Labib_2026_J.Ethnopharmacol_361_121312

ETHNOPHARMACOLOGICAL RELEVANCE: Ellagitannins are natural bioactive polyphenols with well-known antioxidant properties, present in pomegranates, walnuts, berries, and traditional Chinese plants such as Phyllanthus species and Geranium species. Urolithin A (UA) is the main bioavailable metabolite produced from ellagitannins' metabolism by intestinal microbiota. The antioxidant and anti-inflammatory effects of UA are widely reported. Moreover, the neuroprotective effects of UA have been well-documented. Nevertheless, its neuroprotective potential against cyclophosphamide (CP)-provoked neurotoxicity has not been explored yet. AIM: The current investigation explored the neuroprotective potential of different doses of UA (2.5, 5, 10 mg/kg/day i.p. for 10 consecutive days) in CP (200 mg/kg on day 7)-intoxicated rats and the potential underlying mechanisms. RESULTS: UA (5 and 10 mg/kg) reversed cognitive deterioration in rats, recovered the hippocampal histological picture, and lessened the percentage of degenerated neurons. Accordingly, UA (5 mg/kg/day) was selected for the mechanistic study. UA counteracted CP-induced downregulation of the mitochondrial biogenesis signaling pathway, AMPK/SIRT1/PGC-1alpha/TFAM axis, with subsequent elevation in ATP levels. Furthermore, UA demonstrated antioxidant effects via elevating catalase activity and GSH in CP-intoxicated rats. Besides, UA repressed CP-induced increase in proinflammatory markers: NF-kappaB and TNF-alpha, proapoptotic markers: P53 and caspase-3, as well as acetylcholinesterase enzymatic activity. CONCLUSION: the results of this study propose UA as a neuroprotective agent against CP-induced neurotoxicity. These neuroprotective effects could be credited to the antioxidant, anti-inflammatory, and antiapoptotic actions of UA, with an evident relation to modulating acetylcholinesterase activity and upregulating the AMPK/SIRT1/PGC-1alpha/TFAM signaling pathway.