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Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3)
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. Sufficien...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society for Neuroscience
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596140/ https://www.ncbi.nlm.nih.gov/pubmed/26464961 http://dx.doi.org/10.1523/ENEURO.0022-14.2014 |
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author | Quillinan, Nidia Grewal, Himmat Klawitter, Jelena Herson, Paco S. |
author_facet | Quillinan, Nidia Grewal, Himmat Klawitter, Jelena Herson, Paco S. |
author_sort | Quillinan, Nidia |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4596140 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Society for Neuroscience |
record_format | MEDLINE/PubMed |
spelling | pubmed-45961402015-10-13 Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3) Quillinan, Nidia Grewal, Himmat Klawitter, Jelena Herson, Paco S. eNeuro Disorders of the Nervous System 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. Society for Neuroscience 2014-11-12 /pmc/articles/PMC4596140/ /pubmed/26464961 http://dx.doi.org/10.1523/ENEURO.0022-14.2014 Text en Copyright © 2014 Quillinan et al. http://creativecommons.org/licenses/by-nc/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License Attribution-Noncommercial 4.0 International (http://creativecommons.org/licenses/by-nc/4.0/) which permits noncommercial reuse provided that the original work is properly attributed. |
spellingShingle | Disorders of the Nervous System Quillinan, Nidia Grewal, Himmat Klawitter, Jelena Herson, Paco S. Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3) |
title | Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3) |
title_full | Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3) |
title_fullStr | Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3) |
title_full_unstemmed | Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3) |
title_short | Sex Steroids Do Not Modulate TRPM2-Mediated Injury in Females following Middle Cerebral Artery Occlusion(1,2,3) |
title_sort | sex steroids do not modulate trpm2-mediated injury in females following middle cerebral artery occlusion(1,2,3) |
topic | Disorders of the Nervous System |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4596140/ https://www.ncbi.nlm.nih.gov/pubmed/26464961 http://dx.doi.org/10.1523/ENEURO.0022-14.2014 |
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