Sex hormones modulate pathogenic processes in experimental traumatic brain injury

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 5a-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 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.

Depletion of regulatory T cells increases T cell brain infiltration, reactive astrogliosis, and interferon-γ gene expression in acute experimental traumatic brain injury

“…We next examined the CCI-induced and calpain-mediated generation of 145/150 kDa αII-spectrin breakdown products (SBDPs) which can be utilized to assess Ca 2+mediated excitotoxicity and an overall disturbance of Ca 2+ homeostasis in TBI [51,52]. Additionally, we determined protein levels of the microglia/macrophage marker Iba1 and the astrocyte marker GFAP in DEREG and WT mice.…”

Administration of all‐transretinoic acid after experimental traumatic brain injury is brain protective

“…Immunoblotting was performed essentially as described (Gölz et al, 2019). Briefly, brain tissue sections from the injured hemisphere were homogenized using a radio-immunoprecipitation assay (RIPA) buffer (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM (Alexander, Cidlowski, et al, 2019;Alexander, Fabbro, et al, 2019).…”

Estrogen as a Neuroprotectant in Both Sexes: Stories From the Bird Brain

“…Aromatase expression is induced in astrocytes following various forms of insult in the rodent brain (42,(76)(77)(78). In addition, aromatase inhibition following controlled cortical impact in mice results in higher gliosis as measured by the expression of astrocyte-specific markers (18). However, the dramatic injury-induced astrocytic aromatase expression in the finch relative to the murine rodent is perhaps best reflected in the following comparison.…”

“…In rats, gerbils, and mice, females respond more favorably to medial carotid artery occlusion (MCAO) and other experimental inducers of ischemia (15)(16)(17). More recently, in mice subjected to controlled cortical impact, males demonstrated larger lesions compared to females (18). All these effects are apparently linked to circulating ovarian steroids because MCAO causes greater neural damage when it is conducted during metestrus compared to estrus, times of the rodent ovarian cycle when circulating E2 levels are low and high, respectively (15).…”