Androgens predispose males to GABAA-mediated excitotoxicity in the developing hippocampus
Androgens predispose males to GABAA-mediated excitotoxicity in the developing hippocampus
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DOI：
10.1016/j.expneurol.2008.01.001
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发表时间：
2008-04-01
影响因子：
5.3
通讯作者：
McCarthy, Margaret M.
中科院分区：
文献类型：
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作者：
Nunez, Joseph L.;McCarthy, Margaret M.
临床证据和动物模型表明，新生男性受伤后脑损伤更大。在成人中，谷氨酸是兴奋性毒性细胞死亡的主要来源，而类固醇雌二醇具有神经保护作用。在新生儿大脑中，GABA(A) 受体激活后的膜去极化是兴奋的主要来源。随后钙通过 L 型通道的流入通常是营养性的，但在 GABA(A) 受体过度激活期间（例如缺氧缺血、酒精暴露和癫痫发作）会变得兴奋毒性。使用性别特异性海马培养物发现，与女性来源的培养物相比，GABA(A) 激动剂蝇蕈醇诱导的细胞死亡更多。雄激素、二氢睾酮 (DHT) 预处理会增加蝇蕈醇诱导的两性死亡。对钙动力学的探索表明，与预期相反，雌性神经元比雄性神经元获得更高的 [Ca2+](i)，但由于钙的上升和衰减更快，钙瞬态持续时间更短。然而，在第一次暴露后几分钟内第二次暴露于蝇蕈醇，导致雌性神经元中 [Ca2+](i) 显着减弱。相比之下，虽然首次暴露于蝇蕈醇的雄性神经元表现出较低的最大[Ca2+](i)，但当再次暴露于蝇蕈醇时，[Ca2+](i)没有衰减。后一种效应是由 DHT 在女性中诱导的，并且与 GABA(A) 受体的 gamma2 亚基的数量呈负相关。雄激素对 GABA 介导的兴奋性毒性的这种新作用表明，对于具有脑损伤风险的新生儿男性，涉及拮抗雄激素受体的性别特异性治疗方法具有独特的机会。 (C) 2008 Elsevier Inc. 保留所有权利。
Clinical evidence and animal models indicate greater brain damage in newborn males following injury. In adults, glutamate is the primary source of excitotoxic cell death and the steroid, estradiol, is neuroprotective. In neonatal brain, membrane depolarization following activation of GABA(A) receptors is the major source of excitation. Consequent influx of calcium via L-type channels is normally trophic, but becomes excitotoxic during periods of excessive activation of GABA(A) receptors, such as hypoxia-ischemia, alcohol exposure and seizures. The use of sex-specific hippocampal cultures revealed greater cell death induced by the GABA(A) agonist, muscimol, in male- versus female-derived cultures. Pretreatment with the androgen, dihydrotestosterone (DHT) increased muscimol-induced death in both sexes. Exploration of calcium dynamics indicated that, counter to expectation, female neurons achieved higher [Ca2+](i) than male, but the calcium transient duration was shorter due to faster rise and decay. However, a second exposure to muscimol within minutes of the first, caused significant attenuation of [Ca2+](i) in female neurons. In contrast, while male neurons exposed to muscimol for the first time exhibited lower maximal [Ca2+](i), when exposed to muscimol again there was no attenuation in [Ca2+](i). The latter effect was induced in females by DHT, and inversely correlated with the amount of gamma2 subunit of the GABA(A) receptor. This novel effect of androgen on GABA-mediated excitotoxicty suggests a unique opportunity for a sex-specific therapeutic approach involving antagonism of the androgen receptor in neonatal males at risk for brain injury. (C) 2008 Elsevier Inc. All rights reserved.