Senolytic Therapy for Cerebral Ischemia-Reperfusion Injury.

Songhyun Lim,Young-Ju Kim,Cheesue Kim,Tae Jung Kim,Byung-Soo Kim,Sang-Bae Ko

doi:10.3390/ijms222111967

Abstract

Ischemic stroke is one of the leading causes of death, and even timely treatment can result in severe disabilities. Reperfusion of the ischemic stroke region and restoration of the blood supply often lead to a series of cellular and biochemical consequences, including generation of reactive oxygen species (ROS), expression of inflammatory cytokines, inflammation, and cerebral cell damage, which is collectively called cerebral ischemia-reperfusion (IR) injury. Since ROS and inflammatory cytokines are involved in cerebral IR injury, injury could involve cellular senescence. Thus, we investigated whether senolytic therapy that eliminates senescent cells could be an effective treatment for cerebral IR injury. To determine whether IR induces neural cell senescence in vitro, astrocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). OGD/R induced astrocyte senescence and senescent cells in OGD/R-injured astrocytes were effectively eliminated in vitro by ABT263, a senolytic agent. IR in rats with intraluminal middle cerebral artery occlusion induced cellular senescence in the ischemic region. The senescent cells in IR-injured rats were effectively eliminated by intravenous injections of ABT263. Importantly, ABT263 treatment significantly reduced the infarct volume and improved neurological function in behavioral tests. This study demonstrated, for the first time, that senolytic therapy has therapeutic potential for cerebral IR injury.

Highlights

Stroke is a leading cause of mortality and morbidity and is associated with a high disease burden because of disabilities related to the sequelae of stroke
Cell viability evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was not significantly different between normal astrocytes (NA) and astrocytes subjected to oxygen-glucose deprivation/reoxygenation (OGD/R)
This study demonstrated that ABT263, a senolytic drug, has therapeutic potential for the treatment of cerebral IR injury

Summary

Introduction

Stroke is a leading cause of mortality and morbidity and is associated with a high disease burden because of disabilities related to the sequelae of stroke. Of strokes are ischemic strokes that are caused by the occlusion of a cerebral artery [1,2,3]. Restoration of blood supply by reperfusion can salvage ischemic tissue but reperfusion per se causes tissue injury, which is called cerebral ischemia-reperfusion (IR). The pathology of cerebral IR injury involves the generation of excessive reactive oxygen species (ROS), oxidative damage to cells, activation of the inflammatory cascade reaction, and induction of cellular apoptosis in reperfused tissue [6,7,8,9]. Several studies have demonstrated the detrimental effects of ROS-induced damage on long-term stroke outcomes and redox imbalance-mediated impairment of neurobehavioral functions in cerebral IR-injured animals [10,11]. ROS inhibition and maintenance of redox balance would carry significant therapeutic benefit in cerebral IR injury

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Results

Conclusion