Critical Roles of the PI3K-Akt-mTOR Signaling Pathway in Apoptosis and Autophagy of Astrocytes Induced by Methamphetamine

Han-Qing Liu,A-Zhen Hu,Jue-Lian Wu,Ya-Wen An,Yun Chen,Ming-Hua Li,Guang-Hui Cui,Li Liu,Yu Shi

doi:10.1515/chem-2019-0015

Abstract

AbstractThis study aimed to reveal potential roles of the phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway in apoptosis and autophagy of astrocytes induced by methamphetamine (METH). A Cell Counting Kit-8 (CCK-8) was used to determine the reduction in proliferation of U-118 MG cells induced by METH. Hoechst 33258 and flow cytometry were used to observe the astrocytes. Western blot analysis was performed to evaluate protein expression and phosphorylation levels. METH inhibited the proliferation of U-118 MG cells and induced apoptosis and autophagy. Western blot analysis showed that the ratio of LC3-II/I was increased, whereas the expression of Bcl-2 was decreased. The phosphorylation cascade of kinases in the PI3K-Akt-mTOR signaling pathway was significantly inhibited by METH exposure, as were proteins downstream of mTORC1, such as p70s6k, rps6, 4EBP1 and eIF4E. METH inhibited proliferation of U-118 MG cells and induced apoptosis and autophagy. The PI3K-Akt-mTOR signaling pathway likely plays a critical role in these effects.

Highlights

Drug abuse has increased significantly year by year, both in China and the rest of the world, and has reached epidemic proportions
A type of programmed cell death that is independent of apoptosis, is negatively regulated by the mTOR complex-1 (mTORC1) signaling pathway
These results indicated that METH induced both apoptosis and autophagy of U-118 MG cells

Summary

Introduction

Drug abuse has increased significantly year by year, both in China and the rest of the world, and has reached epidemic proportions. The mechanisms contributing to this damage are not fully understood, neuronal cell death has been observed in many animal models following METH exposure. This cell death, which involves cells in reward circuits such as the hippocampus, nucleus accumbens and corpus striatum, may contribute to the pathogenesis of neurotoxicity [1,2,3,4]. The phosphatidylinositol 3 kinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling pathway regulates numerous biological processes, including cell survival, proliferation and growth, and glucose metabolism [7,8,9], and has been demonstrated to be involved in the neuronal adaptations that underlie drugrelated behaviors such as reward seeking and excessive drug intake [10]. The roles of PI3K-Akt-mTOR signaling pathway in

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