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Research Paper

An autophagic mechanism is involved in apoptotic death of rat striatal neurons induced by the non-N-methyl-D-aspartate receptor agonist kainic acid

Yan Wang, Rong Han, Zhong-Qin Liang, Jun-Chao Wu, Xing-Ding Zhang, Zhen-Lun Gu and Zheng-Hong Qin

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Previous studies found that kainic acid (KA)-induced apoptosis involved the lysosomal enzyme cathepsin B, suggesting a possible mechanism of autophagy in excitotoxicity. The present study was sought to investigate activation and contribution of autophagy to excitotoxic neuronal injury mediated by KA receptors. The formation of autophagosomes was observed with transmission electron microscope after excitotoxin exposure. The contribution of autophagic mechanisms to KA-induced up-regulation of microtubule-associated protein 1A/1B light chain 3 (LC3), lysosome-associated membrane protein 2 (LAMP2) and cathepsin B, release of cytochrome c, activation of caspase-3, down-regulation of Bcl-2, up-regulation of Bax, p53, puma and apoptotic death of striatal neurons were assessed with co-administration of the autophagy inhibitor 3-methyladenine (3-MA). These studies showed that KA brought about an increase in the formation of autophagosomes and autolysosomes in the cytoplasm of striatal cells. KA-induced increases in the ratio of LC3-II/LC3-I, LAMP2, cathepsin B, release of cytochrome c and activation of caspase-3 were blocked by pre-treatment with 3-MA. 3-MA also reversed KA-induced down-regulation of Bcl-2 and up-regulation of Bax protein levels, LC3, p53 and puma mRNA levels in the striatum. KA-induced internucleosomal DNA fragmentation and loss of striatal neurons were robustly inhibited by 3-MA. These results suggest that over-stimulation of KA receptors can activate autophagy. The autophagic mechanism participates in programmed cell death through regulating the mitochondria-mediated apoptotic pathway.

Authors

Yan Wang

Mass Spectrometry Resource, Boston University School of Medicine, Boston, MA USA

Rong Han

Department of Pharmacology and Laboratory of Aging and Nervous Diseases; Soochow University School of Medicine; Suzhou, China

Zhong-Qin Liang

Soochow University

Jun-Chao Wu

Soochow University

Xing-Ding Zhang

Department of Pharmacology and Laboratory of Aging and Nervous Diseases; Soochow University School of Medicine; Suzhou, China

Zhen-Lun Gu

Soochow University

Zheng-Hong Qin

Department of Pharmacology and Laboratory of Aging and Nervous Diseases; Soochow University School of Medicine; Suzhou, China

Purchase article for $19

Subscribe to this journal for $99/year