title: Heroin activates Bim via c-Jun N-terminal kinase/c-Jun pathway to mediate neuronal apoptosis.
abstract: Heroin is reported to cause spongiform leukoencephalopathy (SLE) in heroin addicts and the exact mechanism has not yet been identified. In the present study, we found that heroin could induce apoptosis of primary cultured cerebellar granule cells (CGCs) and Bim was upregulated both transcriptionally and post transcriptionally during CGCs apoptosis. Upregulated Bim translocated to mitochondria and Bax was activated under heroin treatment. Genetic knockdown of Bim using lentiviruses significantly prevented neuronal apoptosis induced by heroin. Meanwhile, c-Jun N-terminal kinase (JNK)/c-Jun pathway was activated in heroin-induced apoptosis. Bim was demonstrated as a downstream target of JNK/c-Jun pathway in this process because pharmacological inhibition of JNK reduced the levels of Bim mRNA and protein. These results indicate that Bim plays a critical role in the neurotoxic process by heroin and JNK/c-Jun pathway acts upstream of Bim in regulating heroin-induced neuronal death. This represents a detailed mechanism of heroin-induced neuronal apoptosis and may provide a new and effective strategy to treat heroin-induced addiction and SLE.
authors.affiliation: Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: M
authors.initials: M
authors.lastname: Tan
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Ma
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.forename: A
authors.initials: A
authors.lastname: Lu
authors.forename: W
authors.initials: W
authors.lastname: Gan
authors.forename: P
authors.initials: P
authors.lastname: Su
authors.forename: H
authors.initials: H
authors.lastname: Lin
authors.forename: S
authors.initials: S
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Lai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects*; D000072224:Bcl-2-Like Protein 11; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D003932:Heroin / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects*; D008928:Mitochondria / Q000378:metabolism; D009294:Narcotics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000187:drug effects*; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D009294:Narcotics; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D051028:bcl-2-Associated X Protein; D003932:Heroin; D048031:JNK Mitogen-Activated Protein Kinases