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Heroin Activates ATF3 and CytC via c-Jun N-Terminal Kinase Pathways to Mediate Neuronal Apoptosis

Hongwei Pu, Xuemei Wang, Liping Su, Chuang Ma, Yan Zhang, Liping Zhang, Xiao Chen, Xiujuan Li, Hua Wang, Xiaoshan Liu, Jianlong Zhang

Department of Science and Research Education Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Sinciang, China (mainland)

Med Sci Monit Basic Res 2015; 21:53-62

DOI: 10.12659/MSMBR.893827

Available online: 2015-04-07

Published: 2015-04-07


BACKGROUND: Drug abuse and addiction has become a major public health problem that impacts all societies. The use of heroin may cause spongiform leukoencephalopathy (SLE).
MATERIAL AND METHODS: Cerebellar granule cells were derived from 7-day-old Sprague-Dawley rat pups.
Neurons were dissociated from freshly dissected cerebella by mechanical disruption in the presence of 0.125% trypsin and DNaseI and then seeded at a density of 4×10^6 cells/ml in Dulbecco’s modified Eagle’s medium/nutrient mixture F-12 ham’s containing 10% fetal bovine serum and Arc-C(sigma) at concentrations to inhibit glial cell growth inoculated into 6-well plates and a small dish.
RESULTS: We found that heroin induces the apoptosis of primary cultured cerebellar granule cells (CGCS) and that the c-Jun N-terminal kinase (JNK) pathway was activated under heroin treatment and stimulated obvious increases in the levels of C-jun, Cytc, and ATF3mRNA. CYTC and ATF3 were identified as candidate targets of the JNK/c-Jun pathway in this process because the specificity inhibitors SP600125 of JNK/C-jun pathways reduced the levels of C-jun, Cytc, and ATF3mRNA. The results suggested that SP600125 of JNK/C-jun can inhibit heroin-induced apoptosis of neurons.
CONCLUSIONS: The present study analyzes our understanding of the critical role of the JNK pathway in the process of neuronal apoptosis induced by heroin, and suggests a new and effective strategy to treat SLE.

Keywords: Animals, Activating Transcription Factor 3 - metabolism, Apoptosis - drug effects, Cytochromes c - metabolism, DNA Primers - genetics, Fluorescent Antibody Technique, Heroin - pharmacology, In Vitro Techniques, JNK Mitogen-Activated Protein Kinases - metabolism, Neurons - pathology, Rats, Rats, Sprague-Dawley, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction - drug effects