Biological sex and mechanisms of ischemic brain injury

Abstract

Cerebrovascular disease is a leading cause of death-from-disease and of disability worldwide, affecting some 15 million people. The incidence of stroke or "brain attack" is unlikely to recede for a decade at minimum by most predictions, despite large public health initiatives in stroke prevention. It has been well established that stroke is also one of the most strikingly sex-specific diseases in its epidemiology, and in some cases, in patient outcomes. For example, women sustain lower rates of ischemic stroke relative to men, even beyond their menopausal years. In contrast, outcomes are worse in women in many clinical studies. The biological basis for this sexual dimorphism is a compelling story, and both hormone-dependent and hormone-independent factors are involved, the latter of which is the subject of this brief review. Understanding the molecular and cell-based mechanisms underlying sex differences in ischemic brain injury is an important step toward personalized medicine and effective therapeutic interventions in patients of both sexes.

Keywords: Cerebral ischemia; Gender; Sexual dimorphism; Stroke; Transient receptor potential M2.

Fig 1

Model of male-specific ischemic cell death and the role of androgen/androgen receptor signaling. Abbreviations are: ADPr, ADP-ribose; AIF, Apoptosis-inducing factor; AR, Androgen receptor, NO, Nitric oxide, ONNO⁻, peroxynitrite; PAR, Poly(ADP-ribose) polymer; PARG, Poly(ADP-ribose) glycohydrolase; PARP, Poly(ADP-ribose) polymerase, TRPM2, Transient receptor potential M2 channel