The ellagitannin metabolite urolithin C attenuated cognitive impairment by inhibiting neuroinflammation via downregulation of MAPK/NF-kB signaling pathways in aging mice

The current study aimed to evaluate the preventive effects of urolithin C (Uro C), a gut microbial metabolite of ellagitannins on D-galactose (D-gal)-induced brain damage during the aging process and to elucidate the underlying mechanisms. In our study, the protective effect of Uro C on D-gal-induced BV2 microglia cell-mediated neuroinflammation damage in primary cortical neurons in vitro was confirmed. The results in an aging model in vivo induced by D-gal demonstrated that Uro C prevented D-gal-induced memory impairment, long-term potentiation (LTP) damage, and synaptic dysfunction through behavioral, electrophysiological, and histological examinations. Additionally, amyloidogenesis was observed in the central nervous system. The findings indicated that Uro C exhibited a preventive effect on the D-gal-induced elevation of β-amyloid (1-42 specific) (Aβ_1-42) accumulation, APP levels, ABCE1 levels, and the equilibrium of the cholinergic system in the aging mouse brain. Moreover, Uro C demonstrated downregulation of D-gal-induced glial overactivation through inhibition of the MAPK/NF-kB pathway. This resulted in the regulation of inflammatory mediators and cytokines, including iNOS, IL-6, IL-1β, and TNF-ɑ, in the mouse brain and BV2 microglial cells. Taken together, our results suggested that Uro C treatment could effectively mitigate the D-gal-induced memory impairment and amyloidogenesis, and the underlying mechanism might be tightly related to the improvement of neuroinflammation by suppressing the MAPK/NF-kB pathway, indicating Uro C might be an alternative and promising agent for the treatment of aging and age-associated brain diseases.