Sex hormones modulate pathogenic processes in experimental traumatic brain injury

作者：Christina Gölz, Florian Kirchhoff, Jana Westerhorstmann, Matthias Schmidt, Tobias Hirnet, Gabriele M. Rune, Roland A. Bender, Michael K. E. Schäfer · 发表于：Journal of Neurochemistry · 年份：2019 · DOI：10.1111/jnc.14678 · 被引用次数：64 · 研究领域：Traumatic Brain Injury and Neurovascular Disturbances、S100 Proteins and Annexins、Traumatic Brain Injury Research

Abstract 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 5α‐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 Ca 2+ 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 Tr...