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

• Published in: Journal of neuropathology and experimental neurology Vol. 81; no. 8; pp. 614 - 620
• Main Authors: Baixauli-Martín, Júlia, Aliena-Valero, Alicia, Castelló-Ruiz, María, Burguete, María C, López-Morales, Mikahela A, Muñoz-Espín, Daniel, Torregrosa, Germán, Salom, Juan B
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.08.2022
• Subjects: Aging; Animals; Brain - pathology; Brain cells; Brain damage; Brain Ischemia - metabolism; Care and treatment; Cell cycle; Cells; Cellular Senescence; Cytokines; Degeneration; Diagnosis; Drug therapy; Growth; Health aspects; Infarction, Middle Cerebral Artery - metabolism; Interleukin-6; Interleukins; Ischemia; Ischemic Stroke; Lipofuscin - metabolism; Male; Nervous system; Physiological aspects; Rats; Rats, Wistar; Senescence; Stroke; Stroke (Disease); Tumor necrosis factor; Tumor Necrosis Factor-alpha; Tumor necrosis factor-TNF; Tumor proteins; Tumor Suppressor Protein p53 - metabolism; Spain; Senolytic drugs; Transient middle cerebral artery occlusion; Ischemic stroke; Lipofuscin; Senescence-associated secretory phenotype; Cellular senescence
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/nlac048

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.