Alterations in glutamatergic and GABAergic signaling in ketamine-induced neurotoxicity: mangiferin mitigates neurochemical, oxidative, and astrocytic dysregulation in the rat temporal–frontal cortex

BACKGROUND: Ketamine is an antagonist of the N-Methyl-D-aspartate (NMDA) receptor with the effect of inducing aberrant excitatory-inhibitory neurotransmission and oxidative neurotoxicity, which mimic the cognitive impairments found in schizophrenia. This study explored the potential of mangiferin, a strong antioxidant xanthone polyphenol, to normalize neurotransmitter levels and mitigate oxidative and glial changes in rats subjected to ketamine treatment. METHODS: Male Wistar rats were anaesthetised with ketamine (50 mg/kg, i.p., for 7 days) to induce excitotoxicity and subsequently treated for 14 days with mangiferin (25, 50 or 75 mg/kg, p.o.) or risperidone (2 mg/kg, i.p.). Behavioral performance was assessed using the Morris Water Maze, Y-Maze, Open Field, and Novel Object Recognition tests. Neurochemical assays in the prefrontal, hippocampal and temporal cortices measured glutamate, γ-aminobutyric acid (GABA), dopamine, and acetylcholinesterase (AChE) activities. Cellular pathology was evaluated through histopathology (H&E) and immunohistochemistry for glial fibrillary acidic protein (GFAP) and nuclear factor erythroid 2-related factor 2 (Nrf2). RESULTS: Ketamine induced severe cognitive deficits, hyperlocomotion, anxiety-like behavior, reduced cortical GABA and glutamate levels, increased dopamine, and elevated AChE activity-confirming excitatory-inhibitory imbalance and cholinergic disruption. Mangiferin enhanced spatial learning, working memory, recognition memory, and normalized locomotor activity in a dose-dependent manner, with higher doses restoring performance to near control levels. Neurochemically, mangiferin increased GABA and glutamate to baseline levels while decreasing dopamine and AChE hyperactivity. Histology showed preserved cortical cytoarchitecture and reduced neuronal loss and vacuolation. Notably, mangiferin reversed ketamine-induced astrogliosis (decreased GFAP immunoreactivity) and increased nuclear Nrf2 expression, indicating activated endogenous antioxidant defenses. CONCLUSION: Mangiferin exhibited significant neuroprotection against ketamine-induced excitotoxicity through restoration of neurotransmitter homeostasis, establishment of redox resilience, and regulation of astrocytic reactivity. These multifaceted actions underscore its therapeutic potential for neuropsychiatric diseases associated with oxidative stress and glial dysfunction.