This article [Brunengraber and Roe, 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16763895)] discusses the anaplerotic effects of pyruvate and of odd-chain fatty acids or related compounds (such as propionyl-L-carnitine, which is a "precursor" of propionyl-CoA, an odd-chain acyl-CoA), but the authors also mention that glutamine or glutamate can be anaplerotic and protect against the damaging effects of postischemic reperfusion (the restoration of blood flow that follows a reduction in blood flow) on the heart or other tissues. Researchers have done a lot of research on the glutamate-glutamine cycle in the brain, and it's known to be really important for cellular energy metabolism [Newsholme et al., 2003: (http://www.erin.utoronto.ca/~w3bio452/452%20Papers%202004/GlutamateRev%20CellBiochemFunc03.pdf) (http://www.ncbi.nlm.nih.gov/pubmed/12579515)]. I think the research on glutamine metabolism in the brain, in relation to the tricarboxylic acid (TCA) cycle activity and glucose utilization in general, hasn't really sunken in. The vast majority of research focuses on the damaging effects or neurophysiological effects of extracellular glutamate, which is obviously of central importance to neurotransmission in the brain and to most aspects of brain functioning. But there seems to be an assumption that, in the context of disease states that produce cognitive impairment or psychiatric symptoms, the cellular energy-related side of the glutamate-glutamine cycle is either undisturbed or is disturbed only with relevance to glutamatergic neurotransmission per se. In my opinion, this is not a valid assumption. I think there's a tendency to think in terms of either-or's, to assume that the absence of dramatic, cerebral edema produced by hyperammonemia is an indication that the glutamine-glutamate cycle is functioning with pristine efficiency. I've tended to think that way, but, in view of things I've read, I'm starting to doubt that that's the case. There's a vast amount of research on the use of glutamine or alpha-ketoglutarate, usually in conjunction with arginine (or ornithine), to support protein synthesis in the context of catabolic disease states, such as cachexia due to cancer or viral illnesses or burn injuries. There are too many articles to cite on that topic, but I think that there could be some potential for manipulating, in the context of some disease states, the glutamine-glutamate cycle in the brain. That's just my opinion, and there's research using nucleotides in combination with arginine and glutamine or alpha-ketoglutarate to support, in just about every organ system or tissue other than the brain, recovery from cellular injuries. I'm not sure why this would be any different for the brain, and glutamine and alpha-ketoglutarate have not been shown to produce effects that are similar to monosodium glutamate. That's just my opinion, however, and there would obviously be potential for harm in people with specific brain diseases or liver or kidney diseases. A person should obviously talk with his or her doctor before taking any supplement.
There's a lot of research showing that arginine depletion produces fatty liver by, in part, disrupting pyrimidine biosynthesis and causing orotate accumulation, and the relevance of this goes beyond the issues related to liver disease. I don't have time to go into this in depth now, but, in my opinion, something like arginine alpha-ketoglutarate could be useful in, for example, allowing a person to begin an exercise program, to get it off the ground, etc. I'm not going to refer to any specific disease states, but, in any case, physical exercise puts demands on not only muscle cell energy metabolism but brain energy metabolism [Dalsgaard et al., 2002: (http://jp.physoc.org/cgi/content/full/540/2/681) (http://www.ncbi.nlm.nih.gov/pubmed/11956354?dopt=Abstract)]. Exercise increases the transport of lactate into the brain significantly, and even the "intent to exercise," to perform intentional motor movements, influences brain cell energy metabolism (Dalsgaard et al., 2002). This could be related to the anticipatory increase in the firing rates of noradrenergic neurons in the locus ceruleus (LC), for example, in much the same way as thinking about stressful situations can activate the LC-mediated, noradrenergic "stress response" system. There's a large amount of research showing this type of metabolic stress that is imposed by exercise on the brain, but, for some reason, there seems to be resistance to the idea that these are relevant under normal circumstances. I mean that researchers keep seeming to want, in my opinion, to say that there's no reason for people to be alarmed and that people will always get beneficial effects from exercise. But the fact remains that many people do not sustain even basic exercise programs, and one reason for this, in my opinion, is that these types of mechanisms, involving the brain, come into play.
I was going to put this general information up about arginine vs. ornithine. A lot of the authors of articles on ornithine alpha-ketoglutarate do not seem to realize the potential for detrimental effects that, in my opinion, can result from mass-action effects of exogenous ornithine on arginine:glycine amidinotransferase (AGAT), the first enzyme in creatine biosynthesis. This enzyme catalyzes the reversible conversion of arginine and glycine into guanidinoacetate and ornithine. Exogenous arginine+glycine have been shown to increase creatine biosynthesis in humans [Crim et al., 1976: (http://jn.nutrition.org/cgi/reprint/106/3/371.pdf)], and the combination of exogenous ornithine, limitation of dietary arginine, and exogenous creatine can suppress AGAT activity in people with guanidinoacetate N-methyltransferase deficiency (a genetic disorder) [Stromberger et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/12889668)]. The key point is that an increase in the ratio of dietary ornithine to arginine can decrease guanidinoacetate formation and thereby reduce creatine biosynthesis. Taking exogenous glycine is not, in my opinion, a good idea, but Arias et al. (2004) [Arias et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15234335)] noted that excessive ornithine accumulation, in people with impairments in the activities of urea cycle enzymes, can suppress creatine biosynthesis by producing a reversal of AGAT activity. Arias et al. (2004) also noted that exogenous arginine can enter the brain much more easily than creatine can, and creatine is known, as Arias et al. (2004) discussed, to have neuroprotective and even trophic effects on the brain. If AGAT activity were suppressed outside the brain by ornithine excesses, the contribution of peripheral guanidinoacetate to the brain's creatine pool could, in my opinion, be compromised. More importantly, an excessive accumulation of ornithine in the blood could, in my opinion, enter the brain and suppress de novo guanidinoacetate production by AGAT activity that occurs within the brain (the brain makes much of its own creatine de novo).
As I've said in past postings, arginine, in my opinion, is safer than ornithine, and I don't personally think exogenous creatine supplementation is a good idea. Arginine and nucleotides could conceivably, along with reduced folates and vitamin B12 (which could be expected to disinhibit GAMT activity and increase de novo creatine biosynthesis in the brain, by increasing the ratio of SAM-e to S-adenosylhomocysteine, while simultaneously limiting the accumulation of neurotoxic guanidinoacetate), help to maintain creatine levels in the brain and would not, in my opinion, pose the same kinds of risks that exogenous creatine could conceivably pose, under certain circumstances. Exogenous nucleotides have been shown to help maintain the phosphocreatine to inorganic phosphate ratio during ischemic conditions [Iwasa et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10906568)], and Silveri et al. (2003) [Silveri et al., 2003: (http://www.ncbi.nlm.nih.gov/pubmed/14550683)] found that oral SAM-e increased phosphocreatine levels in the brains of people and decreased beta-nucleoside triphosphate levels. One interpretation of that article is that SAM-e increased the overall pool of purines and, in particular, adenosine nucleotides but did not influence the overall adenylate charge, as implied by the authors, and the elevation in phosphocreatine levels, in my opinion, could be due to an elevation by the SAM-e of the overall ADP+AMP+ATP pool, in spite of an apparent decrease in the absolute nucleotide triphosphate levels. I say this because Renshaw et al. (2001) [Renshaw et al., 2001: (http://ajp.psychiatryonline.org/cgi/content/full/158/12/2048) (http://www.ncbi.nlm.nih.gov/pubmed/11729024)] found decreases in the levels of purines in some people with depression and proposed that the antidepressant effects of SAM-e may be due to the elevation in adenosine (and, in my opinion, the overall purine pool) derived from S-adenosylhomocysteine hydrolase activity. I discussed this in relation to the likelihood, in my opinion, that exogenous nucleotides are likely to have superior bioavailability to SAM-e (http://hardcorephysiologyfun.blogspot.com/2009/01/details-on-nucleotides-bioavailability.html). Exogenous creatine has been researched in the treatment of unipolar, treatment resistant depression, [Roitman et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17988366)] but, in my opinion, exogenous creatine poses risks on a number of levels. That said, that type of approach involving the use of arginine alpha-ketoglutarate, nucleotides, and strategies aimed at disinhibiting GAMT activity could, in my opinion, have some sort of potential to maintain creatine levels in the brain and be applicable to conditions that are characterized by disruptions in brain cell energy metabolism. But that's just my opinion.
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