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  • TP-0903 Beside estrogen several classes of compounds have sh

    2024-04-02

    Beside estrogen, several TP-0903 of compounds have shown significant neuroprotective efficacy when administered shortly after the induction of animal models of stroke, including glutamate (NMDA) receptor antagonists and zinc chelators [25], [26], [27]. Effects of these or other neuroprotective agents on aromatase expression after stroke have not been investigated to date.
    Materials and methods
    Results
    Discussion In this study, we show that aromatase protein was elevated in peri-infarct zones on day 14 after focal cerebral ischemia in male rats. This finding resonates with the first report showing significant increases in aromatase immunoreactivity in the peri infarct zone of female rats at 24h and at day 8 (but not 2h and day 30) after experimental stroke [15]. Our results extend these finding to males, also using a time point (day 14) and measures of infarct size and neuroinflammation which were not included in the prior study. In view of the increasing body of literature suggesting that aromatase plays a neuroprotective role in experimental stroke [12], [36], [37], we examined the relationship between aromatase expression and infarct size in animals subjected to MCAO alone as well as in animals treated with drugs known to reduce infarct through other mechanisms to examine the possibility of synergism. Overall, we found no correlation between aromatase immunoreactivity and infarct size 14days after ischemia. This was true for untreated animals as well as animals given putative neuroprotective agents. Unlike Zhao et al. [29], we did not see a significant reduction in infarct size in animals treated with the Zinc chelator TPEN. Our results are more in line with those of Lee et al. [38] who showed that zinc chelation delays focal infarction without reducing final infarct size (measured on day 14). The NMDA receptor antagonist selfotel, given alone or in combination with a zinc chelator, did reduce the infarct size at day 14 post-MCAO in male rats. This is consistent with numerous previous studies showing that NMDA receptor antagonists are potent neuroprotective agents in experimental stroke when administered prior to or immediately post-injury [39], [40]. Surprisingly, this treatment decreased aromatase immunoreactivity in the peri-infarct area relative to the vehicle treated ischemic control group. Taken together, these results suggest that increased aromatase expression after MCAO is not necessary or sufficient to reduce final (14day) infarct size in male rats. This could be a reflection of sex differences in the effects of aromatase, which are well supported in the literature. Thus, female aromatase knockout mice showed enhanced hippocampal neurodegeneration in response to neurotoxins relative to wild-type mice [12] but infarct size 22h after reperfusion was not affected by knocking out aromatase in male mice [41]. In addition, sex differences in aromatase function have been reported in astrocytic cell death, and aromatase reportedly plays a protective role on cerebrovascular endothelial function in females but has the opposite effects in male vessels [42], [43]. With regard to neuroprotection, it is important to remember that increased aromatase activity increases estrogen but also decreases testosterone levels. Male rodents and humans have more androgen receptors in the brain relative to females [44], [45], [46], [47] and androgens were shown to be neuroprotective in males in an estrogen-independent manner [48], [49], such that the decrease in testosterone may offset neuroprotection derived from increase in estrogen in males; which may even be inherently different than in females [50]. Our study is also the first to investigate the interrelationship between changes in aromatase expression and neuroinflammation in the aftermath of experimental stroke, motivated by reports of both anti- and pro-inflammatory effects of estrogen [51]. The post-ischemic inflammatory process in the brain can be assessed in humans and experimental animals, in vitro and in vivo, by imaging the density of TSPO binding [22], [23], [24], [52]. In the current study, MCAO drastically increased TSPO binding in the infarcted hemisphere, with increases extending beyond the peri infarct zone. This is consistent with our results in females [22] and documented evidence of functionally compromised regions extending beyond the area of infarct in experimental stroke [53]. Unlike aromatase immunoreactivity, TSPO binding in the peri-infarct zone was positively and highly significantly correlated with infarct size. In the same region, we found a moderate though statistically significant negative correlation between aromatase immunoreactivity and TSPO binding in male rats. These results are not what would be expected if neuroinflammation alone was a significant inducer of aromatase expression, as suggested by studies in birds [24]. Conversely, our findings are supportive of a local anti-inflammatory action mediated by aromatase in the peri-infarct zone of male rats, as suggested by Perez-Alvarez et al. [54].