Interplay of Vitamin D3, Wnt/β-Catenin Pathway, and Oxidative DNA Injury in CMS-Induced Depression Model

Biomedicines. 2026 Apr 24;14(5):977. doi: 10.3390/biomedicines14050977.

ABSTRACT

Background/Objectives: Chronic Mild Stress (CMS) provokes neuroendocrine dysregulation and oxidative injury that compromise neuronal integrity and plasticity. Disruption of the canonical Wnt/β-catenin signaling pathway has been increasingly linked to stress-induced neurobiological dysfunction. Vitamin D3, a neuroactive hormone with antioxidant and immunomodulatory properties, may exert neuroprotection through modulation of this pathway and attenuation of oxidative damage. The study aims to investigate whether vitamin D3 mitigates CMS-induced alterations in Wnt/β-catenin signaling, oxidative stress markers, and oxidative DNA damage in male Wistar rats. Methods: Thirty-two male Wistar rats were randomly allocated into four groups (n = 8/group): control, CMS only, CMS + vitamin D3 (1000 IU/kg), and CMS + vitamin D3 (10,000 IU/kg). Vitamin D3 was administered intramuscularly three times weekly for 28 days. Hippocampal mRNA expression of Wnt pathway components and brain-derived neurotrophic factor (BDNF) was quantified by RT-qPCR using the 2^-ΔΔCt method. Oxidative stress was evaluated by measuring malondialdehyde, glutathione, superoxide dismutase, and catalase, while DNA damage was assessed via 8-OHdG ELISA. Results: CMS significantly downregulated Wnt1, β-catenin, and Axin2 mRNA expression (p < 0.05) while markedly upregulating GSK-3β (p < 0.001). Expression of BDNF was also reduced (p < 0.05). Biochemically, CMS increased MDA and 8-OHdG levels (both p < 0.001) and decreased glutathione (p < 0.001), superoxide dismutase, and catalase activities (p < 0.05). Vitamin D3 supplementation significantly reversed these transcriptional and biochemical alterations, restoring β-catenin signaling, improving antioxidant defenses, and reducing oxidative and genotoxic damage. Conclusions: Vitamin D3 confers significant neuroprotection under chronic stress by modulating Wnt/β-catenin signaling and attenuating oxidative and DNA damage, thereby enhancing neuronal resilience to prolonged stress exposure.

PMID:42193305 | PMC:PMC13205061 | DOI:10.3390/biomedicines14050977