Abstract
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 euthanized 24 h 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.
Highlights
Transient receptor potential M2 (TRPM2) channels are nonselective cation channels that are permeable to Naϩ, Kϩ, and Ca2ϩ
The results of this study suggest that the lack of TRPM2mediated injury mechanisms in females is not the result of differences in sex steroids
Neither removal of estrogen nor addition of androgens was capable of engaging TRPM2-mediated injury following experimental stroke in female animals
Summary
Transient receptor potential M2 (TRPM2) channels are nonselective cation channels that are permeable to Naϩ, Kϩ, and Ca2ϩ. The most well characterized role for the TRPM2 channel is its role in excessive Ca2ϩ influx following exposure of cells to oxidative stress, playing a pathological role in oxidative stress-induced cell injury (Kuhn et al, 2005; Miller, 2006; Miller and Zhang, 2011; Simon et al, 2013). Inhibitors and knockdown of TRPM2 expression reduce ischemic injury following experimental stroke [middle cerebral artery occlusion (MCAO)] in the male brain, while having no effect in the female brain (Jia et al, 2011; Shimizu et al, 2013). A male-specific role of TRPM2 in ischemia-induced neuronal injury has been demonstrated following global cerebral ischemia and in vitro (Verma et al, 2012; Nakayama et al, 2013). The focus of the current study is to test the hypothesis that hormonal differences in females underlie the lack of TRPM2 channel engagement following cerebral ischemia
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
