2 . 2 Sex Differences in Ischemic Outcomes : Animal Models

Biological sex is an important genetic determinant of outcome from cerebral ischemia and clinical stroke. Emerging data suggest that sex, as well as reproductive steroids, shapes ischemic cell death in brain. Female sex steroids, the estrogens and progesterone, provide robust neuroprotection in a variety of experimental settings and strongly contribute to sex‐specific responses to ischemia. The purpose of this chapter is: (1) to review the importance of biological sex to ischemic outcome and mechanisms of brain injury, (2) to evaluate the role of female sex steroids as endogenous or exogenous ischemic neuroprotectants, and (3) to review most likely mechanisms by which female sex steroids act to interrupt ischemic cell death pathways. List of Abbreviations: AP1, activator protein 1; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; Ca, calcium; cAMP, cyclic adenosine monophosphate; CREB, cAMP-responsive element-binding protein; E14, embryonic day 14; E2, estradiol; ER, estrogen receptors; αERKO, estrogen receptor deficient knockout mice subtype α; βERKO, estrogen receptor deficient knockout mice subtype β; ERE, estrogen-response elements; GAD, glutamic acid decarboxylase; i.p., intraperitoneal; MCA, middle cerebral artery; MCAO, middle cerebral artery occlusion; MAPK, mitogen-activated protein kinase; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NMDA, N-methyl-D aspartate; NF-κB, nuclear factor-kappa B; OVX, ovariectomized; ERK1 and ERK2, p42/p44 extracellular signal-regulated kinases 1 and 2; ONOO, peroxynitrate; PARP-1, poly-ADP ribose polymerase; PR, progesterone receptor; PKC, protein kinase C; RSF, reproductively senescent female; SHRSP, spontaneously hypertensive stroke prone; SD, SpragueDawley; TBI, traumatic brain injury