Cytoprotective effect of melatonin against MPP+ toxicity in SH-SY5Y cells: Role sharing of two types of antioxidative activities of melatonin

Melatonin is a neurohormone that is not only a regulator of circadian cycles, but also a potent antioxidant. Parkinson's disease (PD) is a major neurodegenerative disease that may result from oxidative stress as a part of its pathogenic cascade. Therefore, antioxidants, including melatonin, have attracted attention as potential candidates for neuroprotection against PD-related neurotoxicity. In this study, we report that melatonin has 2 types of antioxidant mechanisms of neuroprotection in an experimental cellular PD model using 1-Methyl-4-phenylpyridinium ion (MPP+) in human neuroblastoma SH-SY5Y cells. The first mechanism is a classical antioxidative mechanism through the direct action of melatonin, which reduces lipid hydroperoxide and 8-OHdG. The second mechanism is an indirect antioxidative effect via the melatonin receptor (Mel-R)/PI3K/Akt/Nrf2 cascade. Melatonin and Mel-R agonist activated PI3K/Akt signaling and Nrf2. Both Mel-R antagonist and the PI3K inhibitor blocked transcription induced by Nrf2 and the cytoprotective effect of melatonin. Interestingly, the antioxidative effect due to the Nrf2-related mechanism contributed mainly to a decrease of protein carbonyl, but not to lipid hydroperoxide and 8-OHdG. Mel-R agonist also showed a similar effect. Our results elucidate the mechanism of melatonin's powerful antioxidative effect and suggest the application of melatonin therapy to PD-related cytotoxicity. [Display omitted] •Melatonin protects SH-SY5Y cells from Parkinson's disease-related toxicities.•Melatonin exerts two types of antioxidative activities, one is a direct antioxidant activity and the other is a receptor/signal transduction-related antioxidative activity, in SH-SY5Y cells.•Transduction-related antioxidative activity of melatonin mainly inhibits protein carbonylation.