Journal
EXPERIMENTAL NEUROLOGY
Volume 283, Issue -, Pages 151-156Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2016.06.015
Keywords
TRPM2 channel; Experimental stroke; Cerebral ischemia; Aging; Sex
Categories
Funding
- [NIH R01 NS092645]
- [NIH R01 NS080851]
- [AHA 14GRNT18190012]
- [NIH T32 HD 007186]
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Introduction: TRPM2 channels have been suggested to play a role in ischemic neuronal injury, specifically in males. A major hindrance to TRPM2 research has been the lack of specific TRPM2 inhibitors. The current study characterized the specificity and neuroprotective efficacy of a novel TRPM2 inhibitor. Methods: Fluorescent calcium imaging (Fluo5F) was used to determine inhibitor efficacy of the TRPM2 peptide inhibitor (tat-M2NX) in HEK293 cells stably expressing hTRPM2. Adult (2-3 months) and aged (18-20 months) mice were subjected to 60 min middle cerebral artery occlusion (MCAO) and injected with tat-M2NX, control scrambled peptide (tat-SCR) or clotrimazole (CTZ) either 20 min prior or 3 h after reperfusion. Infarct size was assessed using TTC staining. Results: TRPM2 inhibition by tat-M2NX was observed by decreased Ca2+ influx following H2O2 exposure human TRPM2 expressing cells. Male mice pre-treated with tat-M2NX had smaller infarct volume compared to tat-SCR. No effect of tat-M2NX on infarct size was observed in female mice. Importantly, male TRPM2(-/-) mice were not further protected by tat-M2NX, demonstrating selectivity of tat-M2NX. Administration of tat-M2NX 3 h after re perfusion provided significant protection to males when analyzed at 24 h or 4 days after MCAO. Finally, we observed that tat-M2NX reduced ischemic injury in aged male mice. Conclusions: These data demonstrate the development of a new peptide inhibitor of TRPM2 channels that provides protection from ischemic stroke in young adult and aged male animals with a clinically relevant therapeutic window. (C) 2016 Elsevier Inc All rights reserved.
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