title: Sex differences in neuroprotection provided by inhibition of TRPM2 channels following experimental stroke.
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.
authors.affiliation: Department of Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, Oregon 97201, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Jia
authors.forename: Saurabh
authors.initials: S
authors.lastname: Verma
authors.forename: Shin
authors.initials: S
authors.lastname: Nakayama
authors.forename: Nidia
authors.initials: N
authors.lastname: Quillinan
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.forename: Patricia D
authors.initials: PD
authors.lastname: Hurn
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003022:Clotrimazole / Q000008:administration & dosage / Q000627:therapeutic use; D003470:Culture Media / Q000737:chemistry; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008845:Microinjections; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010100:Oxygen / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D012727:Sex Characteristics; D020521:Stroke / Q000378:metabolism / Q000517:prevention & control*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D003470:Culture Media; D018696:Neuroprotective Agents; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D003022:Clotrimazole; D005947:Glucose; D010100:Oxygen