Sex hormones modulate pathogenic processes in experimental traumatic brain injury
Sex hormones modulate pathogenic processes in experimental traumatic brain injury
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DOI：
10.1111/jnc.14678
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发表时间：
2019-07-01
影响因子：
4.7
通讯作者：
Schaefert, Michael K. E.
中科院分区：
文献类型：
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作者：
Goelz, Christina;Kirchhoff, Florian Paul;Schaefert, Michael K. E.
临床和动物研究已经揭示了创伤性脑损伤（TBI）后组织病理学和神经学结果的性别特异性差异。围手术期使用性类固醇抑制剂对TBI的影响仍然难以捉摸。在这里，我们进行了男性和女性C57 Bl/6 N小鼠的TBI的控制皮质撞击（CCI）模型和应用类固醇激素合成的药理学抑制剂，即来曲唑（LET，抑制雌二醇合成的芳香化酶）和非那肽（FIN，抑制双氢睾酮合成的5 α-还原酶），分别从CCI前72小时开始，并继续CCI后48小时。初步基因表达分析表明，雄激素（Ar）和雌激素受体（Esr 1）的性别特异性改变CCI后72小时。当检查脑损伤大小时，我们发现雄性小鼠的损伤大于雌性小鼠，但没有观察到FIN或LET治疗的影响。然而，LET治疗加剧了CCI后24和72小时的神经功能缺损。在分子水平上，FIN给药减少了钙蛋白酶依赖性血影蛋白分解产物，这是兴奋性毒性和Ca 2+稳态紊乱的代表，特别是在男性中，而LET增加了反应性星形胶质细胞标志物胶质细胞酸性蛋白，特别是在女性中。神经营养因子（脑源性神经营养因子，神经元生长因子，NT-3）及其受体（p75（NTR），TrkA，TrkB，TrkC）的检查显示CCI诱导的TrkB和TrkC蛋白表达下调，这是减少了两种性别的LET。有趣的是，FIN仅在男性中降低神经元生长因子mRNA表达及其受体TrkA的蛋白水平。总之，我们的数据表明，性别特异性的影响，在创伤性脑损伤后的致病过程。因此，性激素可以调节实验性TBI的致病过程。
Clinical and animal studies have revealed sex-specific differences in histopathological and neurological outcome after traumatic brain injury (TBI). The impact of perioperative administration of sex steroid inhibitors on TBI is still elusive. Here, we subjected male and female C57Bl/6N mice to the controlled cortical impact (CCI) model of TBI and applied pharmacological inhibitors of steroid hormone synthesis, that is, letrozole (LET, inhibiting estradiol synthesis by aromatase) and finasteride (FIN, inhibiting dihydrotestosterone synthesis by 5 alpha-reductase), respectively, starting 72 h prior CCI, and continuing for a further 48 h after CCI. Initial gene expression analyses showed that androgen (Ar) and estrogen receptors (Esr1) were sex-specifically altered 72 h after CCI. When examining brain lesion size, we found larger lesions in male than in female mice, but did not observe effects of FIN or LET treatment. However, LET treatment exacerbated neurological deficits 24 and 72 h after CCI. On the molecular level, FIN administration reduced calpain-dependent spectrin breakdown products, a proxy of excitotoxicity and disturbed Ca2+ homeostasis, specifically in males, whereas LET increased the reactive astrocyte marker glial fibrillary acid protein specifically in females. Examination of neurotrophins (brain-derived neurotrophic factor, neuronal growth factor, NT-3) and their receptors (p75(NTR), TrkA, TrkB, TrkC) revealed CCI-induced down-regulation of TrkB and TrkC protein expression, which was reduced by LET in both sexes. Interestingly, FIN decreased neuronal growth factor mRNA expression and protein levels of its receptor TrkA only in males. Taken together, our data suggest a sex-specific impact on pathogenic processes in the injured brain after TBI. Sex hormones may thus modulate pathogenic processes in experimental TBI.