Exploring In situ neuroprotective mechanisms of nicotine in an MPTP-Induced Parkinson’s disease rat model using spatial metabolomics

Parkinson’s disease (PD) is characterized by profound metabolic disturbances in the brain, yet how these alterations vary across brain regions and respond to neuroprotective intervention remains poorly understood. Here, we applied airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) to map spatial metabolic changes in whole brains from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rats and to define the in situ metabolic effects of nicotine. Spatial metabolomics revealed marked region-dependent metabolic disruption in the PD brain and showed that nicotine broadly reversed the MPTP-induced shift in metabolic trajectories. In particular, nicotine restored dopamine-related metabolites in the striatum and midbrain, normalized γ-aminobutyric acid and serotonin in the hippocampus and thalamus, and alleviated biochemical features of mitochondrial stress by reducing AMP accumulation and restoring glutathione levels. Pathway analysis further identified glycerophospholipid metabolism as a shared regulatory axis across multiple brain regions, suggesting that recovery of membrane lipid homeostasis is a central component of nicotine-mediated neuroprotection. Together, these findings indicate that nicotine exerts spatially coordinated neuroprotective effects in PD by remodeling neurotransmitter balance, improving redox and energy homeostasis, and repairing membrane lipid metabolism. More broadly, this study highlights the value of spatial metabolomics for revealing brain-region-specific metabolic mechanisms of neurodegeneration and drug action.