Autophagy as an important mechanism in methamphetamine toxicity

Publish Year: 1398
نوع سند: مقاله کنفرانسی
زبان: English
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TOXICOLOGY15_201

تاریخ نمایه سازی: 15 بهمن 1398

Abstract:

Introduction: Methamphetamine (MeA) is a powerful, highly addictive stimulant that affects the CNS. Also known as meth, blue, ice, and crystal, among many other terms, it takes the form of a white, odorless, bitter-tasting crystalline powder that easily dissolves in water or alcohol. In the current science, autophagy is a self-digesting mechanism responsible for elimination of long-lived proteins, damaged organelles, and malformed proteins during biosynthesis by lysosome organelle. The evidence demonstrates that autophagy process is meant for regulating diverse cellular functions including growth, differentiation, response to nutrient deficit and oxidative stress, cell death, and macromolecule and organelle turnover. Material and methods: The review is summarized from some popular scientific search engines like Pubmed, Google Scholar, ScienceDirect, Elsevier, Jstor, Scopus with different combination of the key-words such as methamphetamine, toxicity, autophagy, cardiovascular, CNS , and psychomotor. Results: Numerous studies indicated that MeA through different mechanisms motivate autophagy both in vitro and in vivo. However, the exact role of autophagy in MeA-induced toxicity needs to be investigate in much more details. Some studies report it pro-survival and some report it as cell death promotor. It may also be suggested that, depending on the kind of the cell, MeA concentration and exposure, autophagy has different effect in MeA toxicity. Discussion: Autophagy has an important role in the destruction and elimination of oxidative damaged proteins. It has been reported that MeA produces reactive oxygen species (ROS) that are able to misfold and aggregate proteins. Then, as a protective mechanism, autophagic degradation take place. Inhibition of this process promote apoptosis. A target that has been introduced at the top of the autophagy pathway by MeA is the Kappa opioid receptor. It is suggested that MeA, through activation of Kappa opioid receptor, inhibited both protein kinase B (Akt) and mTOR and activated extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. Blockade of this receptor attenuated autophagy and increased apoptosis. Furthermore, the ability of PD98059 as a mitogen-activated protein kinase 1/2 (MEK 1/2) inhibitor to stop autophagy implies that Ras/Raf-1/MEK1/2/ERK1/2 pathway is also involved in MeA-induced autophagy. Moreover, MeA was able to promote autophagy by activation of the class III phosphatidylinositol 3-phosphate kinase (PI3K). Activation of PI3K increased α-synuclein and ubiquitin-proteasome-positive bodies in the rat pheochromocytoma, PC12, and the human neuroblastoma SH-SY5Y cell lines that were reversed by administration of 3MA as a PI3K inhibitor.According to previous mentioned studies, mTOR is an important target in MeA-induced autophagy. This target is considered very important in cell growth and proliferation. Two very recent studies showed that MeA, by activation of DDIT4, promoted autophagy. In addition, decrease in mTOR activity induces autophagy by enhancing the formation of autophagosomes. Two complexes construct the autophagosomes: first, a complex of Atg6 (Beclin 1), class III PI3K plus Atg14 and the second is constructed by Atg12, Atg16, Atg5, and Atg7. The later has a crucial role in the recruitment of Atg8 (LC3). It was shown that exposure to MeA, through activation of Kappa opioid receptor, increased Beclin 1 and LC3 II as two important autophagic biomarkers. It has been demonstrated that Bcl-2, as an anti-apoptotic protein, binds to Beclin 1 and thereby decreases autophagy.Accordingly, it is presumed that formation and dissociation of Bcl-2/Beclin 1 complex is a mechanism through which apoptosis and autophagy have cross talk. This complex stands between cell survival and cell death. It was revealed that MeA dissociated Bcl-2/Beclin 1 complex.This effect of MeA is mediated by phosphorylation and activation of c-Jun- N-terminal kinase 1 (JNK 1). Phosphorylated JNK1 dissociates Bcl-2/Beclin 1 complex and increases autophagy. This mechanism may explain the discrepancies between studies regarding the prosurvival or death promoting effects of MeA.

Authors

Iman Mirnezami

Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

Ali Roohbakhsh

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Gholamreza Karimi

Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Kobra Shirani

Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran