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Toxicol Lett. 2019 Sep 15;312:11-21. doi: 10.1016/j.toxlet.2019.05.003. Epub 2019 May 3.

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

Author information

1
School of Forensic Medicine, Southern Medical University, Guangzhou 510515, People's Republic of China.
2
Guangzhou Forensic Science Institute, Guangzhou 510030, People's Republic of China.
3
School of Basic Medicine Science, Southern Medical University, Guangzhou 510515, People's Republic of China.
4
Nanfang Hospital, Southern Medical University, The First Clinical Medicine School, Southern Medical University, Guangzhou 510515, People's Republic of China.
5
School of Forensic Medicine, Southern Medical University, Guangzhou 510515, People's Republic of China. Electronic address: wangqi_legmed@126.com.
6
School of Forensic Medicine, Southern Medical University, Guangzhou 510515, People's Republic of China. Electronic address: lingpzy@163.com.

Abstract

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 Parkin over-expression. Based on the present data, a novel of mechanism on METH-induced cell toxicity is proposed, METH exposure increased C/EBPβ protein expression, triggered DDIT4/TSC2/mTOR signaling pathway, and evoked Trib3/Parkin/α-syn-related mitochondrial apoptotic signaling pathway. Collectively, these results suggest that C/EBPβ plays an important role in METH-triggered autophagy and apoptosis and it may be a potential target for therapeutics in METH-caused neurotoxicity.

KEYWORDS:

Apoptosis; Autophagy; C/EBPβ; Methamphetamine (METH); Neurotoxicity

PMID:
31059759
DOI:
10.1016/j.toxlet.2019.05.003
[Indexed for MEDLINE]

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