Sex-specific cognitive benefits and anti-inflammatory effects of coumestrol pretreatment in transient global cerebral ischemia

Abstract

Cerebral Global Ischemia (CGI) is a devastating neurological condition affecting millions globally each year, leading to significant inflammatory responses and long-term consequences, including delayed neuronal death and neurocognitive impairment. Following brain injury, resident microglial cells are activated, triggering pro-inflammatory cytokine expression and altering neuroimmune processes in a sex-dependent manner, particularly within the hippocampus. Coumestrol, a plant estrogen, is promoted as an alternative to post-menopausal hormone therapy due to its various mechanisms that enhance brain health, including its anti-inflammatory effects. This study aimed to investigate whether coumestrol pretreatment could attenuate the neuroinflammatory response following CGI by regulating pro-inflammatory pathways (GFAP, S100B, TNF-α, and IL-1β) and reversing CGI-induced memory loss.

Male and female rats underwent CGI for 10 min or a sham surgery and received an ICV infusion of 20 μg of coumestrol or vehicle 1 h before CGI induction. Our findings revealed intriguing sex-specific effects of coumestrol pretreatment on gliosis following CGI and reperfusion, suggesting modulation of glial responses after ischemic insults. Coumestrol pre-administration significantly reduced levels of pro-inflammatory cytokines TNF-α and IL-1β during both reperfusion periods in both sexes, thereby mitigating CGI-induced neuroinflammation. Moreover, coumestrol pretreatment effectively reduced stroke-induced cognitive impairment, alleviating ischemia-induced memory deficits in both male and female rats. These results demonstrate the coumestrol's ability to attenuate cognitive deficits induced by CGI and highlight its potential sex-specific effects on inflammatory pathways. This study suggests that coumestrol modulates the glial and microglial inflammatory response, offering a promising approach to mitigate memory deficits associated with cerebral global ischemia.