Urolithin A protects against domoic acid-induced cognitive deficits via promoting estrogen receptor-α-mediated mitochondrial biogenesis signaling in mice

Abstract

Recent studies have indicated that stress in the endoplasmic reticulum (ER) plays a role in the development of domoic acid-induced neurodegeneration. Urolithin A (Uro A) is an active metabolite of the plant polyphenol ellagic acid, which is generated by intestinal flora and offers positive health and biological benefits. Recent research has indicated that anthocyanins possess estrogenic properties and can boost the expression of estrogen receptor-α (ERα). In this study, we examined the effects of Uro A on cognitive deficits resulting from hippocampal mitochondrial dysfunction in mice exposed to domoic acid (DA) and explored the underlying mechanisms. Oral administration of Uro A to the DA-treated mice significantly improved their performance in behavioral tasks, such as step-through passive avoidance, Morris water maze, and open field test. These advancements were, to some extent, driven by the stimulation of mitochondrial biogenesis signaling through estrogen receptor-α and also by lowered expression levels of p47phox and gp91phox. A reduction in reactive oxygen species and protein carbonylation was noted, along with the inhibition of the signaling pathway related to ER stress. Moreover, Uro A greatly reduced ER stress-induced apoptosis, which prevented synaptic damage and restored the expression of memory-related proteins. The partial attenuation of the neuroprotective effects of Uro A in the mice given a combination of Uro A and DA, following the knockdown of ERα via short hairpin RNA, suggests that Uro A exerts its effects via several routes. Our findings imply that Uro A can be used to prevent and treat cognitive deficits associated with excitotoxicity and other brain disorders.