Chapter 12 - Gender and the injured brain
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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Cited by (23)
Single dose of 17β-estradiol provides transient neuroprotection in female juvenile mice after cardiac-arrest and cardiopulmonary resuscitation
2019, Neurochemistry InternationalCitation Excerpt :Epidemiologic studies in adults have suggested that females have better outcomes after CA when compared to males (Herlitz et al., 2001; Kitamura et al., 2010; Topjian et al., 2010). Numerous experimental studies in adult animal models have recapitulated this clinical data, demonstrating that female animals exhibit significantly less brain injury following cerebral ischemia compared to males (Herson and Hurn, 2010). The sex difference in outcome is due primarily to the high levels of circulating estrogen in adult female animals, as removal of endogenous sex steroids (ovariectomy) increases female brain injury (Fukuda et al., 2000; Rusa et al., 1999).
The effect of age, sex and strains on the performance and outcome in animal models of stroke
2019, Neurochemistry InternationalCitation Excerpt :In this article, we summarize the differences between young and aged animals, the impact of age on outcome in animal models of stroke, and emphasize age as a key factor in preclinical stroke studies. Increased scientific rigor in the use of aged rodents for stroke models may increase the translation of rodent models to humans in stroke (Herson and Hurn, 2010; Rosenzweig and Carmichael, 2013; Sommer, 2017). Biomedical researchers who use adult and aged animals as experimental tools often face the question: “At what age are laboratory rats and mice considered adult or aged”?
Gender-related protection from or vulnerability to severe CNS diseases: Gonado-structural and/or gonado-activational? A meta-analysis of relevant epidemiological studies
2014, International Journal of Developmental NeuroscienceSex difference in sensitivity to allopregnanolone neuroprotection in mice correlates with effect on spontaneous inhibitory post synaptic currents
2011, NeuropharmacologyCitation Excerpt :Few studies utilize both sexes in the same set of experiments, yet it is of great clinical relevance to do so. Comparison of male and female response to CA/CPR revealed that females exhibit less damage compared to males, consistent with the large body of literature demonstrating that females are relatively protected compared to males due to the well-characterized neuroprotection by ovarian hormones, estrogen and progesterone (Herson et al., 2009; Herson and Hurn, 2010; Liu et al., 2010). Despite the less severe damage observed in females, ALLO provided further protection, decreasing damage by over 50%.