Journal
JOURNAL OF PINEAL RESEARCH
Volume 52, Issue 3, Pages 312-321Publisher
WILEY
DOI: 10.1111/j.1600-079X.2011.00945.x
Keywords
autophagy; kainic acid; melatonin; mitochondria mass; ubiquitination; a-synuclein aggregation
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Funding
- Institute of Biomedical Sciences, Academia Sinica
- School of Life Sciences, National Yang-Ming University
- Ministry of Education, Aim for the Top University Plan, Taipei, Taiwan, China
- [NSC100-2320-B-010-005]
- [VGH100C-010]
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In this study, the protective effect of melatonin on kainic acid (KA)-induced neurotoxicity involving autophagy and a-synuclein aggregation was investigated in the hippocampus of C57/BL6 mice. Our data showed that intraperitoneal injection of KA (20 mg/kg) increased LC3-II levels (a hallmark protein of autophagy) and reduced mitochondrial DNA content and cytochrome c oxidase levels (a protein marker of mitochondria). Atg7 siRNA transfection prevented KA-induced LC3-II elevations and mitochondria loss. Furthermore, Atg7 siRNA attenuated KA-induced activation of caspases 3/12 (biomarkers of apoptosis) and hippocampal neuronal loss, suggesting a pro-apoptotic role of autophagy in the KA-induced neurotoxicity. Nevertheless, KA-induced a-synuclein aggregation was not affected in the Atg7 siRNA-transfected hippocampus. The neuroprotective effect of melatonin (50 mg/kg) orally administered 1 hr prior to KA injection was studied. Melatonin was found to inhibit KA-induced autophagy-lysosomal activation by reducing KA-induced increases in LC3-II, lysosomal-associated membrane protein 2 (a biomarker of lysosomes) and cathepsin B (a lysosomal cysteine protease). Subsequently, KA-induced mitochondria loss was prevented in the melatonin-treated mice. At the same time, melatonin reduced KA-increased HO-1 levels and a-synuclein aggregation. Our immunoprecipitation study showed that melatonin enhanced ubiquitination of a-synuclein monomers and aggregates. The anti-apoptotic effect of melatonin was demonstrated by attenuating KA-induced DNA fragmentation, activation of caspases 3/12, and neuronal loss. Taken together, our study suggests that KA-induced neurotoxicity may be mediated by autophagy and a-synuclein aggregation. Moreover, melatonin may exert its neuroprotection via inhibiting KA-induced autophagy and a subsequent mitochondrial loss as well as reducing a-synuclein aggregation by enhancing a-synuclein ubiquitination in the CNS.
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