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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Baixauli-Martín, Júlia  ORCID logo  https://orcid.org/0000-0003-1222-9171
Aliena-Valero, Alicia  ORCID logo  https://orcid.org/0000-0001-8858-0481
Castelló-Ruiz, María  ORCID logo  https://orcid.org/0000-0001-7814-4045
López-Morales, Mikahela A  ORCID logo  https://orcid.org/0000-0001-8282-0966

Abstract

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.

Description

Keywords

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

Journal Title

J Neuropathol Exp Neurol

Conference Name

Journal ISSN

0022-3069
1554-6578

Volume Title

81

Publisher

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