Ischemic Postconditioning Reduces NMDA Receptor Currents Through the Opening of the Mitochondrial Permeability Transitio
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ORIGINAL RESEARCH
Ischemic Postconditioning Reduces NMDA Receptor Currents Through the Opening of the Mitochondrial Permeability Transition Pore and KATP Channel in Mouse Neurons Yudai Morisaki1 · Ichiro Nakagawa1 · Yoichi Ogawa2 · Shohei Yokoyama1 · Takanori Furuta1 · Yasuhiko Saito2 · Hiroyuki Nakase1 Received: 25 July 2020 / Accepted: 3 November 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Ischemic postconditioning (PostC) is known to reduce cerebral ischemia/reperfusion (I/R) injury; however, whether the opening of mitochondrial ATP-dependent potassium (mito-KATP) channels and mitochondrial permeability transition pore (mPTP) cause the depolarization of the mitochondrial membrane that remains unknown. We examined the involvement of the mito-KATP channel and the mPTP in the PostC mechanism. Ischemic PostC consisted of three cycles of 15 s reperfusion and 15 s re-ischemia, and was started 30 s after the 7.5 min ischemic load. We recorded N-methyl-d-aspartate receptors (NMDAR)-mediated currents and measured cytosolic Ca2+ concentrations, and mitochondrial membrane potentials in mouse hippocampal pyramidal neurons. Both ischemic PostC and the application of a mito-KATP channel opener, diazoxide, reduced NMDAR-mediated currents, and suppressed cytosolic C a2+ elevations during the early reperfusion period. An mPTP blocker, cyclosporine A, abolished the reducing effect of PostC on NMDAR currents. Furthermore, both ischemic PostC and the application of diazoxide potentiated the depolarization of the mitochondrial membrane potential. These results indicate that ischemic PostC suppresses Ca2+ influx into the cytoplasm by reducing NMDAR-mediated currents through mPTP opening. The present study suggests that depolarization of the mitochondrial membrane potential by opening of the mito-KATP channel is essential to the mechanism of PostC in neuroprotection against anoxic injury. Keywords Ischemic postconditioning · NMDA receptor · Mitochondrial KATP channel · Mitochondrial permeability transition pore · Ca2+
Introduction Brain tissue ischemia–reperfusion (I/R) injury is a common characteristic of ischemic stroke which occurs when blood supply is restored after a period of ischemia. Although reperfusion is the main treatment for acute ischemic stroke (AIS), it can also worsen tissue damage and limit the recovery of Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10571-020-00996-y) contains supplementary material, which is available to authorized users. * Ichiro Nakagawa nakagawa@naramed‑u.ac.jp 1
Department of Neurosurgery, Nara Medical University, Shijocho 840, Kashihara, Japan
Department of Neurophysiology, Nara Medical University, Shijocho 840, Kashihara, Japan
2
function. It has been shown that the mechanisms underlying I/R injury include leukocyte infiltration, platelet activation, oxidative stress, complement activation, mitochondria-mediated mechanisms, disruption of the blood–brain barrier, and ul
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