Deleterious Effects of Dihydrotestosterone on Cerebral Ischemic Injury

Abstract

Outcome from cerebral ischemia is sexually dimorphic in many experimental models. Male animals display greater sensitivity to ischemic injury than do their female counterparts; however, the underlying mechanism is unclear. The present study determined if the potent and nonaromatizable androgen, dihydrotestosterone (DHT), exacerbates ischemic damage in the male rat and alters postischemic gene expression after middle cerebral artery occlusion. At 22 h reperfusion, removal of androgens by castration provided protection from ischemic injury in both cortex and striatum (2,3,5-triphenyltetrazolium chloride (TTC) histology), whereas DHT replacement (50 mg subcutaneous implant) restored infarction volume to that of the intact male; testosterone (50 mg) had similar but less potent effects. We utilized microarray and real-time quantitative polymerase chain reaction (PCR) to identify genes differentially expressed at 6 h reperfusion in periinfarct cortex from castrated rats with or without DHT replacement. We identify, for the first time, a number of gene candidates that are induced by DHT with or without ischemia, many of which could account for cell death through enhanced inflammation, dysregulation of blood–brain barrier and the extracellular matrix, apoptosis, and ionic imbalance. Our data suggest that androgens are important mediators of ischemic damage in male brain and that transcriptional mechanisms should be considered as we seek to understand innate male sensitivity to cerebral ischemia.