Ketamine, an NMDA receptor antagonist, induces cognitive impairments and neurotransmitter imbalances that resemble schizophrenia. In male Wistar rats, mangiferin—a potent antioxidant—was tested for its ability to reverse these effects. Mangiferin dose-dependently improved spatial learning, working memory, and recognition memory, and normalized locomotor activity. It restored cortical GABA and glutamate levels, reduced dopamine and acetylcholinesterase activity, preserved brain cell structure, and reversed ketamine-induced astrogliosis while increasing Nrf2 expression, indicating activation of antioxidant defenses. Mangiferin shows potential for treating neuropsychiatric conditions involving oxidative stress and glial dysfunction.
Ketamine triggers a rapid increase in histone H3 Ser10 phosphorylation in mouse hippocampal neurons and in the mouse hippocampus, an effect driven by JNK activation. Blocking JNK with SP600125 reversed this epigenetic change and reduced ketamine-induced hyperlocomotion and cognitive deficits. Multi-omics analysis 30 minutes after ketamine identified 262 differentially expressed genes, including MAP3K9, enriched in MAPK signaling and neuroactive ligand-receptor pathways, and 165 differentially accessible chromatin regions, with CTCF as a potential regulator. The findings suggest that JNK-mediated H3S10 phosphorylation links ketamine exposure to psychosis-like behaviors, offering a mechanistic connection between stress-sensitive signaling, rapid chromatin remodeling, and transcriptional reprogramming.