Premium
Melatonin attenuates kainic acid‐induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α‐synuclein aggregation
Author(s) -
Chang ChiaFu,
Huang HuiJu,
Lee HsinChen,
Hung KaiChih,
Wu RongTsun,
Lin Anya MaanYuh
Publication year - 2012
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2011.00945.x
Subject(s) - melatonin , neurotoxicity , neuroprotection , autophagy , kainic acid , chemistry , apoptosis , medicine , biology , endocrinology , microbiology and biotechnology , biochemistry , pharmacology , glutamate receptor , toxicity , receptor
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.