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Mangiferin Mitigates Ketamine-Induced Dopaminergic and Glial Dysregulation and Modulates Nrf2 Expression in a Rat
Victoria Onyemachi Chukwu1,2, Godson Emeka Anyanwu3, Nto Johnson Nto1
1Department of Anatomy, University of Nigeria Enugu Campus, Enugu, Nigeria.
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.
Insights
Mangiferin, a natural compound, improved behavioral and neurobiological changes induced by ketamine in rats. This suggests mangiferin
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Schizophrenia is linked to dopamine imbalance, oxidative stress, and glial activation.
- Mangiferin, a plant polyphenol, has antioxidant and anti-inflammatory properties, potentially through Nrf2 signaling.
Purpose of the Study:
- To investigate mangiferin's effects on ketamine-induced behavioral and neurobiological changes in rats.
- To explore mangiferin's impact on motor-cognitive circuits, specifically the basal ganglia-substantia nigra-cerebellar axis.
Main Methods:
- Rats received ketamine, mangiferin, or both, with behavioral tests (Y-maze, open-field) and neurochemical analyses (dopamine, oxidative stress, inflammation, GFAP, Nrf2).
- Dose-response effects of mangiferin (25-75 mg/kg) were assessed, alongside a comparison with risperidone.
Main Results:
- Ketamine induced behavioral deficits, oxidative stress, inflammation, and altered glial/Nrf2 markers.
- Mangiferin (50-75 mg/kg) reversed ketamine-induced behavioral impairments, restored antioxidant defenses, reduced inflammation, and increased Nrf2 levels.
- Risperidone showed benefits but was less effective than high-dose mangiferin in normalizing redox and Nrf2 markers.
Conclusions:
- Mangiferin effectively counteracts ketamine-induced neurobiological and behavioral alterations.
- Results suggest mangiferin modulates redox-glial pathways, including Nrf2 signaling.
- Mangiferin shows potential as an adjunctive therapy for schizophrenia targeting redox-glial dysfunction.
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