This article [Xia et al., 1996: (http://www.pnas.org/cgi/reprint/93/13/6770.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/8692893)] is one of many showing that depletion of intracellular arginine tends to increase peroxynitrite formation by multiple mechanisms. When nitric oxide synthase (NOS) enzymes are not occupied by arginine or are competitively inhibited by asymmetric N(G),N(G)-dimethylarginine (ADMA) or by other methylarginines, which are inhibitors of NOS enzymes that are produced normally during the breakdown of proteins, the NOS enzymes produce superoxide and can also produce NO and superoxide at the same time. The NOS-derived NO and superoxide tend to react to form peroxynitrite. The depletion of cytosolic arginine by roughly half produced a fivefold increase in the sensitivities of the cells to a cytotoxic stimulus that increased nNOS activity. Similarly, Xia and Zweier (1997) [Xia and Zweier, 1997: (http://www.pnas.org/cgi/content/full/94/13/6954)] found that arginine depletion from activated macrophages produced large increases in peroxynitrite levels, and these increases were almost entirely blocked by either 1 mM extracellular arginine or 1 mM extracellular urate (the form that uric acid is in at physiological pH values).
This is relevant to the effects of arginine and purines in the brain. I think that maintaining an adequate urate level in the cerebrospinal fluid and also intracellularly, in neurons and astrocytes, is likely to be really important for maintaining cellular energy metabolism and also for maintaining the normal nitrergic regulation of noradrenergic and dopaminergic transmission, such as through the effects of nitric oxide on NMDA receptor activation. Roitman et al. (2007) [cited here: (http://hardcorephysiologyfun.blogspot.com/2009/03/arginine-agmatine-and-nitric-oxide-in.html)] noted some of the evidence that impairments in cellular energy metabolism can be found in people with depression and other psychiatric symptoms. Phosphocreatine (PCr) levels have been shown, in research using magnetic resonance spectroscopy techniques, to be drastically depleted in the brains of people with depression, for example (cited in Roitman et al., 2007). Mitochondrial dysfunction and ATP depletion would reasonably be expected to produce PCr depletion, even in the absence of a deficit in the formation of new creatine from arginine, etc. There's actually a large amount of research showing protection by uric acid/urate against mitochondrial damage due to peroxynitrite (inactivation of complex I and mitochondrial dysfunction) (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=mitochondrial+peroxynitrite+uric+OR+urate).
The reason I didn't see those articles in the past is that I think the authors of many articles showing protective effects of urate tend to not mention multiple sclerosis or Parkinson's disease, two neurodegenerative diseases in which inosine, a precursor of urate, is being tested (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=Parkinson%27s+uric+OR+urate); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22multiple+sclerosis%22+uric+OR+urate)]. They would be much better off (and would, in my opinion, get substantially more robust therapeutic effects) using guanosine and adenosine monophosphates or triphosphates as precursors of urate instead of inosine, in my opinion, but that's beside the point. The research tends to be very focused in on one little area, and I've never seen those articles on mitochondrial protection, by urate, cited in the context of Parkinson's disease or MS. But the potential for the protection, by urate (or arginine), against the compromising of cellular energy metabolism, by peroxynitrite, would be very important, in my opinion, in the contexts of those and other disorders. West et al. (2002) [cited here: (http://hardcorephysiologyfun.blogspot.com/2009/03/arginine-agmatine-and-nitric-oxide-in.html)] cited research showing that peroxynitrite tends to decrease dopamine release (as in tonic, excitatory, nitrergically-mediated dopamine release), and that's obviously relevant to cognition and psychiatric conditions. I think the peroxynitrite-reducing potential of arginine would be more likely to be effective in combination with normalization of CSF and intracellular urate levels in the brain. If a person's plasma urate (blood uric acid) is already high, the person wouldn't need to do this. But the notion that any old urate level is as "good" as any other, within the normal range, is not defensible, given the overwhelming evidence, in my opinion, showing major effects across small increments in extracellular and, by extension, intracellular urate concentrations. I don't have time to go into the articles showing high intracellular urate levels, but the main idea is, in my opinion, that the use of urate as a peroxynitrite scavenger makes the use of most other antioxidants look like child's play. The concentrations of urate that scavenge peroxynitrite meaningfully, in vitro, are comparable to achievable and normal in vivo concentrations (this is not the case at all for many antioxidants). The concentrations of urate, both intracellularly and extracellularly, are much, much higher than the concentrations one is going to achieve with most antioxidants, in my opinion. Additionally, urate is less like an antioxidant scavenger of peroxynitrite than it is like a peroxynitrite "sink" and is, for the most part, excreted. It is not regnerated (doesn't need to be regenerated) by oxidoreductase enzymes but can actually be degraded, in a series of intramolecular degradative reactions (to allantoin or other molecules), upon its nitrosylation/nitration/etc. That's a really unique property that sets it apart from most other so-called "antioxidants" that consume reducing equivalents in their regeneration. I do think there's a lot of validity to the peroxynitrite-reducing effects of arginine in the context of brain disorders [Wiesinger, 2001: (http://www.ncbi.nlm.nih.gov/pubmed/11275358)], but I think that approach would work better in combination with normalization of urate levels. Obviously, one should discuss this type of thing with one's doctor.
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