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Int. J. Mol. Sci. 2014, 15(1), 1625-1646; doi:10.3390/ijms15011625
Article

Resveratrol Partially Prevents Rotenone-Induced Neurotoxicity in Dopaminergic SH-SY5Y Cells through Induction of Heme Oxygenase-1 Dependent Autophagy

1,2,3,†
, 1,2,3,†
, 1,2,3,4
, 1,2,3,4
, 1,3
, 2,5
, 2,6,* , 2,7
, 2,8
, 2,9
 and 1,2,3,*
1 Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 2 Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 3 Center of Parkinson's Disease, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 4 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan 5 Division of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 6 Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 7 Department of Chinese Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 8 Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 9 Department of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 11 November 2013 / Revised: 8 January 2014 / Accepted: 14 January 2014 / Published: 22 January 2014
(This article belongs to the Special Issue Neuroprotective Strategies 2014)
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Abstract

Parkinson disease (PD) is a complex neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons. Mitochondrial dysfunction, oxidative stress or protein misfolding and aggregation may underlie this process. Autophagy is an intracellular catabolic mechanism responsible for protein degradation and recycling of damaged proteins and cytoplasmic organelles. Autophagic dysfunction may hasten the progression of neuronal degeneration. In this study, resveratrol promoted autophagic flux and protected dopaminergic neurons against rotenone-induced apoptosis. In an in vivo PD model, rotenone induced loss of dopaminergic neurons, increased oxidation of mitochondrial proteins and promoted autophagic vesicle development in brain tissue. The natural phytoalexin resveratrol prevented rotenone-induced neuronal apoptosis in vitro, and this pro-survival effect was abolished by an autophagic inhibitor. Although both rotenone and resveratrol promoted LC3-II accumulation, autophagic flux was inhibited by rotenone and augmented by resveratrol. Further, rotenone reduced heme oxygenase-1 (HO-1) expression, whereas resveratrol increased HO-1 expression. Pharmacological inhibition of HO-1 abolished resveratrol-mediated autophagy and neuroprotection. Notably, the effects of a pharmacological inducer of HO-1 were similar to those of resveratrol, and protected against rotenone-induced cell death in an autophagy-dependent manner, validating the hypothesis of HO-1 dependent autophagy in preventing neuronal death in the in vitro PD model. Collectively, our findings suggest that resveratrol induces HO-1 expression and prevents dopaminergic cell death by regulating autophagic flux; thus protecting against rotenone-induced neuronal apoptosis.
Keywords: Parkinson’s disease; oxidative stress; mitochondrial dysfunction; autophagy; apoptosis; resveratrol; heme oxygenase-1 Parkinson’s disease; oxidative stress; mitochondrial dysfunction; autophagy; apoptosis; resveratrol; heme oxygenase-1
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Lin, T.-K.; Chen, S.-D.; Chuang, Y.-C.; Lin, H.-Y.; Huang, C.-R.; Chuang, J.-H.; Wang, P.-W.; Huang, S.-T.; Tiao, M.-M.; Chen, J.-B.; Liou, C.-W. Resveratrol Partially Prevents Rotenone-Induced Neurotoxicity in Dopaminergic SH-SY5Y Cells through Induction of Heme Oxygenase-1 Dependent Autophagy. Int. J. Mol. Sci. 2014, 15, 1625-1646.

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