Diosmetin attenuates chronic unpredictable mild stress induced-depression-like behavior in mice via modulation of oxidative stress, neuroinflammation, and the gut-brain axis.
Depression is a highly prevalent affective disorder, and current pharmacotherapies are often limited by suboptimal efficacy and adverse effects. Diosmetin, a dietary flavonoid, exhibits neuroprotective properties through antioxidant and anti-inflammatory mechanisms; however, its antidepressant potential remains insufficiently explored. This study evaluated the antidepressant-like effects of diosmetin in a chronic unpredictable mild stress (CUMS)-induced mouse model. For the induction of depression-like behavior, male BALB/c mice were subjected to a different stressor protocol. Diosmetin (10, 20, and 40 mg/kg (p.o.)) was administered for 4 weeks alongside continued stress exposure. Behavioral outcomes were complemented by photoacoustic imaging, followed by biochemical, molecular, and histological analyses of brain tissues. Colon tissues were also assessed for oxidative stress and histopathological changes, and fecal samples were analyzed for short-chain fatty acid (SCFA) levels. CUMS exposure induced significant depressive-like behavior and cognitive deficits, which were markedly attenuated by diosmetin treatment. Diosmetin reduced oxidative stress (decreased ROS and nitrite; increased GSH) and upregulated antioxidant markers NRF2 and HO-1. It also suppressed neuroinflammation (reduced iNOS and NLRP3), inhibited apoptosis (decreased cytochrome c and cleaved caspase 3), and restored BDNF levels. Imaging findings indicated improved cerebral hemodynamics, while histological analysis showed reduced neuronal degeneration with diosmetin treatment. Additionally, diosmetin ameliorated colonic oxidative stress and restored altered SCFA profiles. Overall, diosmetin exhibited significant antidepressant-like effects that were associated with normalization of the NRF2/HO-1 antioxidant and NLRP3 inflammasome pathways, reduced apoptosis, improved neurotrophic signaling, and restoration of SCFA levels. These findings suggest that the interconnected pathways may contribute to the antidepressant-like effects of diosmetin, warranting further mechanistic investigation.