This is a really interesting article [Sahlin et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10502075)], and the authors found that plasma hypoxanthine increased by a mean of 7.78-fold during exercise in humans. There was some variation in the magnitudes of the increases in plasma hypoxanthine among individuals. The increases in plasma uric acid (urate) and xanthine, which is derived from the metabolism of hypoxanthine by xanthine oxidoreductase (xanthine oxidase is technically a modified form of xanthine reductase that's been modified by proteolytic cleavage, etc., but people typically refer to the enzyme activity as being "xanthine oxidase" activity), were larger in terms of the amounts of those purines formed, but the percent increases were lower (mean increases of 5 percent for urate and 223%, or a 2.23-fold increase, for xanthine). The effect of that increase in plasma hypoxanthine on the brain should not be underestimated. In a past posting, I discussed some of the research showing neuroprotective effects of remarkably low doses of hypoxanthine [Mink and Johnston, 2007, cited and discussed here: (http://hardcorephysiologyfun.blogspot.com/2009/03/protection-against-postischemic-damage.html)]. There's still the fact that the exercise-induced increases in neuronal activity in the brain would be expected to substantially, albeit transiently, increase the rates of purine export from neurons. I can't immediately find any articles showing elevated cerebrospinal fluid hypoxanthine and xanthine and urate levels, following exercise, but it's very likely that those elevations would occur, in my opinion, especially following high-intensity exercise. So that supposed depleting effect of exercise on neuronal and astrocyte purine nucleotide levels would be expected to lessen the impact of an increase in the plasma hypoxanthine level. I would think that, as a person's muscle mass increased over time, the muscles' capacity to export hypoxanthine would be increased and would produce more significant effects on the brain. But the person would, in my opinion, keep having to push the limits and produce glycogen depletion, as discussed below. Other researchers have discussed the effects of muscle-derived purines on the brain. There's one article from 1978 or 1979 that discusses the potential effects of exercise-induced elevations in extracellular ATP, released from endothelial cells, on the brain, but the authors focused too much on ATP per se. Extracellular ATP is rapidly degraded to ADP and then adenosine and hypoxanthine, etc., and so one would expect to see much more of an effect of exercise on adenosine or hypoxanthine than on ATP. I mean that the purines that might be expected to enter the brain in significant amounts, during exercise, and to also exert meaningful effects on nucleotide pools in neurons or astrocytes would be hypoxanthine or, conceivably, adenosine and not ATP, in my opinion. Xanthine is not salvaged efficiently (but can, in fact, be salvaged in small amounts to xanthosine and then guanosine), but hypoxanthine and adenosine are salvaged relatively efficiently by cells in the brain.
Sahlin et al. (1999) discuss the fact that researchers have generally found glycogen depletion from the skeletal muscles to be a prerequisite for the most pronounced, exercise-induced increases in plasma purines, including hypoxanthine. True glycogen depletion from a muscle group generally requires exhaustive exercise, and the research has generally shown, in my opinion, that resistance exercise produces more-pronounced degrees of glycogen depletion and purine depletion from the muscles [the general idea is that ATP depletion causes a loss of the capacity to salvage adenosine (and also guanosine), and this causes inosine monophosphate to accumulate and be converted into hypoxanthine and xanthine in the muscle cells] than exercise at low intensity does. Hellsten et al. (1998) [Hellsten et al., 1998: (http://ajpendo.physiology.org/cgi/content/full/274/4/E600)(http://www.ncbi.nlm.nih.gov/pubmed/9575819)] discuss research showing that a high-intensity exercise program causes a 20 percent decrease in the total adenine nucleotide contents of skeletal muscles (when people are not exercising, meaning post-exercise and all the time). That's a remarkable fact and suggests to me that some benefit might be derived from low-dose adenosine or guanosine supplementation, particularly early in an exercise program. But that's my opinion. The effects of hypoxanthine on the brain should not be underestimated, and a single exercise session that produces an 8-fold elevation in plasma hypoxanthine levels, during the hour or few hours following exercise, could have a significant effect on the pools of adenine nucleotides, in particular, in the brain. Mink and Johnston (2007), cited above, discuss the fact that hypoxanthine appeared to be salvaged to a large extent, even during ischemia. The brain has an extremely low capacity to make purines de novo and depends almost entirely on purines exported from either the endothelial cells lining the cerebral blood vessels or from the blood.
Of course, creatine and glutamine have been shown to augment the salvage of purine or pyrimidine nucleotides in various articles [cited and discussed here or in other postings: (http://hardcorephysiologyfun.blogspot.com/2009/02/interactions-of-glutamine-and-arginine.html)], but any supposed improvement in purine or pyrimidine salvage, in the brain, that might occur in response to the administration of those types of supplements might be offset by the increase in, for example, purine nucleotide export that could accompany a creatine- or glutamine-induced increase in exercise intensity. I don't think that's the way it would work, though, as long as the doses of creatine or glutamine are kept low, but that's just my opinion. For example, the combination of glutamine and inosine, which is hypoxanthine riboside (hypoxanthine attached to ribose to make a nucleotide), [Hodges and Snyder, 2004, cited here: (http://hardcorephysiologyfun.blogspot.com/2009/02/contribution-of-glutamine-to-pool-of.html)]. That's just my opinion. In my opinion, low doses of glutamine, creatine and adenosine and guanosine might produce some sort of buffering effect on brain energy metabolism and purine nucleotide pools. Creatine increases or "stimulates" oxidative metabolism, in part by maintaining the intramitochondrial ADP pool, and this would be expected to increase the extent to which glutamine, upon its metabolism into glutamate, can be metabolized into alpha-ketoglutarate and undergo oxidative metabolism in neurons or astrocytes in the brain. People discuss creatine as if it participates only in anaerobic metabolism, but this is just not the case. Creatine can prolong "aerobic" exercise and is known to increase oxidative glucose utilization in cells, etc.
Similarly, cytidine was recently shown to decrease the glutamine+glutamate pool in parts of the brains of humans [Yoon et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19194376)], and that type of effect could be explained in terms of an increase in the flux of substrates through the nonoxidative pentose cycle, via the ribose-1-phosphate derived from cytidine catabolism in the brain, and glycolytic pathways. Uridine is converted into cytidine, and ribose derived from purines might be expected to produce a similar effect, to some extent. Hodges and Snyder (2004), in fact, discuss research showing that either glucose or glutamine can serve as an energy substrate for cultured cells but that inosine or some other "pentose source," meaning ribose derived from inosine, had to be present, in combination with glutamine, to maintain ATP levels in cultured cells that lacked a source of glucose. Exogenous nucleotides have been shown to elevate lactate levels in many articles, and those effects could be partly attributable to the ribose-induced increases in the activities of glycolytic enzymes. The effect of cytidine could also have been the result of some effect on receptors that bind pyrimidine triphosphates, etc., but that type of mechanism, in my opinion, is less plausible. Nonetheless, I don't think ribose, by itself would substitute for uridine, past a certain point.
My overall point is that some of these energy substrates, such as creatine and glutamine and ribose, can increase the flux of intermediates through one pathway and produce beneficial effects that might, in my opinion, be expected to be limited by the "depleting" effect that might result from that shift in the metabolism of one or another intermediates. At high doses, however, these types of supplements start to produce really complicated effects. The glutamine-induced decreases in plasma free fatty acids, for example, could, in my opinion, begin to become counterproductive, with respect to the brain, at higher dosages. Obviously, one would want to discuss any of these supplements with one's doctor before taking any of them or beginning any kind of exercise program.
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