Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3).
Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3).
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DOI：
10.1523/eneuro.0022-14.2014
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发表时间：
2014-11
期刊：
影响因子：
3.4
通讯作者：
Herson PS
中科院分区：
文献类型：
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作者：
Quillinan N;Grewal H;Klawitter J;Herson PS
TRPM2 是一种离子通道，中风时缺血会激活，仅导致男性神经元损伤。我们测试了女性中风后 TRPM2 激活缺失是否是由性类固醇差异引起的。钙渗透性瞬时受体电位 M2 (TRPM2) 离子通道激活会导致脑缺血损伤，尤其是男性。在雄性小鼠中，克霉唑 (CTZ) 抑制 TRPM2 需要循环雄激素，以在实验性中风后提供保护。足够水平的循环雄激素对于支持缺血诱导的聚 ADP 核糖聚合酶 (PARP) 激活以及随后的 TRPM2 通道激活是必要的。在这项研究中，我们测试了性类固醇的差异是否导致女性缺乏 CTZ 神经保护作用。使用激素完整、卵巢切除（OVX）或二氢睾酮（DHT）治疗的成年雌性小鼠进行大脑中动脉闭塞（MCAO）。再灌注时给予CTZ或媒介物，24小时后对动物实施安乐死，并收集脑和血清。梗塞分析显示 CTZ 对完整雌性或缺乏内源性类固醇 (OVX) 的雌性没有影响。有趣的是，用强效雄激素受体激动剂 DHT 治疗雌性小鼠对缺血性损伤没有影响，并且不允许 CTZ 神经保护。同样，经过 DHT 治疗的雌性在缺血后并没有表现出 ADP 核糖（PARP 产生的 TRPM2 配体）水平升高。男性和女性之间未观察到 TRPM2 或雄激素受体表达存在差异。这些数据表明，实验性中风后女性 TRPM2 激活的缺乏并不是由于雌激素的存在或雄激素的缺乏。总之，我们的数据表明，虽然循环雄激素对于男性 PARP 介导的 TRPM2 损伤是必需的，但它们不足以在女性中产生 TRPM2 激活。
TRPM2 is an ion channel that is activated by ischemia in stroke and contributes to neuronal injury only in males. We tested whether the lack of TRPM2 activation following stroke in females is caused by differences in sex steroids. Calcium-permeable transient receptor potential M2 (TRPM2) ion channel activation contributes to cerebral ischemic injury specifically in males. In male mice, circulating androgens are required for TRPM2 inhibition with clotrimazole (CTZ) to provide protection following experimental stroke. Sufficient levels of circulating androgens are necessary to support ischemia-induced activation of poly ADP ribose polymerase (PARP) and consequent activation of TRPM2 channels. In this study, we tested whether differences in sex steroids contribute to the lack of CTZ neuroprotection in females. Middle cerebral artery occlusion (MCAO) was performed using adult female mice that were hormonally intact, ovariectomized (OVX) or dihydrotestosterone (DHT) treated. CTZ or vehicle was administered at the time of reperfusion, animals were euthanized 24 h later and brains and serum were collected. Infarct analysis revealed no effect of CTZ in intact females or females lacking endogenous sex steroids (OVX). Interestingly, treatment of female mice with the potent androgen receptor agonist DHT had no effect on ischemic injury and did not permit CTZ neuroprotection. Similarly, DHT-treated females did not exhibit increased levels of ADPribose, the TRPM2 ligand generated by PARP, following ischemia. No differences in TRPM2 or androgen receptor expression were observed between males and females. These data suggest that the lack of TRPM2 activation in females following experimental stroke is not due to the presence of estrogen or the absence of androgens. In conclusion, our data demonstrate that while circulating androgens are necessary for PARP-mediated TRPM2 injury in males, they are not sufficient to produce TRPM2 activation in females.