Activation of Nrf2 by methylene blue is associated with the neuroprotection against MPP+ induced toxicity via ameliorating oxidative stress and mitochondrial dysfunction

Abstract

The neuropathological hallmark of Parkinson's disease (PD) is the preferential loss of dopaminergic neurons in the substantia nigra and presence of Lewy bodies in the dying neurons. Though specific molecular mechanisms for the neurodegeneration remains to be clarified, mitochondrial dysfunction and increased oxidative stress are major players associated with PD pathogenesis and these pathogenic mechanisms can be reproduced in cells and animals by application of various neurotoxins such as MPP⁺. In this study, we attempted to determine the neuroprotective effects of methylene blue (MB) against 1-methyl-4-phenylpyridinium (MPP⁺)-induced neurotoxicity, and to elucidate its action mechanism. We observed that MB attenuated MPP⁺-induced apoptotic cell death in SH-SY5Y cells and the mescencephalic dopaminergic neurons. In addition, MB protected the cells against MPP⁺-induced oxidative stress and mitochondrial dysfunction as evidenced by restoration of mitochondrial complex I activity and ATP levels, and attenuation of oxidative stress. Moreover, we demonstrated that MB induced antioxidant molecules, and activated Nrf2 pathway through AKT activation. These results indicate that MB protects the neurons from MPP⁺-induced toxicity through activation of antioxidant system, thereby reducing the oxidative stress and mitochondrial impairment, implying the potential use of MB in the treatment of neurodegenerative diseases such as PD.

Keywords: MPP(+); Methylene blue; Mitochondria; Oxidative stress; Parkinson’s disease.