Glutathione as a Potential Neuroprotectant Against MDMA-Induced Oxidative Stress, Neuroinflammation, and Apoptosis in the Rat Brain.

In male Wistar rats given MDMA (ecstasy) orally for 56 days, the drug caused oxidative damage, inflammation, neurotransmitter imbalances, and cell death in the brain, especially in the hippocampus. Co-administration of the antioxidant glutathione partially reversed these harmful effects at moderate MDMA doses by restoring antioxidant defenses, reducing inflammation, and preserving hippocampal structure. However, at higher MDMA doses, glutathione's protective effects were much weaker, indicating that additional treatments are needed to address excitotoxicity and mitochondrial dysfunction.

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Abstract

3,4-Methylenedioxymethamphetamine (MDMA), widely misused for its euphoric and stimulant properties, induces overt neurotoxicity in rodents and non-human primates and is associated with profound neurochemical and structural brain alterations. Its deleterious effects are primarily mediated through oxidative stress, neuroinflammatory responses, and apoptotic pathways. Glutathione, a crucial endogenous antioxidant, has been proposed as a potential neuroprotective agent capable of mitigating MDMA-induced cerebral damage.Sixty adult male Wistar rats were randomly assigned to six experimental groups and administered oral treatments for 56 days: MDMA (5 mg/kg or 15 mg/kg), glutathione (15 mg/kg), or their combinations. After treatment, brain tissues were harvested and evaluated for oxidative stress biomarkers (8-OHdG, MDA, GPx, GSH, GST, SOD), pro-inflammatory cytokines (MPO, NF-κB, TNF-α), ion transport enzymes (Na⁺/K⁺ ATPase, Ca²⁺ ATPase), neurotransmitter levels (dopamine, serotonin, AChE), and the apoptotic marker caspase-3. Histological analysis of the hippocampus was conducted to assess structural integrity. MDMA administration led to significant elevations in MDA and 8-OHdG, reductions in antioxidant enzymes (GPx, GST, GSH, SOD), upregulation of inflammatory mediators (MPO, NF-κB, TNF-α), and disruption of ion homeostasis via altered Na⁺/K⁺ ATPase and Ca²⁺ ATPase activities. Neurotransmitter imbalances were observed, characterized by increased AChE and serotonin levels and decreased dopamine. Caspase-3 activity was markedly elevated, indicating enhanced apoptosis. Co-administration of glutathione at low MDMA doses ameliorated these effects, restoring antioxidant defenses, suppressing inflammation, and preserving hippocampal architecture. However, its protective efficacy was notably diminished at higher MDMA concentrations. Glutathione confers partial neuroprotection against MDMA-induced neurotoxicity, particularly under moderate exposure conditions. Its antioxidative capacity contributes to the restoration of redox equilibrium and cellular integrity. Nonetheless, under high-dose MDMA exposure, the therapeutic potential of glutathione is limited, suggesting the necessity for complementary interventions targeting excitotoxicity and mitochondrial dysfunction.