Sex Differences in Caspase Activation After Stroke

Background And Purpose: Over the past 5 years, experimental data have emerged that ischemia-induced cell death pathways may differ in males and females. Cell death in males is triggered by poly(ADP-ribose) polymerase activation and nuclear translocation of apoptosis-inducing factor. We have previously shown that interference with this pathway benefits males but not females after an experimental stroke. In contrast, caspase activation may be the major pathway activated after ischemic injury in females. The aim of this study is to examine whether sex differences exist in caspase activation in adult mice after stroke and to determine if interference with stroke-induced caspase activation preferentially protects females.

Methods: Focal stroke was induced by reversible middle cerebral artery occlusion (90 minutes) in young and aging C57BL/6 mice of both sexes. The pan-caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy was administered at reperfusion. Histological outcomes were assessed 48 hours after middle cerebral artery occlusion. Separate cohorts were used for protein analysis of key cell death proteins, including caspase-3, caspase-8, cytochrome C, and apoptosis-inducing factor.

Results: Drug-treated female mice had significantly decreased infarct volumes and improved neurological deficits after stroke compared to vehicle-treated mice. Quinoline-Val-Asp(Ome)-CH2-O-phenoxy administration had no effect in male mice. The expression of cytochrome C and nuclear caspase-8 levels were increased in females after stroke.

Conclusions: Female mice had an early release of cytochrome C and enhanced caspase activation after middle cerebral artery occlusion. Caspase inhibition benefited females but not males. Sex differences exist in both the response to ischemic injury and the efficacy of neuroprotective agents.