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

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.

Automated summary

Aging is a risk factor for cerebral infarction, and brain cell senescence develops during acute ischemic infarction. The treatment of acute ischemic stroke might be enhanced using senolytic drugs.