Gender-linked brain injury as exemplified in rat models of hypoxia and ischemia.

摘要

Until menopause, women enjoy a lower incidence of cardiovascular disease than men. Observational studies of postmenopausal women suggest hormone replacement therapy decreases their risk of cardiovascular and cerebrovascular events. I established experimental paradigms in rat models for studying these gender-related differences. Chronic cerebral hypoperfusion (CCH) is implicated in age-related dementias and Alzheimer's disease. Chronic cerebral hypoperfusion can be modeled by ligation of the bilateral carotid arteries to permanently occlude them (2VO). Transient global forebrain ischemia by the four-vessel occlusion method (4VO) causes cerebral damage characterized by a delayed neuronal loss in the hippocampal CAI layer similar to that inflicted by cardiac arrest. Reversible occlusion of the middle cerebral artery (MCAO) by intraluminal filament in rat causes focal infarction like that caused by common stroke in humans. I hypothesized that female Wistar rats, when compared to males, would exhibit: (1) mitigated losses in cortical neuronal and oligodendroglial populations as well as decreased gliosis under CCH conditions modeled by 2VO; (2) decreased neuronal loss in the CAI hippocampus after transient forebrain ischemia modeled by 4VO; and (3) reduced infarct volume subsequent to focal ischemia as modeled by MCAO. Surprisingly, male survival one day after 2VO was better than females. Between weeks two and twelve after 2VO, the neuronal population in the medial hippocampus declined in males but not in females. After two, eight, and twelve weeks of 2VO, vacuolization within the corpus callosum, indicative of oligodendroglial health, was attenuated in females compared to males. Likewise, gliosis at two weeks post-2VO was reduced in females compared to males. Infarct volume after MCAO was reduced by 51.2% in females compared to males. In contrast, neuronal survival following either 12 or 20 minutes 4VO did not show significant gender differences. The results of these studies indicate that, while female rats may enjoy gender-related neuroprotection under conditions of CCH and focal ischemia, they may be no less vulnerable to effects of global forebrain ischemia than their male counterparts. Although the mechanisms are unclear, the absence of gender effect in global ischemia may be due to a combination of vascular phenomena and delayed cell death.