• Takahiko Imai, Hirofumi Matsubara, Shinsuke Nakamura, Hideaki Hara, and Masamitsu Shimazawa.
• Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
• Neuroscience. 2020 Sep 1; 443: 110-119.

AbstractAfter ischemic stroke, oxygen and nutrition depletion induce mitochondrial dysfunction, which aggravates brain injury. Bendavia, a mitochondria-targeted tetra-peptide, has anti-oxidative and anti-inflammatory activities. We previously reported that bendavia protected human brain microvascular endothelial cells against oxygen/glucose deprivation (OGD)-induced damage via preserving mitochondrial function. The effects of bendavia on mitochondrial function include the inhibition of reactive oxygen species (ROS) production, inhibition of apoptosis, and restoration of adenosine tri-phosphate synthesis. However, the influence of bendavia on the blood-brain barrier (BBB) and neurons after brain ischemia/reperfusion damage is unclear. The aim of this study was to investigate whether bendavia has protective effects against ischemia/reperfusion damage using both in vivo and in vitro models. The in vivo experiments were conducted in mice, which were subjected to transient middle cerebral occlusion (t-MCAO) to induce brain ischemia/reperfusion damage. After t-MCAO, the cerebral blood flow (CBF), neurological deficits, infarct volume, BBB permeability, and microglia/macrophage activation were assessed. Compared to the vehicle group, bendavia administration (administered twice; immediately after reperfusion and 4 h later) attenuated the sensori-motor dysfunction and infarct formation independent of CBF variation. In addition, bendavia decreased BBB hyper-permeability and microglia/macrophage activation. The in vitro experiments were conducted utilizing two models: (1) OGD/re-oxygenation (OGD/R) or (2) hydrogen peroxide (H2O2)-induced neuron damage. In both models, bendavia inhibited neuronal cell death induced by OGD/R or H2O2. These findings indicated that bendavia attenuated brain ischemia/reperfusion damage and has direct neuroprotective effects against cell injury. Therefore, bendavia may be a novel therapeutic agent to improve ischemic stroke patient outcome.Copyright © 2020 IBRO. Published by Elsevier Ltd. All rights reserved.

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