Both authors contributed equally to this work.
Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α-synuclein aggregation
Article first published online: 29 DEC 2011
© 2011 John Wiley & Sons A/S
Journal of Pineal Research
Volume 52, Issue 3, pages 312–321, April 2012
How to Cite
Chang, C.-F., Huang, H.-J., Lee, H.-C., Hung, K.-C., Wu, R.-T. and Lin, A. M.-Y. (2012), Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α-synuclein aggregation. Journal of Pineal Research, 52: 312–321. doi: 10.1111/j.1600-079X.2011.00945.x
- Issue published online: 20 MAR 2012
- Article first published online: 29 DEC 2011
- Accepted manuscript online: 29 NOV 2011 11:08AM EST
- Received October 5, 2011; Accepted November 23, 2011.
- kainic acid;
- mitochondria mass;
- α-synuclein aggregation
Abstract: In this study, the protective effect of melatonin on kainic acid (KA)-induced neurotoxicity involving autophagy and α-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 α-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 α-synuclein aggregation. Our immunoprecipitation study showed that melatonin enhanced ubiquitination of α-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 α-synuclein aggregation. Moreover, melatonin may exert its neuroprotection via inhibiting KA-induced autophagy and a subsequent mitochondrial loss as well as reducing α-synuclein aggregation by enhancing α-synuclein ubiquitination in the CNS.