Vitamin D3 (VD) deficiency is a global health concern, and supplementation has been shown to alleviate inflammation and oxidative stress in numerous neurological disorders. However, the beneficial effect of this common nutraceutical in schizophrenia (SCZ) remains inadequately explored. The present study investigated the presupplementation effects of VD on positive and cognitive symptoms in a MK-801induced mouse model of SCZ. MK-801, a non-competitive NMDA receptor antagonist, is a widely used drug that mimics some of the psychotic symptoms associated with SCZ. The repeated administration of a single dose of MK-801 (0.5mg/kg; intraperitoneally) for two weeks produced hyperlocomotion, anxiety- like behavior, and working memory deficits in SCZ mice. These behavioral abnormalities were significantly attenuated in VS5 mice (SCZ mice presupplemented with 500 IU/kg/day of VD). At the molecular level, VD rescued gene expression of major NMDA receptor subunits (NR1, NR2A, NR2B), alpha7 nicotinic acetylcholine receptors (alpha7nAChRs), and neurotrophin factors (NGF and BDNF). A restoration of PSD-95 protein expression, accompanied by downregulation of calcineurin, was also observed in the prefrontal cortex (PFC) of VS5 mice, suggesting a VD synaptic-savior effect and neuroprotection in SCZ. In vitro studies showed that calcitriol treatment of HEK-293 T cells transfected with alpha7nAChRs potentiated the single-channel current amplitude and demonstrated a direct modulatory effect of this nutraceutical on ligand-gated ion-channel activity. In silico JASPAR analysis further identified putative Vitamin D response elements (VDREs) within the promoter regions of various target genes, supporting the genomic action of VD. Additionally, VD deficiency was observed in Indian SCZ patients, highlighting its potential clinical relevance. Together with our previous findings of an anti-inflammatory, anti-cholinesterase, and neurotrophic-enhancing effect following post-supplementation with VD in a mouse model of HD (Manjari et al., 2022, 2023), the present study shows that VD presupplementation mitigates behavioral and molecular abnormalities in SCZ. Overall, our data deepens the knowledge on the multifaceted neuroprotective effects of D3 neurosteroid and nutraceutical in neuropsychiatric disorders like SCZ.
Komal, P.
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