Pathways to ischemic neuronal cell death: are sex differences relevant?

Abstract

We have known for some time that the epidemiology of human stroke is sexually dimorphic until late in life, well beyond the years of reproductive senescence and menopause. Now, a new concept is emerging: the mechanisms and outcome of cerebral ischemic injury are influenced strongly by biological sex as well as the availability of sex steroids to the brain. The principal mammalian estrogen (17 beta estradiol or E2) is neuroprotective in many types of brain injury and has been the major focus of investigation over the past several decades. However, it is becoming increasingly clear that although hormones are a major contributor to sex-specific outcomes, they do not fully account for sex-specific responses to cerebral ischemia. The purpose of this review is to highlight recent studies in cell culture and animal models that suggest that genetic sex determines experimental stroke outcome and that divergent cell death pathways are activated after an ischemic insult. These sex differences need to be identified if we are to develop efficacious neuroprotective agents for use in stroke patients.

Figure 1

Proposed model of cell death pathways in response to ischemia in females and males.

Figure 2

The effects of the selective PARP-1 inhibitor PJ-34 in WT mice of both genders. Treatment with PJ-34 at ischemic onset reduced total infarction in male mice compared to saline treated controls (*; p < .001). A significant increase in ischemic damage was seen in PJ-34 treated females compared to control (*; p < .001) [4].

Figure 3

Effect of estrogen on infarction volume in PARP-/- females. Physiological levels of E2 were restored to ovariectomized (OVX) PARP-/- and WT female mice. WT females had significant reductions in total, cortical (CTX) and striatal (CP) infarct volumes after E2 replacement compared to oil treated WT females (*; p < .01). PARP-/- females demonstrated increased damage compared to WT (**; p < .01). Interestingly the neuroprotective effect of E2 was completely absent in PARP -/- females. E2 treatment exacerbated stroke damage; both striatal and total infarct volumes were significantly higher in E2 treated vs. oil treated PARP-/- mice (***; p < .05) [4].