Alterations in glutamatergic and GABAergic signaling in ketamine-induced neurotoxicity: mangiferin mitigates neurochemical, oxidative, and astrocytic dysregulation in the rat temporal-frontal cortex.
Godson Emeka Anyanwu, Victoria Onyemachi Chukwu, Nto Johnson Nto, Vivian Onyinye Ojiakor, Chinyere Nkemjika Anyanwu
Behavioral and Brain Functions June 28, 2026 DOI: 10.1186/s12993-026-00348-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Controlled experiment Peer reviewed |
|---|---|
| Population | Male Wistar rats |
| Interventions | Ketamine Mangiferin Risperidone |
| Dose | Ketamine 50 mg/kg i.p. for 7 days; Mangiferin 25, 50, or 75 mg/kg p.o. for 14 days; Risperidone 2 mg/kg i.p. |
| Duration | 7-day ketamine treatment followed by 14-day mangiferin or risperidone treatment |
| Measures | Morris Water Maze, Y-Maze, Open Field, Novel Object Recognition, glutamate, GABA, dopamine, acetylcholinesterase (AChE), histopathology (H&E), GFAP, Nrf2 |
| Topics | Ketamine Esketamine |
| Keywords | Astrocytes Cognitive impairment Gaba Gfap Glutamate Mangiferin Neurotransmitters Nrf2 Oxidative stress Wistar rats |
| Key findings | Mangiferin dose-dependently reversed ketamine-induced cognitive deficits, neurotransmitter imbalances, and glial changes in rats. |
Abstract
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. 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). 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. 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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 4
- The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders Molecular Psychiatry October 3, 2017
- Ketamine: NMDA Receptors and Beyond Journal of Neuroscience November 2, 2016
- Effect of Ketamine on Limbic GABA and Glutamate: A Human In Vivo Multivoxel Magnetic Resonance Spectroscopy Study Frontiers in Psychiatry September 8, 2020
- Mangiferin Mitigates Ketamine-Induced Dopaminergic and Glial Dysregulation and Modulates Nrf2 Expression in a Rat Schizophrenia-Like Model Journal of Experimental Pharmacology April 1, 2026