Induction of Autophagy and Activation of SIRT‐1 Deacetylation Mechanisms Mediate Neuroprotection by the Pomegranate Metabolite Urolithin A in BV2 Microglia and Differentiated 3D Human Neural Progenitor Cells

Scope Urolithin A is an anti‐inflammatory and neuroprotective gut‐derived metabolite from ellagitannins and ellagic acid in pomegranate, berries, and nuts. The roles of SIRT‐1 and autophagy in the neuroprotective activity of urolithin A are investigated. Methods and results Analyses of culture supernatants from lipopolysaccharide‐stimulated BV2 microglia show that urolithin A (2.5–10 µ m ) produced significant reduction in the production of nitrite, tumor necrosis factor (TNF)‐α and IL‐6. The anti‐inflammatory effect of the compound is reversed in the presence of sirtuin (SIRT)‐1 and the autophagy inhibitors EX527 and chloroquine, respectively. Protein analyses reveal reduction in p65 and acetyl‐p65 protein. Treatment of BV2 microglia with urolithin A results in increased SIRT‐1 activity and nuclear protein, while induction of autophagy by the compound is demonstrated using autophagy fluorescent and autophagy LC3 HiBiT reporter assays. Viability assays reveal that urolithin A produces a neuroprotective effect in APPSwe‐transfected ReNcell VM human neural cells, which is reversed in the presence of EX527 and chloroquine. Increase in both SIRT‐1 and autophagic activities are also detected in these cells following treatment with urolithin A. Conclusions It has been proposed that SIRT‐1 activation and induction of autophagy are involved in the neuroprotective activity of urolithin A in brain cells.