Uric Acid, PARP, etc.

I've been reading about ribose in the context of neuroprotection, and I'm not sure. The jury's still out on its usefulness in the context of the post-ischemic, neurotrophic effects one would be looking for, in the context of neurodegenerative diseases, from it. There's a whole series of articles on the use of ribose in replenishing ATP in cardiac myocytes after partial ischemia (reduction in the appropriate blood flow). There are some issues with those studies, though, mainly because the changes that follow chronic, mild ischemia or ongoing deficits in mitochondrial activity, as occur in diseases like Alzheimer's, are different and more complicated than the changes in ATP that follow a single episode of experimental ischemia. I got the basic toxicological information on it (ribose), and I'll put it up tomorrow, maybe.

Here's a link to one of the articles that shows some of the neuroprotective effects of uric acid, though. Purines, especially, have really strong neurotrophic and neuroprotective effects, and inosine has been used (to elevate uric acid, among other effects) with some success in preventing relapses in multiple sclerosis. Many people with multiple sclerosis have pathologically low uric acid levels, but the time course required to restore normal uric acid levels, in people with M.S., implies that the inosine is gradually being used to replenish purine nucleotide levels. It took a long time in one article, and another article showed that 2 grams of inosine didn't elevate uric acid much at all in some people. Inosine definitely is converted into uric acid, and in normal people, the elevations in uric acid are very rapid. It's possible to double uric acid levels in athletes in 5 days, whereas there can be this plodding, impossibly long time period of replenishment in people with M.S. Oral inosine does, in fact, elevate plasma hypoxanthine and inosine, and this indicates that some would reach the brain or endothelial cells in cerebral blood vessels and be converted into GMP and AMP, etc. I'll put up the links to these things at some point. There's reason to think oral guanosine monophosphate or other purines would be more effective than inosine for M.S., however, for that reason (elevation of hypoxanthine and inosine in the blood following oral absorption, meaning that guanosine would be more potent in replenishing purine levels in the brain) and other reasons.

Despite the problems with delivery and the nightmarish (to see) way in which research on treating strokes is done (and despite the potential downsides and delivery problems), purines and nucleotides, in general, are really promising. I'll probably end up writing a lot more about them, as I read more and explore the issues. Here's one of many articles on the neuroprotective effects of elevating uric acid (exists mainly as urate in the body), even though I doubt peroxynitrite scavenging is the only mechanism. I bet there's some effect on buffering purine export or metabolism--something--from cells under ischemic conditions, during or after the experimental conditions showing neuroprotective effects by urate. Anyway (shows that uric acid works partly by inhibiting PARP activity, partly, but probably not entirely, by inhibiting peroxynitrite-induced DNA damage or other PARP-inducing effects):

http://www.pnas.org/content/102/9/3483.full