Sex-Dependent Regional Vulnerability and Recovery Mechanisms in a Mouse Model of Transient Global Cerebral Ischemia.

Abstract

This study investigates the influence of sex on region-specific neural vulnerability following global cerebral ischemia using a Bilateral Common Carotid Artery Occlusion (BCCAo) mouse model that mimics severe ischemic brain stroke condition in humans. Comprehensive behavioral assessments, neuropathological analyses, and molecular profiling were conducted across multiple time points post-ischemia in male and female CD1 mice. Both sexes exhibited early motor deficits, cortical-striatal mitochondrial dysfunction, inflammation, and cell death at day 1, with gradual behavioral recovery. However, the hippocampus demonstrated a clear sex-specific divergence: males exhibited delayed yet prolonged inflammation, apoptotic cell death, and increased autophagy/mitophagy activity, while females were largely protected despite hypoxic and inflammatory gene expression. Molecular assays revealed prolonged upregulation of hypoxia-inducible factor 1α (HIF-1α), IL-1β, IL-6, TNF-α, and apoptotic markers in males, especially in the hippocampus, alongside increased expression of autophagy (Beclin-1, LC3-II, ATG7) and mitophagy (PINK1, BNIP3L) regulators and a shift in mitochondrial dynamics favoring fission.