Vitamin D3 Neuroprotection Against Rotenone and MPTP in SH-SY5Y Cells.

Environmental neurotoxicants such as rotenone (RO) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are known to induce cytotoxicity in neural cells. This study aimed to investigate the neuroprotective properties of active vitamin D3 against the cytotoxic effects of RO and MPTP on undifferentiated human neuroblastoma (SH-SY5Y) cells. Exposure to these neurotoxins resulted in concentration- and time-dependent reductions in cell viability. Cotreatment with vitamin D significantly mitigated the cytotoxic impact of both compounds. Furthermore, vitamin D attenuated disruptions in noradrenaline turnover and acetylcholinesterase activity caused by neurotoxin exposure. Mechanistic exploration revealed that vitamin D preserved cellular bioenergetics by maintaining ATP levels, supporting Mitochondrial Complexes I and III activities, stabilizing mitochondrial membrane potential and reducing lactate accumulation. Vitamin D also reduced oxidative stress, as evidenced by lower reactive species production and lipid peroxidation, while enhancing catalase (CAT) activity in treated cells. In addition, vitamin D counteracted the upregulation of neurodevelopmental genes CAMK2A and CAMK2B induced by neurotoxin exposure. Collectively, these findings demonstrate that vitamin D3 confers significant neuroprotection against RO- and MPTP-induced toxicity in SH-SY5Y cells by modulating mitochondrial function, oxidative stress and neurochemical balance. These results support the potential therapeutic use of vitamin D3 to prevent or ameliorate neurodegenerative conditions and other neurological disorders characterized by mitochondrial dysfunction and oxidative damage.

© 2026 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.