Combined Vitamin D and Resveratrol Treatment Attenuates Motor Deficits and Neurodegeneration in a 6-OHDA Mouse Model of Parkinson's Disease in Male Mice: A Focus on Sirt1 and Lingo-1 Pathways in the Ventral Tegmental Area.

BACKGROUND: Parkinson's disease (PD) is characterized by progressive dopaminergic neurodegeneration, leading to severe motor impairments. Lingo-1 negatively regulates neuronal survival, while Sirtuin-1 (Sirt1) supports mitochondrial function and oxidative stress resistance. Given the neuroprotective properties of Vitamin D3 (VitD3) and resveratrol, this study examined whether their combined administration could modulate Sirt1 and Lingo-1 expression and attenuate neurodegeneration in a 6-hydroxydopamine (6-OHDA) model of PD. METHODS: Male Swiss mice were assigned to six groups: Control, Sham, 6-OHDA, 6-OHDA + Resveratrol (5 mg/kg), 6-OHDA + VitD3 (0.1 µg/kg), and 6-OHDA + Res + VitD3. Behavioral performance was evaluated using open field, footprint, wire grip, and rotarod tests. Neuronal integrity within the ventral tegmental area (VTA) was assessed via Nissl staining, while Sirt1 and Lingo-1 gene expression levels were quantified by RT-qPCR. RESULTS: 6-OHDA lesioning produced marked reductions in locomotor activity, grip strength, and rotarod performance, accompanied by significant neuronal loss in the VTA and dysregulated Sirt1/Lingo-1 expression. Treatment with VitD3 or resveratrol alone partially improved motor performance and reduced neuronal loss, whereas the combination therapy produced the most pronounced neuroprotection. Co-administration of VitD3 and resveratrol normalized Sirt1 expression, suppressed Lingo-1 upregulation, and preserved neuronal morphology in the VTA. CONCLUSIONS: Combined treatment with VitD3 and resveratrol mitigates motor deficits and neurodegeneration in 6-OHDA-lesioned mice which was associated with activation of Sirt1 and suppression of Lingo-1. The results suggest the therapeutic potential of targeting the Sirt1 and Lingo-1 signaling pathways via nutraceutical interventions as a disease-modifying strategy in PD.