Sex differences in neuroprotection provided by inhibition of TRPM2 channels following experimental stroke

Jia Jia, Saurabh Verma, Shin Nakayama, Nidia Quillinan, Marjorie R. Grafe, Patricia D. Hurn, Paco S. Herson

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

The calcium-permeable transient receptor potential M2 (TRPM2) ion channel is activated following oxidative stress and has been implicated in ischemic damage; however, little experimental evidence exists linking TRPM2 channel activation to damage following cerebral ischemia. We directly assessed the involvement of TRPM2 channels in ischemic brain injury using pharmacological inhibitors and short-hairpin RNA (shRNA)-mediated knockdown of TRPM2 expression. Each of the four TRPM2 inhibitors tested provided significant protection to male neurons following in vitro ischemia (oxygen-glucose deprivation, OGD), while having no effect in female neurons. Similarly, TRPM2 knockdown by TRPM2 shRNA resulted in significantly reduced neuronal cell death following OGD only in male neurons. The TRPM2 inhibitor clotrimazole reduced infarct volume in male mice, while having no effect on female infarct volume. Finally, intrastriatal injection of lentivirus expressing shRNA against TRPM2 resulted in significantly smaller striatal infarcts only in male mice following middle cerebral artery occlusion, having no significant effect in female mice. Data presented in the current study demonstrate that TRPM2 inhibition and knockdown preferentially protects male neurons and brain against ischemia in vitro and in vivo, indicating that TRPM2 inhibitors may provide a new therapeutic approach to the treatment of stroke in men.

Original languageEnglish (US)
Pages (from-to)2160-2168
Number of pages9
JournalJournal of Cerebral Blood Flow and Metabolism
Volume31
Issue number11
DOIs
StatePublished - Nov 1 2011

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Keywords

  • TRPM2
  • ischemia
  • neuroprotection
  • stroke

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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