Sex differences in ischaemic stroke: potential cellular mechanisms

Stroke remains a leading cause of mortality and disability worldwide. More women than men have strokes each year, in part because women live longer. Women have poorer functional outcomes, are more likely to need nursing home care and have higher rates of recurrent stroke compared with men. Despite continued advancements in primary prevention, innovative acute therapies and ongoing developments in neurorehabilitation, stroke incidence and mortality continue to increase due to the aging of the U.S. population. Sex chromosomes (XX compared with XY), sex hormones (oestrogen and androgen), epigenetic regulation and environmental factors all contribute to sex differences. Ischaemic sensitivity varies over the lifespan, with females having an “ischaemia resistant” phenotype that wanes after menopause, which has recently been modelled in the laboratory. Pharmacological therapies for acute ischaemic stroke are limited. The only pharmacological treatment for stroke approved by the Food and Drug Administration (FDA) is tissue plasminogen activator (tPA), which must be used within hours of stroke onset and has a number of contraindications. Pre-clinical studies have identified a number of potentially efficacious neuroprotective agents; however, nothing has been effectively translated into therapy in clinical practice. This may be due, in part, to the overwhelming use of young male rodents in pre-clinical research, as well as lack of sex-specific design and analysis in clinical trials. The review will summarize the current clinical evidence for sex differences in ischaemic stroke, and will discuss sex differences in the cellular mechanisms of acute ischaemic injury, highlighting cell death and immune/inflammatory pathways that may contribute to these clinical differences.