title: Insulin-like growth factor binding protein 5 (IGFBP5) mediates methamphetamine-induced dopaminergic neuron apoptosis.
abstract: Overexposure to methamphetamine (METH), a psychoactive drug, induces a variety of adverse effects to the nervous system, including apoptosis of dopaminergic neurons. Insulin-like growth factor binding protein 5 (IGFBP5), a member of insulin-like growth factor (IGF) system, is a pro-apoptotic factor that plays important roles in neuronal apoptosis. To test the hypothesis that IGFBP5 can mediate METH-induced neuronal apoptosis, we examined IGFBP5 mRNA and protein expression changes in PC12 cells exposed to METH (3.0mM) for 24h and in the striatum of rats following 15 mg/kg × 8 intraperitoneal injections of METH at 12h interval. We also checked the effect on neuronal apoptosis after silencing IGFBP5 expression with TUNEL staining and flow cytometry; Western blot was used for detecting the expression of apoptotic markers active-caspase3 and PARP. To elucidate the mechanisms underlying IGFBP5-mediated neuronal apoptosis, we determined the release of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria after METH treatment with or without IGFBP5 knockdown. Our results showed that IGFBP5 expression was increased significantly after METH exposure in PC12 cells and in the METH-treated rats' striatum. Further, METH-exposed PC12 cells exhibited higher apoptosis-positive cell number and activity of caspase3 and PARP compared with control cells, while these changes can be blocked by silencing IGFBP5 expression. In addition, a significant increase of cyto c release from mitochondria after METH exposure was observed and it was inhibited after silencing IGFBP5 expression in PC12 cells. These results indicate that IGFBP5 plays key roles in METH-induced neuronal apoptosis and may be a potential gene target for therapeutics in METH-caused neurotoxicity.
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Dongfang
authors.initials: D
authors.lastname: Qiao
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Jingtao
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Cuiyun
authors.initials: C
authors.lastname: Le
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Enping
authors.initials: E
authors.lastname: Huang
authors.affiliation: Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
authors.forename: Pingming
authors.initials: P
authors.lastname: Qiu
authors.affiliation: Interdisciplinary Toxicology Program and Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA.
authors.forename: Zhoumeng
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China. Electronic address: xieweib@126.com.
authors.forename: Wei-Bing
authors.initials: WB
authors.lastname: Xie
authors.affiliation: Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, People's Republic of China. Electronic address: hjwang711@yahoo.cn.
authors.forename: Huijun
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects; D045304:Cytochromes c / Q000037:antagonists & inhibitors / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D020868:Gene Silencing; D020287:In Situ Nick-End Labeling; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism*; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage / Q000633:toxicity*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000209:etiology / Q000473:pathology / Q000628:therapy; D016716:PC12 Cells; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
chemical_list: D017304:Annexin A5; D018975:Insulin-Like Growth Factor Binding Protein 5; D012333:RNA, Messenger; D008694:Methamphetamine; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Apoptosis; Insulin-like growth factor binding protein 5 (IGFBP5); Methamphetamine (METH); Neurotoxicity