Neuroprotective and Antidepressant Effects of Isorhamnetin: Mechanistic Evaluations in a Reserpine-Induced Mouse Model of Pain and Depression.

Depression and pain are frequently comorbid and interact to produce a more difficult clinical picture and decreased response to therapy. Isorhamnetin, a naturally occurring flavonoid, has been suggested to exert an impact on oxidative stress, inflammation, and neurotransmitter pathways related to both disorders. The objective of this work was to investigate the neuroprotective, antidepressant, and antinociceptive effects of isorhamnetin in reserpine-treated mice, which represent a model of pain-depression dyad. Three days of consecutive reserpine (0.5 mg/kg; s.c.) injection was used to establish the depression and pain model in adult male mice. Isorhamnetin (50 mg/kg) or gabapentin (10 mg/kg) was given orally 30 min before reserpine. Behavioral analyses, including electronic von Frey test (eVF) pressure application measurement (PAMF), forced swim test (FST), and Morris water maze (MWM), were performed. Biochemical analysis involved levels of oxidative stress markers (GSH, TBARS), the activity of monoamine oxidase-A (MAO-A) enzyme, proinflammatory cytokines (TNF-α, IL-1β), and brain aromatics levels (5-HT, NE, glutamate). Isorhamnetin restored the paw withdrawal thresholds to approximately those measured in the control group and decreased immobility times (p < 0.01). In the MWM, isorhamnetin significantly shortened the latency to find the platform (p < 0.001), implying good spatial memory. Biochemical assessments showed that isorhamnetin significantly reduced oxidative burden, as evidenced by elevated GSH concentrations (p < 0.001) and decreased TBERS levels (p < 0.05), while suppressing MAO-A activity (p < 0.05). It also decreased serum levels of TNF-α and IL-1β (p < 0.01) and normalized levels of neurotransmitters, with decreased glutamate and increased serotonin and norepinephrine (p < 0.05). Isorhamnetin exhibited marked antidepressant, antinociceptive, and cognitive-improving activities possibly mediated via antioxidant, anti-inflammatory, and monoaminergic modulatory actions. These observations emphasize the therapeutic promise for treating the complex clinical coexistence of chronic pain and depression.