Methamphetamine exposure drives cell cycle exit and aberrant differentiation in rat hippocampal-derived neurospheres

Frontiers in Pharmacology

Pharmacology

Qian Wei¹  Yanping Dai²  Qian Bu²  Linhong Jiang²  Xiaobo Cen²  Yinglan Zhao²  Liang Wang²  Shaomin Wang²  Ni Zhang³  Weihong Kuang³ 

[1] Cell and Immunology Laboratory, Chengdu West China Frontier Pharmatech Co., Ltd., Chengdu, China;Mental Health Center and National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu, China;Mental Health Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China;

关键词: methamphetamine;    neurospheres;    neurodevelopmental toxicity;    cell cycle exit;    aberrant differentiation;   

DOI  :  10.3389/fphar.2023.1242109

 received in 2023-06-18, accepted in 2023-09-05,  发布年份 2023

来源: Frontiers

【 摘 要 】

Introduction: Methamphetamine (METH) abuse by pregnant drug addicts causes toxic effects on fetal neurodevelopment; however, the mechanism underlying such effect of METH is poorly understood.Methods: In the present study, we applied three-dimensional (3D) neurospheres derived from the embryonic rat hippocampal tissue to investigate the effect of METH on neurodevelopment. Through the combination of whole genome transcriptional analyses, the involved cell signalings were identified and investigated.Results: We found that METH treatment for 24 h significantly and concentration-dependently reduced the size of neurospheres. Analyses of genome-wide transcriptomic profiles found that those down-regulated differentially expressed genes (DEGs) upon METH exposure were remarkably enriched in the cell cycle progression. By measuring the cell cycle and the expression of cell cycle-related checkpoint proteins, we found that METH exposure significantly elevated the percentage of G0/G1 phase and decreased the levels of the proteins involved in the G1/S transition, indicating G0/G1 cell cycle arrest. Furthermore, during the early neurodevelopment stage of neurospheres, METH caused aberrant cell differentiation both in the neurons and astrocytes, and attenuated migration ability of neurospheres accompanied by increased oxidative stress and apoptosis.Conclusion: Our findings reveal that METH induces an aberrant cell cycle arrest and neuronal differentiation, impairing the coordination of migration and differentiation of neurospheres.

【 授权许可】

Unknown   
Copyright © 2023 Wang, Wang, Bu, Wei, Jiang, Dai, Zhang, Kuang, Zhao and Cen.