The effect of male sex hormones, or androgens, on outcomes following ischemia remains unclear. Some studies have reported that androgens exhibit deleterious effects on ischemic outcome. Our preliminary data, however, demonstrated that ischemic brain damage is reduced when testosterone and its metabolite 5α-dihydrotestosterone (DHT) are present at physiological levels compared to supraphysiological levels. Interestingly, the decline in testosterone levels following acute stroke has been clinically associated with increased stroke severity, infarct size, and 6-month mortality. Therefore, we hypothesized that male sensitivity to ischemia is a result of this loss of androgens rather than the presence of androgens themselves.

Unlike testosterone, DHT cannot be aromatized to estrogen and, thus, acts exclusively through androgen receptors (AR). When an ischemic event occurs, DHT induces transcription of salt induced kinase (SIK1). Evidence suggests that SIK1 is an endogenous inhibitor of histone deacetylase (HDAC) in neurons, and inhibition of HDAC is protective against experimental stroke damage. The purpose of this study is to confirm that DHT protects male brains from focal cerebral ischemia and that SIK1 has an essential role in the AR-dependent mechanism by which DHT provides this neuroprotection via HDAC inhibition.

This study is funded by an American Heart Association Fellowship award.