Activation of Cellular Antioxidant Defense System by Naturally Occurring Dibenzopyrone Derivatives Confers Neuroprotection against Oxidative Insults

Seven dibenzopyrone phenolic derivatives, i.e., alternariol (1), alternariol 5-O-methyl ether (2), altenusin B (3), dehydroaltenusin (4), altenuene (5), altenusin (6), and alterlactone (7), were isolated from endophytic fungi Alternaria alternata extract, and these compounds' structures were elucidated based on various spectroscopic data. Compound 3, a diphenic acid derivative, was determined as a new compound. In this study, compounds 3, 4, 6, and 7 displayed remarkable neuroprotective effects against oxidative injuries by acting as potent activators of nuclear factorerythroid derived 2-like 2 (Nrf2) in PC12 cells. A mechanistic study indicated that these compounds induced the nuclear accumulation of Nrf2, promoted the expression of Nrf2-governed cytoprotective genes, and increased the cellular antioxidant capacity. More importantly, genetic silence of Nrf2 expression deprived the observed cytoprotection, highlighting the important role of Nrf2 in the protection of these compounds.

Automated summary

Seven dibenzopyrone phenolic derivatives were isolated from endophytic fungi Alternaria alternata extract, with compound 3 determined as a new compound. Compounds 3, 4, 6, and 7 showed significant neuroprotective effects in PC12 cells through activating Nrf2, promoting the expression of Nrf2-governed genes, and enhancing cellular antioxidant capacity. The genetic silence of Nrf2 expression eliminated the observed cytoprotection, emphasizing the crucial role of Nrf2 in the protection offered by these compounds.