Methamphetamine exposure triggers apoptosis and autophagy in neuronal cells by activating the C/EBPβ‐related signaling pathway

• Published in: The FASEB journal 2018-06, Vol.32 (12), p.6737-6759
• Main Authors: Xu, Xiang, Huang, Enping, Luo, Baoying, Cai, Dunpeng, Zhao, Xu, Luo, Qin, Jin, Yili, Chen, Ling, Wang, Qi, Liu, Chao, Lin, Zhoumeng, Xie, Wei‐Bing, Wang, Huijun
• Format: Article
• Language: English
• Subjects: C/EBPβ/IGFBP5 signaling axis; C/EBPβ/Trib3 signaling axis; ER Stress; neurotoxicity
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201701460RRR

ABSTRACT Methamphetamine (Meth) is a widely abused psychoactive drug that primarily damages the nervous system, notably causing dopaminergic neuronal apoptosis. CCAAT‐enhancer binding protein (C/EBPβ) is a transcription factor and an important regulator of cell apoptosis and autophagy. Insulin‐like growth factor binding protein (IGFBP5) is a proapoptotic factor that mediates Meth‐induced neuronal apoptosis, and Trib3 (tribbles pseudokinase 3) is an endoplasmic reticulum (ER) stress‐inducible gene involved in autophagic cell death through the mammalian target of rapamycin (mTOR) signaling pathway. To test the hypothesis that C/EBPβ is involved in Meth‐induced IGFBP5‐mediated neuronal apoptosis and Trib3‐mediated neuronal autophagy, we measured the protein expression of C/EBPβ after Meth exposure and evaluated the effects of silencing C/EBPβ, IGFBP5, or Trib3 on Meth‐induced apoptosis and autophagy in neuronal cells and in the rat striatum after intrastriatal Meth injection. We found that, at relatively high doses, Meth exposure increased C/EBPβ protein expression, which was accompanied by increased neuronal apoptosis and autophagy; triggered the IGFBP5‐mediated, p53‐up–regulated modulator of apoptosis (PUMA)‐related mitochondrial apoptotic signaling pathway; and stimulated the Trib3‐mediated ER stress signaling pathway through the Akt‐mTOR signaling axis. We also found that autophagy is an early response to Meth‐induced stress upstream of apoptosis and plays a detrimental role in Meth‐induced neuronal cell death. These results suggest that Meth exposure induces C/EBPβ expression, which plays an essential role in the neuronal apoptosis and autophagy induced by relatively high doses of Meth; however, relatively low concentrations of Meth did not change the expression of C/EBPβ in vitro. Further studies are needed to elucidate the role of C/EBPβ in low‐dose Meth‐induced neurotoxicity.—Xu, X., Huang, E., Luo, B., Cai, D., Zhao, X., Luo, Q., Jin, Y., Chen, L., Wang, Q., Liu, C., Lin, Z., Xie, W.‐B., Wang, H. Methamphetamine exposure triggers apoptosis and autophagy in neuronal cells by activating the C/EBPβ‐related signaling pathway. FASEB J. 32, 6737–6759 (2018). www.fasebj.org