This article [Mink and Johnston, 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17335786)] shows that the intravenous infusion of 600 umol/kg/hr of hypoxanthine (HPX) reduced damage to the brain following experimental hypoxia and cerebral ischemia (8 minutes of each). The authors compared the degree of damage in the group that had received HPX, given during the interval of 30-minutes before and 30 minutes after the induction of ischemia (the 30 minutes "after" had included the 16 minutes during which the animals had been subjected to hypoxia and then ischemia), to the degrees of damage in the groups that had received either an infusion of xanthine (XAN) or an inactive vehicle. The relative degrees of damage were not significantly different in the groups that had received either xanthine or the vehicle, and the authors noted that these data, along with other data, argue against the notion that free-radical production from xanthine oxidase activity contributes strongly to damage following cerebral ischemia. The authors also found that the cerebral HPX levels, measured after the four hours of reperfusion had elapsed, were actually much lower in the group that had received the HPX infusion than in the other groups. Given that these decreases in the post-reperfusion HPX levels had been accompanied by reductions in postischemic brain damage, the authors noted that the HPX had probably been salvaged heavily or converted into xanthine, etc. Some of the XAN in the XAN group may have also been used for salvage (XAN can be salvaged to xanthosine and guanosine).
These results are important and suggest, as noted by the authors, that the protective effects of allopurinol, a xanthine oxidase inhibitor used to treat hyperuricemia, against cerebral ischemia are mediated by mechanisms other than XO inhibition per se. In other words, the reduction in uric acid is probably not protective in and of itself (especially since uric acid has been shown in many studies to protect against experimental, ischemic brain injuries) and, more importantly, the xanthine oxidase activity per se seems unlikely to be a major source of oxidative damage to the brain. The authors provided more XO substrates, which are HPX and XAN, and did not find increases in ischemic damage. The authors noted that the high Km value for XAN binding to XO (88 uM) as a substrate means that XO was not saturated with XAN during the experiments and wasn't in untreated animals either (the brain XAN content in the cerebral cortex of the rabbits was only 18 uM at 30 minutes after the initiation of reperfusion). This means that exogenous XAN is likely to have been utilized as a substrate for XO, as noted by the authors, but also means that the XO activity in the control group might not have necessarily been lower (the XO enzymes in the control rabbits would presumably have had access to plenty of endogenously-produced XAN, etc.). There's an article showing that allopurinol can exert antinociceptive effects that are evidently due to elevations in the cerebrospinal fluid guanosine and adenosine levels, and some of the antinociceptive effects can be blocked by adenosine receptor antagonists [Schmidt et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19133997)]. Those types of elevations in CSF guanosine and adenosine could also explain the neuroprotective effects of allopurinol. Even though the paper by Mick and Johnston (2007) doesn't necessarily preclude a damaging effect of XO-derived reactive oxygen species, the evidence, in my opinion, that XO activity is "all-bad" or that uric acid is a mediator of ischemic damage is not compelling at all, to say the least. Betz et al. (1991) [Betz et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1996699)] also noted that XO activity is unlikely to make a large contribution to oxidative damage following ischemia. To the contrary, uric acid has been shown to protect against postischemic damage, in many articles, in both humans and animals [here are a couple of the articles that show or discuss this: Yu et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9726432); Amaro et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18271711); Chamorro et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/14962621); Amaro et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17525395)(http://stroke.ahajournals.org/cgi/reprint/38/7/2173.pdfhttp://stroke.ahajournals.org/cgi/reprint/38/7/2173.pdf); Romanos et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/16596120); Teng et al., 2002: (http://www.ncbi.nlm.nih.gov/pubmed/12398932); Keller et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9425011)]. Uric acid and xanthine have both been shown to exert fairly strong feedback inhibition of XO activity [Rubbo et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1653611); Radi et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1322703)], and this feedback inhibition appears to be significant at normal, physiological concentrations in humans [Tan et al., 1993: (http://www.ncbi.nlm.nih.gov/pubmed/8134172)]. But the feedback inhibition has actually been shown to increase superoxide production by XO in vitro (by the isolated enzyme) (Rubbo et al., 1991; Radi et al., 1992). At the same time, Tan et al. (1993) found that 150 or 300 uM uric acid reduced the production of superoxide in human plasma overall by 23.2 and 32.0 percent, respectively. This indicates, in my opinion, that the overall effect of uric acid, despite its potential to increase superoxide production by XO, is to decrease superoxide formation. So elevations in uric acid levels, produced by exogenous purines or exogenous uric acid, during ischemia protect against ischemic damage, may increase free radical production by XO, but appear to decrease superoxide formation in the blood overall. This is consistent with the results of many other articles. The articles I've discussed provide more evidence, in my opinion, that uric acid per se and XO activity per se should not be viewed as being major factors, in the absence of exogenous uric acid or purine precursors of uric acid, contributing to oxidative damage following ischemia.
When one considers the nearly countless articles showing protection by uric acid against experimental autoimmune encephalomyelitis (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=encephalomyelitis+uric+OR+urate) and mitochondrial damage (http://scholar.google.com/scholar?q=mitochondrial+peroxynitrite+uric+OR+urate&hl=en&lr=), etc., these association studies, implying that uric acid is "independently" damaging, become bizarre to see, in my opinion. Hozawa et al. (2006) noted that elevations in serum urate are a risk factor for stroke but that uric acid itself "may" not cause strokes [Hozawa et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16239005)]. It's important to remember that ischemia itself (meaning ongoing, intermittent, low-level cerebral ischemia or ischemia in blood vessels outside the brain) increases purine nucleotide export and XO activity and uric acid production in a very reliable manner. It's worthwhile to remember that statistic-driven association studies are not a substitute for reasoning.
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