Chapter 12 - Gender and the injured brain

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Abstract

Ischemic brain injury is increasingly recognized as progressing through non-identical mechanisms in the male vs female brain. It is increasingly accepted that women are protected from cerebrovascular disease relative to men even beyond their menopausal years, and that young boys have higher stroke rates than do girls. The biological basis for this sexual dimorphism in epidemiology of ischemic brain injury, and less clearly in its outcome, is only partially known. However, both hormone-dependent and hormone-independent factors are likely involved, the latter of which is emphasized in this chapter. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury is an important step toward designing more effective therapeutic interventions and molecular targets in stroke.

Section snippets

Sexual dimorphism of clinical stroke and brain injury

Cerebrovascular disease is the second leading cause of death-from-disease worldwide, affecting some 15 million people. Recent predictions suggest that the incidence of stroke or “brain attack” is unlikely to recede for a decade at minimum, despite large public health initiatives in stroke prevention. Curiously, this disabling disease is also one of the most strikingly sex-specific in its epidemiology (for recent review, see Appelros et al., 2009). It has been recognized for many years that

Animal models of ischemic stroke—sex differences

Animal data clearly suggest that the male brain must cope with a more “ischemia-sensitive” phenotype than does the female. These studies have been conducted almost entirely in rodents, and all focus on tissue outcome rather than risk (Alkayed et al., 1998, Carswell et al., 1999, Hall et al., 1991, McCullough et al., 2005, Zhang et al., 1998). A landmark study of over 2000 female and male spontaneously hypertensive and genetically stroke-prone rats showed that development of cerebral hemorrhage

In vitro models of cell death—innate sex differences

Recent studies using male and female neuronal cultures grown in the absence of sex steroids have begun to reveal cell autonomous sex differences in sensitivity to injury.

For example, cultured female dopaminergic neurons (embryonic day 14, E14) tolerate exposure to toxic dopamine concentrations and survive twofold relative to male cells (Lieb et al., 1995). In cortical neuronal cultures, sensitivity to glutamate, peroxynitrite (ONOO), and staurosporine is sex-specific, with male neurons being

Female cell death—caspase-dependent apoptosis

Emerging evidence points toward enhanced sensitivity of female brain to caspase-dependent apoptosis resulting in delayed neuronal cell death, compared to males. Ischemic stroke involves loss of blood flow to focal regions within the brain, resulting in extensive necrotic cell death within the core of the injury and a less severely affected border region termed the “penumbra.” A great deal of research has focused on the penumbra, as it appears to be the region of greatest potential for

Male cell death—PARP and TRPM2

The most compelling mechanism of neuronal cell death shown to be preferentially engaged in the male brain following cerebral ischemia is the cascade of events leading to over-activation of PARP and consequent cell death. Briefly, cerebral ischemia causes overstimulation of neuronal nitric oxide synthase (nNOS) resulting in excessive levels of NO which is rapidly converted into the highly damaging oxidant ONOO. Subequent oxidative and nitrosative DNA damage activates the key repair enzyme

Summary

We have understood for several years that stroke is a sexually dimorphic disease, with women being protected relative to men. A great deal of research has focused on the role of sex steroids, particularly estrogen in female protection (for review see Herson et al., 2009, Hurn and Brass, 2003). However, the observation that sexual dimorphism exists in post-menopausal women and pre-puberty indicates that intrinsic, non-steroidal factors contribute to ischemic outcome. Indeed, over the past few

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