Senolytic Therapy for Cerebral Ischemia-Reperfusion Injury

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.

EGCG protects the mouse brain against cerebral ischemia/reperfusion injury by suppressing autophagy via the AKT/AMPK/mTOR phosphorylation pathway

“…Tissue plasminogen activator (tPA) is the only supported pharmacological thrombolytic medicine because of its ability to recanalize arteries and improve clinical outcomes ( National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group, 1995 ). Restoration of the blood supply into the ischemic stroke region may also induce cerebral ischemia/reperfusion injury (CIRI) ( Lim et al, 2021 ). Moreover, only a shortage of patients with CIS benefits from tPA treatment due to the narrow therapeutic time window, tendency to transform into a hemorrhage, and other side effects ( Bansal et al, 2013 ; Yeo et al, 2013 ; Bhaskar et al, 2018 ).…”

Primary Graft Dysfunction: The Role of Aging in Lung Ischemia-Reperfusion Injury

“…Of additional clinical relevance, senolytics applied to organ donors prior to procurement, prolonged the survival of old cardiac allografts beyond that of young donors ( 125 ). Most recently, experimental models have indicated that IRI itself can induce senescence and that senolytics have the potential to ameliorate this injury ( 126 – 128 ). Notably, senolytics have been tested before in patients with idiopathic pulmonary fibrosis.…”

Regulatory mechanisms of tetramethylpyrazine on central nervous system diseases: A review

“…Evidence suggests that thrombolytic therapy effectively treats ischemic stroke and decreases morbidity and mortality when timely provided ( Man et al, 2020 ). Ischemia and reperfusion result in several cellular and biochemical consequences, including intracellular Ca 2+ overload, excitatory amino acid poisoning, inflammatory response, oxidative damage, apoptosis, and so forth ( Lo et al, 2003 ; Khatri et al, 2012 ; Radak et al, 2017 ; Lian et al, 2020 ; Lim et al, 2021 ). Novel treatments are urgently needed to prevent and treat the cerebral ischemia-reperfusion (I/R) injury.…”