Mangiferin Mitigates Ketamine-Induced Dopaminergic and Glial Dysregulation and Modulates Nrf2 Expression in a Rat Schizophrenia-Like Model

Introduction: Schizophrenia involves dopaminergic dysregulation, oxidative stress, and glial activation within motor–cognitive circuits. Mangiferin, a polyphenolic C-glucoside from Mangifera indica , exerts antioxidant and anti-inflammatory effects partly via modulation of nuclear factor erythroid 2–related factor 2 (Nrf2) signaling. This study evaluated whether mangiferin attenuates ketamine-induced behavioral and neurobiological alterations along the basal ganglia–substantia nigra–cerebellar axis in rats. Methods: Male Wistar rats were assigned to seven groups (n = 6) and received vehicle, ketamine (50 mg/kg/day, i.p. 7 days), mangiferin (25– 75 mg/kg, p.o. 14 days), ketamine plus mangiferin (25, 50, 75 mg/kg), or ketamine plus risperidone (2 mg/kg, p.o). Y-maze and open-field tests were conducted at baseline, after ketamine, and after treatment. Striatum, substantia nigra, and cerebellum were analyzed for dopamine (HPLC), oxidative stress markers, inflammatory mediators, and immunohistochemistry for GFAP and Nrf2. Results: Ketamine produced behavioral alterations characterized by reduced exploratory activity, hyperlocomotion, and anxiety-like behavior, alongside elevated dopamine, reduced antioxidant enzyme activities, increased lipid peroxidation and pro-inflammatory mediators, enhanced GFAP immunoreactivity, and decreased Nrf2 immunoreactivity. Mangiferin, particularly at 50– 75 mg/kg, increased Y-maze arm entries toward control values (indicating improved locomotor activity), restored antioxidant defenses, reduced oxidative and inflammatory indices toward control levels, reduced astrocytosis, and increased Nrf2 immunoreactivity. Risperidone improved behavior and neuroinflammatory indices but showed less consistent normalization of redox markers and Nrf2 compared with high-dose mangiferin. Discussion: These findings indicate that mangiferin attenuates ketamine-induced behavioral, oxidative, inflammatory, and glial alterations in motor–cognitive circuits and are consistent with modulation of redox–glial interactions, including Nrf2-associated antioxidant signaling. Collectively, the results support further evaluation of mangiferin and related Nrf2-modulating natural products as adjunctive strategies targeting redox–glial dysfunction in schizophrenia. Keywords: schizophrenia, mangiferin, oxidative stress, Nrf2 pathway, astroglial activation