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Brain Cell Senescence: A New Therapeutic Target for the Acute Treatment of Ischemic Stroke.

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Baixauli-Martín, Júlia  ORCID logo
Aliena-Valero, Alicia  ORCID logo
Castelló-Ruiz, María  ORCID logo
López-Morales, Mikahela A  ORCID logo


Aging is a major risk factor for cerebral infarction. Since cellular senescence is intrinsic to aging, we postulated that stroke-induced cellular senescence might contribute to neural dysfunction. Adult male Wistar rats underwent 60-minute middle cerebral artery occlusion and were grouped according to 3 reperfusion times: 24 hours, 3, and 7 days. The major biomarkers of senescence: 1) accumulation of the lysosomal pigment, lipofuscin; 2) expression of the cell cycle arrest markers p21, p53, and p16INK4a; and 3) expression of the senescence-associated secretory phenotype cytokines interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β) were investigated in brain samples. Lipofuscin accumulation was scarce at the initial stage of brain damage (24 hours), but progressively increased until it reached massive distribution at 7 days post-ischemia. Lipofuscin granules (aggresomes) were mainly confined to the infarcted areas, that is parietal cortex and adjacent caudate-putamen, which were equally affected. The expression of p21, p53, and p16INK4a, and that of IL-6, TNF-α, and IL-1β, was significantly higher in the ischemic hemisphere than in the non-ischemic hemisphere. These data indicate that brain cell senescence develops during acute ischemic infarction and suggest that the acute treatment of ischemic stroke might be enhanced using senolytic drugs.



Cellular senescence, Ischemic stroke, Lipofuscin, Senescence-associated secretory phenotype, Senolytic drugs, Transient middle cerebral artery occlusion, Animals, Brain, Brain Ischemia, Cellular Senescence, Infarction, Middle Cerebral Artery, Interleukin-6, Ischemic Stroke, Lipofuscin, Male, Rats, Rats, Wistar, Stroke, Tumor Necrosis Factor-alpha, Tumor Suppressor Protein p53

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J Neuropathol Exp Neurol

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Oxford University Press (OUP)
Medical Research Council (MR/R000530/1)
Cancer Research UK (A26989)
Cancer Research UK (C62187/A29760)