Protective effects of duloxetine against cerebral ischemia-reperfusion injury via transient receptor potential melastatin 2 inhibition

Takahiro Toda, Shinichiro Yamamoto, Noriko Umehara, Yasuo Mori, Minoru Wakamori, Shunichi Shimizu

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Activation of transient receptor potential melastatin 2 (TRPM2), an oxidative stress–sensitive Ca21-permeable channel, contributes to the aggravation of cerebral ischemia-reperfusion (CIR) injury. Recent studies indicated that treatment with the antidepressant duloxetine for 24 hours (long term) attenuates TRPM2 activation in response to oxidative stress in neuronal cells. To examine the direct effects of antidepressants on TRPM2 activation, we examined their short-term (0–30 minutes) treatment effects on H2O2-induced TRPM2 activation in TRPM2-expressing human embryonic kidney 293 cells using the Ca21 indicator fura-2. Duloxetine exerted the strongest inhibitory effects on TRPM2 activation among the seven antidepressants tested. These inhibitory effects appeared to be due to the inhibition of H2O2-induced TRPM2 activation via an open-channel blocking-like mechanism, because duloxetine reduced the sustained phase but not the initial phase of increases in intracellular Ca21 concentrations. In a whole-cell patch-clamp study, duloxetine reduced the TRPM2-mediated inward current during the channel opening state. We also examined the effects of duloxetine in a mouse model of CIR injury. The administration of duloxetine to wild-type mice attenuated CIR injury, similar to that in Trpm2 knockout (KO) mice. The administration of duloxetine did not reduce CIR injury further in Trpm2 KO mice, suggesting that it exerts neuroprotective effects against CIR injury by inhibiting TRPM2 activation. Regarding drug repositioning, duloxetine may be a useful drug in reperfusion therapy for ischemic stroke because it has already been used clinically in therapeutics for several disorders, including depression.

Original languageEnglish
Pages (from-to)246-254
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume368
Issue number2
DOIs
Publication statusPublished - 2019 Feb

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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