Leptin enhances MPP+-induced mitochondrial dysfunction: a potential for neuroprotection in parkinsonism

Abstract

OBJECTIVE: To investigate the effects of leptin in MPP+-induced mitochondrial dysfunction and oxidative stress in SH-SY5Y cells. BACKGROUND: Mitochondrial dysfunction, ATP deficiency, and oxidative stress are associated with neuronal cell death in Parkinson’s disease. Studies in regulation of energy balance in neurocircuitry are rapidly emerging. Recent studies have shown that the fat-derived hormone leptin acts as an afferent signal in a negative feedback loop to regulate energy homeostasis through receptor-mediated pathways in the central nervous system. We hypothesize that leptin administration might improve neuronal energy level by modulation of mitochondrial membrane potential and ATP production. METHODS: Leptin (0.1_M) were incubated in SH-SY5Y cells in normal and MPP_-induced (0.5mM) toxicity conditions for 24hr. ATP level, mitochondrial membrane potential and oxidative stress were measured by luciferase-luciferin bioassay and flow cytometry, respectively. RESULTS: MPP+ (0.5mM) at 24hr induced mitochondrial membrane depolarization by 45% and oxidative stress by 2.8 folds in SH-SY5Y cells. Leptin (0.1_M) slightly hyperpolarized mitochondrial membrane potential by 20% and significantly prevented MPP+ induced mitochondrial membrane depolarization. Single regimen of leptin alone remarkably increased ATP level by 48% at 4hr but declined to basal level after 48hr. Leptin had no effect on MPP_ induced oxidative stress. CONCLUSIONS: Leptin treatment improved mitochondrial efficiency by restoration of MPP_-induced mitochondrial depolarization and increase ATP production. These findings might contribute to the understanding of role of leptin in the neurocircuitry and provide insights on therapeutic possibilities in Parkinson’s disease.