Extended Therapeutic Window of a Novel Peptide Inhibitor of TRPM2 Channels Following Focal Cerebral Ischemia
Medicine and Health Sciences
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 (2–3months) 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.
Venna, Venugopal Reddy, "Extended Therapeutic Window of a Novel Peptide Inhibitor of TRPM2 Channels Following Focal Cerebral Ischemia" (2016). UCHC Articles - Research. 304.
Exp Neurol. Author manuscript; available in PMC 2017 Jan 17. Published in final edited form as: Exp Neurol. 2016 Sep; 283(Pt A): 151–156. Published online 2016 Jun 15. doi: 10.1016/j.expneurol.2016.06.015 PMCID: PMC5240152 NIHMSID: NIHMS839587