Title

Investigation of the Underlying Mechanisms of Sex Differences in Cerebral Ischemia

Date of Completion

January 2011

Keywords

Biology, Neuroscience|Biology, Cell|Biology, Neurobiology

Degree

Ph.D.

Abstract

Stroke has been known as a sexually dimorphic disease for many years. These sex differences have been largely attributed to the neuroprotective effects of estrogen. The only treatment for stroke patients is recombinant tissue plasminogen activator (rt-Pa), which can only be administered within 4.5 hours of stroke onset. In the past ten years it has become clear that both hormonal and non-hormonal sex differences exist in cell death pathways, which adds to the complexity of ischemic cell death. Interestingly, the majority of studies focusing on ischemic stroke have used male subjects in their experiments. In order to fully elucidate the mechanisms underlying sex differences in cerebral ischemia female subjects must be studied as well. The overall theme of this thesis is to clarify mechanisms by which sex differences in ischemic cell death pathways occur. The ultimate goal is to better understand these sex differences in order to develop more specific therapeutic agents to target male and female stroke patients individually. Sex differences were studied from multiple angles including: 1) the genetic contribution of the X-chromosome to ischemic sensitivity, 2) The role and regulation of XIAP in ischemic cell death, and 3) differences in energy metabolism as measured by NAD+.^ First, the contribution of the X-chromosome to ischemic sensitivity was examined. No differences were seen between Both Paf XO and EdaTa/O mice and their wildtype littermates. This suggests that the X-chromosome does not play a role in ischemic sensitivity.^ Next, the role of XIAP in ischemic cell death was examined. Sex differences exist in XIAP expression. miR-23a was discovered as a novel regulator of XIAP and miR-23a levels are higher in the female brain. These data suggest that XIAP plays an integral role in ischemic cell death in the female brain and that miR-23a may have therapeutic relevance in females.^ Finally, sex differences in NAD+ levels were assessed in both wildtype and PARP-1-/- mice. PARP-1-/- mice appear more like males and experience a stroke-induced depletion of NAD+. NAD+ depletion occurs in wildtype males, while wildtype females maintain NAD+. Nicotinamide, a NAD+ precursor, is protective in males, PARP-1-/- males, and PARP-1-/- females. These data suggest that sex differences exist in energy metabolism and nicotinamide may have therapeutic relevance in males. Overall, these results suggest sex differences must be taken into account when developing novel stroke therapies. ^