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Extended therapeutic window of a novel peptide inhibitor of TRPM2 channels following focal cerebral ischemia

2016; Elsevier BV; Volume: 283; Linguagem: Inglês

10.1016/j.expneurol.2016.06.015

1090-2430

Takeru Shimizu, Robert M. Dietz, Ivelisse Cruz‐Torres, Frank Strnad, Ana K. Garske, Myriam Moreno, Venugopal Reddy Venna, Nidia Quillinan, Paco S. Herson,

Neuroscience and Neuropharmacology Research

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. 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. 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 reperfusion 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. 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.