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

Autores de IIS La Fe

• Julia Baixauli Martín

  Autor

• Alicia Aliena Valero

  Autor

• María Castelló Ruiz

  Autor

• María Consuelo Burguete López

  Autor

• Mikahela Andrea López Morales

  Autor

• Germán Torregrosa Bernabé

  Autor

• Juan Bautista Salom Sanvalero

  Autor

Participantes ajenos a IIS La Fe

• Munoz-Espin, Daniel

Grupos

• Unidad Mixta de Investigación Cerebrovascular

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 p16(INK4a); and 3) expression of the senescence-associated secretory phenotype cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) 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 p16(INK4a), and that of IL-6, TNF-alpha, and IL-1 beta, 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.

© The Author(s) 2022. Published by Oxford University Press on behalf of American Association of Neuropathologists, Inc. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Keywords

• Cellular senescence; Ischemic stroke; Lipofuscin; Senescence-associated secretory phenotype; Senolytic drugs; Transient middle cerebral artery occlusion