Investigating Molecular Mechanisms in Ischemic Preconditioning-Induced Resiliency to Severe Acute Global Cerebral Ischemia Using a Mouse Model of Chronic Cerebral Hypoperfusion

Cerebral ischemic preconditioning offers a promising strategy to enhance resilience to severe ischemic insults. Unilateral common carotid artery occlusion (UCCAo) is a valuable model to simulate chronic cerebral hypoperfusion (CCH). This study explored UCCAo-induced CCH as a preconditioning stimulus to induce ischemic tolerance against transient global cerebral ischemia (tGCI) induced by bilateral common carotid artery occlusion (BCCAo) in both male and female mice. We evaluated the effects of CCH preconditioning on neuroprotection and recovery through behavioral, histopathological, and molecular analyses. Laser Doppler Imaging (LDI) confirmed significant cerebral hypoperfusion post-UCCAo. Preconditioning reduced mortality rates at days 1 and 7 post-surgery as compared to BCCAo, suggesting its neuroprotective potential. Neurodeficit scoring demonstrated significant protection in preconditioned animals with recovery aligning closer to sham controls. Behavioral assays revealed improved motor and cognitive outcomes in preconditioned groups, with sex-specific differences evident in recovery dynamics. Molecular analyses indicated reduced reactive astrocyte (GFAP) and microglial (IBA1) activation in preconditioned animals, reflecting controlled glial responses. Sex-dependent variations in markers of hypoxia (Hif1a), autophagy (Becn1), and neurogenesis (Sox2) highlighted neuroadaptive and cellular influences on ischemic resilience. Preconditioning enhanced synaptic plasticity by upregulating PSD-95, synaptophysin and BDNF levels. In addition, preconditioning increased VEGF expression in blood serum reflecting vascular remodeling and neuroprotective angiogenesis. This study positions UCCAo-induced CCH as a reliable model for exploring ischemic tolerance mechanisms to advance therapeutic strategies for mitigating the effects of ischemic stroke.