can serve to export GABA in a somewhat-frequency-independent manner: Waagepetersen et al., 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11170185)], can reduce blood pressure in humans and animals (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=GABA+antihypertensive+oral+OR+orally) and can release growth hormone in humans [Cavagnini et al., 1980a: (http://www.ncbi.nlm.nih.gov/pubmed/7376786); Cavagnini et al., 1980b: (http://www.ncbi.nlm.nih.gov/pubmed/7419665); Powers et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18091016)]. This seems puzzling at first glance, given that GABA is not known to be able to cross the blood-brain barrier to any significant degree. In contrast to the case of glutamine, in which researchers have drawn erroneous conclusions about the pharmacology of glutamine, I think the research on GABA was done more carefully, back when some of the earlier anticonvulsants were being developed. I think that the oral GABA, administered to the people or animals in those articles, just underwent transamination to glutamate and succinate semialdehyde in hepatocytes and then, after the conversion of succinate semialdehyde to succinate, by succinate semialdehyde dehydrogenase, entered the tricarboxylic acid cycle as succinate. That could produce a decrease in plasma free fatty acid concentrations and induce GH release, even though it doesn't look like GABA is a very strong or reliable GH releaser, in my opinion. The site of action could be in the liver or in adipocytes, I guess. Glutamine probably releases GH, in part, by suppressing lipolysis in adipocytes or in the skeletal muscles, outside the brain, and thereby decreasing FFA levels. Glutamine can also increase the oxidation of fatty acids, under some circumstances, and that type of effect could occur with succinate. Powers et al. (2008) suggested that the metabolism of the GABA in the liver had increased the export of some amino acid by the liver and thereby led to GH release (upon the entry of some amino acid, other than GABA, into the brain), and that's possible. But the use of the 3-gram dosage of GABA would argue against that conclusion, given that no known "metabolite" of GABA is known to induce GH release, by way of its entry from the blood into the brain, in amounts in the range of 3 grams or, I should say, in amounts crudely or even nearly equimolar to the 3-gram dosage of GABA. It's conceivable that changes in plasma amino acids, following the metabolism of GABA in the liver (see Ferenci et al., 1988, cited below), suppressed lipolysis in adipocytes, but I think that the GABA-derived succinate may have just increased fatty acid oxidation in the liver. Succinate is known to stimulate oxidative metabolism, etc. [this is not a great example, but it's still an interesting article: Endlicher et al., 2008: (http://www.biomed.cas.cz/physiolres/pdf/prepress/1635.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/19093725)]. A transient increase in beta-oxidation is a sort of generalized outcome that can result from changes in the ratios of TCA cycle intermediates, but I don't want to get into all of that.
Also, the suggestion by Powers et al. (2008) (and by Cavagnini et al., 1980b, in the abstract of one of those articles I can't get the full texts of) that the reversal of the oral GABA-induced GH release by pimozide and not domperizone provided evidence of a central site of action (i.e. in the brain) of oral GABA is not valid. If GABA reduced the plasma concentration of free fatty acids, the effect would be to disinhibit some of the neurobiological mechanisms that normally inhibit GH release from the pituitary (FFAs act on the pituitary to suppress GH release). The fact that a D2 dopamine receptor antagonist like pimozide blocked the effect does not mean that GABA had to have entered the brain. All that is necessary, in the absence of pimozide or whatever other centrally-acting drug that reduces the GH release in response to a decrease in FFAs, is for a reduction in plasma FFA levels to occur. The research on growth hormone releasers can be mind-bending, because, at first glance, it seems like a study like that is saying that oral GABA has some kind of bizarre, inexplicable, dopaminergic effect. It doesn't mean that. There are all sorts of neurotransmitter systems that converge and interact in complex ways in the hypothalamus and regulate GH release. It's like watching a tire on a green car go flat and cause a traffic jam, when it blocks one of the lanes, and then concluding that traffic jams are caused by green cars but not yellow or red cars (or concluding that the flat tire must have been caused by something on the highway, when it could have been caused by something outside the highway, as in the case of GABA). In reality, a car of just about any color could get a flat tire (analogous to the drug that blocks some GH-releasing effect) and cause a traffic jam, as in the hypothalamic regulatory "highway" that governs GH release. I'm sorry to have to resort to analogies, but it's easier than trying to get into all the nightmarishly-complex neuroanatomy.
Another reason I'm interpreting the research this way is that oral GABA is very efficiently transported into the livers of rats and, following its metabolism into succinate, oxidized to CO2 [Ferenci et al., 1988: (http://www.ncbi.nlm.nih.gov/pubmed/3391367)]. It's also interesting that, in the brain, GABA, through its conversion to succinate in the so-called "GABA shunt," is thought to make a surprisingly large contribution to oxidative energy production in neurons and astrocytes [Patel et al., 2005: (http://www.pnas.org/content/102/15/5588.full.pdf+html)(http://www.ncbi.nlm.nih.gov/pubmed/15809416)]. Also, propionylcarnitine and C5 ketone bodies are thought to exert their anaplerotic effects by entering the TCA cycle as succinyl-CoA, which is then converted to succinate by succinyl-CoA ligase. That enzyme has about 20 different names, and I discussed it in past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/vitamin-b12-succinyl-coa-ligases-and.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/plausible-mechanism-for-inhibition-of.html)]
I should say that at least one of the articles showing antihypertensive effects of oral GABA, in animals, is bizarre and basically can't be true, because the authors found some effect from 0.5 mg/kg bw of oral GABA. That scales to a human dose of 7.5 mg or something, and I just can't see how that could be true. All of it would be taken up by the liver. Even if one used a dose of 0.5 mg/kg for a human, the dose would be 35 mg for a 70-kg human. How could that possibly produce any biological effects? In any case, I thought this was vaguely interesting, but I can't really see any obvious therapeutic applications.
No comments:
Post a Comment