Note on Purines in Nonhuman Species; Neuroprotective Effects of Purines

One thing that allows rodents and other species to tolerate larger doses of purines is that humans and a couple of monkey species, I think, (this article confounds that issue: http://www.ncbi.nlm.nih.gov/pubmed/3928241) are the only species that have no urate oxidase activity. In humans, urate can degraded to allantoin in a series of successive, nonenzymatic nitration or nitrosylation reactions, but effectively the same reaction is done enzymatically in most other species. People have suggested the loss of urate oxidase may have contributed to cognitive development in hominids or something, but that's not my area. I can't find the references quickly.

The thing is, though, purines have really powerful neuroprotective and neurotrophic effects, and they have potential uses in treating brain injuries. I know one pharmaceutical company is testing an intravenous inosine preparation in treating either strokes or some sort of brain injuries, and that would be the way to do it. But there are many articles showing that oral guanosine or guanosine monophosphate have fairly significant effects on the brain, at remarkably low doses. Also, it's not true that oral purines are all degraded into uric acid in the intestinal tract. Researchers would have to consider the pharmacokinetic aspects, though, and also use forms of purines that are actually soluble (the disodium salts of the monophosphates are soluble, and the other forms have much more limited solubility). Here's one reference showing that oral inosine is absorbed intact and elevates plasma hypoxanthine and, nonsignificantly, inosine (and also xanthine): (http://www.ncbi.nlm.nih.gov/pubmed/11912550). There's a lot of animal research showing neuroprotective effects of inosine, but I'm forgetting what the status of the human research is. Here are some examples of neuroprotective effects of inosine (this will help me collect some of these):

http://atvb.ahajournals.org/cgi/content/full/25/9/1998
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/15976325?dopt=Abstract)

http://www.inotekcorp.com/publications/pdf/ipcpub306.pdf
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/15019271)

http://www.iovs.org/cgi/content/full/45/2/662
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/14744912?dopt=Abstract)

http://stroke.ahajournals.org/cgi/content/full/36/3/654
(pubmed: http://www.ncbi.nlm.nih.gov/pubmed/15692110?dopt=Abstract)

http://www.ncbi.nlm.nih.gov/pubmed/15146976 (tests guanosine and adenosine also)

There are tons of them, but here's a long and frequently-cited review on the neurotrophic effects of purines:

http://www.ncbi.nlm.nih.gov/pubmed/10845757

There is this concentration issue, the fact that some studies in vitro use very high concentrations, but the effects in vivo, in animals, are really significant and suggest that it would be possible to use purines over the longer-term, at lower dosages, to treat traumatic brain injuries, to enhance recovery after strokes, etc. The issues with the interactions of purines with other aspects of metabolism, such as mitochondrial DNA turnover and so on, are really interesting to me.