Nicotine modulates α7nAChR associated ceramide-mitochondrial stress responses in Parkinsonian models

Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration accompanied by mitochondrial dysfunction and oxidative stress, yet the metabolic mechanisms underlying these pathological changes remain incompletely understood. Here, we investigated whether nicotine preserves dopaminergic integrity by modulating ceramide homeostasis through α7 nicotinic acetylcholine receptor (α7nAChR) signalling. In an MPTP mouse model, nicotine improved motor and exploratory deficits, preserved striatal tyrosine hydroxyl positive fibres, and selectively reversed ceramide accumulation in the striatum and plasma. Transcriptional analysis further showed that nicotine suppressed the induction of ceramide biosynthetic genes, suggesting regulation of sphingolipid remodelling in vivo. In MPP⁺ challenged SH-SY5Y cells, nicotine restored cell viability, mitochondrial membrane potential, respiratory function, and mitochondrial morphology while reducing reactive oxygen species (ROS) production and apoptosis. Time-resolved analyses revealed that nicotine modulated an evolving stress response, in which early oxidative stress preceded detectable ceramide accumulation, while later ceramide dysregulation was associated with sustained mitochondrial vulnerability. Targeted lipidomics confirmed that nicotine directly restrained ceramide accumulation in stressed neuronal cells. Genetic (siSPTLC1 or siCHRNA7), pharmacological (Myriocin or MLA), and exogenous ceramide supplementation studies further supported a model in which nicotine limits this ceramide associated mitochondrial stress response through α7nAChR associated metabolic regulation. Mechanistically, nicotine restored AKT signalling and the BCL2 to BAX balance while suppressing cleaved caspase-3. Together, these findings identify ceramide dysregulation as a functionally relevant component of Parkinsonian mitochondrial stress responses and support an α7nAChR associated ceramide regulatory mechanism through which nicotine limits neuronal vulnerability.