RRC ID 60746
著者 Toda T, Yamamoto S, Umehara N, Mori Y, Wakamori M, Shimizu S.
タイトル Protective Effects of Duloxetine against Cerebral Ischemia-Reperfusion Injury via Transient Receptor Potential Melastatin 2 Inhibition.
ジャーナル J Pharmacol Exp Ther
Abstract Activation of transient receptor potential melastatin 2 (TRPM2), an oxidative stress-sensitive Ca2+-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 Ca2+ 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 Ca2+ 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.
巻・号 368(2)
ページ 246-254
公開日 2019-1-1
DOI 10.1124/jpet.118.253922
PII jpet.118.253922
PMID 30523061
MeSH Animals Antidepressive Agents / pharmacology Antidepressive Agents / therapeutic use Brain Ischemia / metabolism* Brain Ischemia / prevention & control Dose-Response Relationship, Drug Duloxetine Hydrochloride / pharmacology Duloxetine Hydrochloride / therapeutic use* HEK293 Cells Humans Male Mice Mice, Inbred C57BL Mice, Knockout Neuroprotective Agents / pharmacology Neuroprotective Agents / therapeutic use* Reperfusion Injury / metabolism* Reperfusion Injury / prevention & control TRPM Cation Channels / antagonists & inhibitors* TRPM Cation Channels / metabolism*
IF 3.561
引用数 2
リソース情報
ヒト・動物細胞 293(RCB1637)