Involvement of C/EBPβ-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis

• Published in: Toxicology letters 2019-09, Vol.312, p.11-21
• Main Authors: Huang, Enping, Huang, Hongyan, Guan, Tianshan, Liu, Chao, Qu, Dong, Xu, Yue, Yang, Jiao, Yan, Lei, Xiong, Yahui, Liang, Ting, Wang, Qi, Chen, Ling
• Format: Article
• Language: English
• Subjects: Apoptosis; Autophagy; C/EBPβ; Methamphetamine (METH); Neurotoxicity
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2019.05.003

C/EBPβ is involved in METH-induced autophagy and apoptosis through DDIT4/TSC2/mTOR signal axis and Trib3/Parkin/α-syn signaling pathway. [Display omitted] •Methamphetamine (METH) exposure increased p-TSC2/TSC2 protein expression ratio, decreased Parkin protein level.•C/EBPβ is involved in METH-induced autophagy through DDIT4/TSC2/mTOR signaling pathway.•C/EBPβ is involved in METH-induced apoptosis through Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Methamphetamine (METH) is a widely abused illicit psychoactive drug. Our previous study has shown that CCAAT-enhancer binding protein β (C/EBPβ) is an important regulator in METH-induced neuronal autophagy and apoptosis. However, the detailed molecular mechanisms underlying this process remain poorly understood. Previous studies have demonstrated that DNA damage-inducible transcript 4 (DDIT4), Trib3 (tribbles pseudo kinase 3), alpha-synuclein (α-syn) are involved in METH-induced dopaminergic neurotoxicity. We hypothesized that C/EBPβ is involved in METH-induced DDIT4-mediated neuronal autophagy and Trib3-mediated neuronal apoptosis. We tested our hypothesis by examining the effects of silencing C/EBPβ, DDIT4, Trib3 or α-syn with small interfering ribonucleic acid (siRNA) on METH-induced autophagy and apoptosis in the human neuroblastoma SH-SY5Y cells. We also measured the levels of phosphorylated tuberous sclerosis complex 2 (TSC2) protein and Parkin protein level in SH-SY5Y cells. Furthermore, we demonstrated the effect of silencing C/EBPβ on METH-caused neurotoxicity in the striatum of rats by injecting LV-shC/EBPβ lentivirus using a stereotaxic positioning system. The results showed that METH exposure increased C/EBPβ, DDIT4 protein expression. Elevated DDIT4 expression raised up p-TSC2/TSC2 protein expression ratio, inhibited mTOR signaling pathway, activating cell autophagy. We also found that METH exposure increased the expression of Trib3, α-syn, decreased the Parkin protein expression. Lowering levels of Parkin raised up α-syn expression, which initiated mitochondrial apoptosis by down-regulating anti-apoptotic Bcl-2, followed by up-regulation of pro-apoptotic Bax, resulting in translocation of cytochrome c (cyto c), an apoptogenic factor, from the mitochondria to cytoplasm and activation of caspase-dependent pathways. These findings were supported by data showing METH-induced autophagy and apoptosis was significantly inhibited by silencing C/EBPβ, DDIT4, Trib3 or α-syn, or by P