RT Journal Article SR Electronic T1 Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion JF eneuro JO eneuro FD Society for Neuroscience SP ENEURO.0022-14.2014 DO 10.1523/ENEURO.0022-14.2014 A1 Nidia Quillinan A1 Himmat Grewal A1 Jelena Klawitter A1 Paco S. Herson YR 2014 UL http://www.eneuro.org/content/early/2014/11/18/ENEURO.0022-14.2014.abstract AB Calcium permeable transient receptor potential M2 (TRPM2) ion channel activation contributes to cerebral ischemic injury specifically in males. In male mice, circulating androgens are required for TRPM2 inhibition with clotrimazole (CTZ) to provide protection following experimental stroke. Sufficient levels of circulating androgens are necessary to support ischemia-induced activation of poly ADP ribose polymerase (PARP) and consequent activation of TRPM2 channels. In this study we tested whether differences in sex steroids contribute to the lack of CTZ neuroprotection in females. Middle cerebral artery occlusion (MCAO) was performed using adult female mice that were hormonally intact, ovariectomized (OVX) or dihydrotestosterone (DHT) treated. CTZ or vehicle was administered at the time of reperfusion, animals were sacrificed 24 hours later and brains and serum were collected. Infarct analysis revealed no effect of CTZ in intact females or females lacking endogenous sex steroids (OVX). Interestingly, treatment of female mice with the potent androgen receptor agonist DHT had no effect on ischemic injury and did not permit CTZ neuroprotection. Similarly, DHT treated females did not exhibit increased levels of ADPribose, the TRPM2 ligand generated by PARP, following ischemia. No differences in TRPM2 or androgen receptor expression were observed between males and females. These data suggest that the lack of TRPM2 activation in females following experimental stroke is not due to the presence of estrogen or the absence of androgens. In conclusion, our data demonstrate that while circulating androgens are necessary for PARP-mediated TRPM2 injury in males, they are not sufficient to produce TRPM2 activation in females. Significance statement: TRPM2 is an ion channel that is activated by ischemia in stroke and contributes to neuronal injury only in males. We tested whether the lack of TRPM2 activation following stroke in females is caused by differences in sex steroids. Using adult female mice we show that removal of female steroids or addition of males hormones fail to engage TRPM2-mediated injury. This study is an important negative preclinical study demonstrating that alterations in sex steroids fails to engage the TRPM2 cell death pathways in the female brain.