title: Caspase-11 plays an essential role in methamphetamine-induced dopaminergic neuron apoptosis.
abstract: Methamphetamine (METH) is an extremely addictive stimulant drug that is widely used with high potential of abuse. Previous studies have shown that METH exposure damages the nervous system, especially dopaminergic neurons. However, the exact molecular mechanisms of METH-induced neurotoxicity remain unclear. We hypothesized that caspase-11 is involved in METH-induced neuronal apoptosis. We tested our hypothesis by examining the change of caspase-11 protein expression in dopaminergic neurons (PC12 and SH-SY5Y) and in the midbrain of rats exposed to METH with Western blotting. We also determined the effects of blocking caspase-11 expression with wedelolactone (a specific inhibitor of caspase-11) or siRNA on METH-induced apoptosis in PC12 cells and SH-SY5Y cells using Annexin V and TUNEL staining. Furthermore, we observed the protein expression changes of the apoptotic markers, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase 1 (PARP), after silencing the caspase-11 expression in rat midbrain by injecting LV-shcasp11 lentivirus using a stereotaxic positioning system. Results showed that METH exposure increased caspase-11 expression both in vitro and in vivo, with the effects in vitro being dose- and time-dependent. Inhibition of caspase-11 expression with either wedelolactone or siRNAs reduced the number of METH-induced apoptotic cells. In addition, blocking caspase-11 expression inhibited METH-induced activation of caspase-3 and PARP in vitro and in vivo, suggesting that caspase-11/caspase-3 signal pathway is involved in METH-induced neurotoxicity. These results indicate that caspase-11 plays an essential role in METH-induced neuronal apoptosis and may be a potential gene target for therapeutics in METH-caused neurotoxicity.
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Weiye
authors: W
authors: Huang
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506 hjwang711@yahoo.cn.
authors: Wei-Bing
authors: WB
authors: Xie
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Dongfang
authors: D
authors: Qiao
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Pingming
authors: P
authors: Qiu
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Enping
authors: E
authors: Huang
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Bing
authors: B
authors: Li
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Chuanxiang
authors: C
authors: Chen
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Chao
authors: C
authors: Liu
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Qi
authors: Q
authors: Wang
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506.
authors: Zhoumeng
authors: Z
authors: Lin
authors: *Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China, Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China and Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506 hjwang711@yahoo.cn.
authors: Huijun
authors: H
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D020868:Gene Silencing; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D008694:Methamphetamine; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases
keywords: apoptosis; caspase-11; dopamine; methamphetamine; neurotoxicity
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