Extracellular Vesicle-Encapsulated miR-183-5p from Rhynchophylline-Treated H9c2 Cells Protect against Methamphetamine-Induced Dependence in Mouse Brain by Targeting NRG1.

Yuting Zhou,Jinying Ou,Chen Zhu,Zhijie Chen,Chan Li,Zhixian Mo,Qichun Zhou,Jing Li,Yifei Chen,Chaohua Luo,Shilin Xiao,Xing Li

doi:10.1155/2021/2136076

Abstract

Methamphetamine (Meth) is a highly addictive substance and the largest drug threat across the globe. There is evidence to indicate that Meth use has serious damage on central nervous system (CNS) and heart in several animal and human studies. However, the connection in the process of Meth addiction between these two systems has not been determined. Emerging data suggest that extracellular vesicles (EVs) carrying behavior-altering microRNA (miRNAs) play a crucial role in cell communication between CNS and peripheral system. Rhynchophylline (Rhy), an antiaddictive alkaloid, was used to protect the brain and heart from Meth-induced damage, which has caught our attention. Here, we used Meth-dependent conditioned place preference (CPP) animal model and cell model to verify the protective effect of Rhy-treated EVs. Further, small RNA sequencing analysis, qPCR, dual-luciferase reporter assay, and transfection test were used to identify the key EVs-encapsulated miRNAs, isolated from cultured H9c2 cells with different treatments, involved in the therapeutic effect and the underlying mechanisms of Rhy. The results demonstrate that Rhy-treated EVs exert protective effects against Meth dependence through the pathway of miR-183-5p-neuregulin-1 (NRG1). Our collective findings provide novel insights into the roles of EVs miRNAs in Meth addiction and support their potential application in the development of novel therapeutic approaches.

Highlights

Methamphetamine (Meth) abuse, a highly addictive synthetic derivative of amphetamine, is one of the most widely abused illegal drugs with over 17.2 million users worldwide and is a major contributor to public health problem and economic consequences [1, 2]
We found that Rhy-extracellular vesicles (EVs) can inhibit the conditioned place preference (CPP) effect induced by Meth dependence, as well as Rhy treatment
We further identified that miR183-5p mediated the inhibition of NRG1 expression and that the transfer of exosomal miR-183-5p-mimic, produced by H9c2 cells, to HT22 cells exerted inhibitory effect of NRG1 expression. ese results indicate that Rhy-EVs inhibited the Meth dependence via miR-183-5p/NRG1 pathway and provide evidence of EVs as the communicated mediators for the antidrug addictive effect of Rhy treatment

Summary

Introduction

Methamphetamine (Meth) abuse, a highly addictive synthetic derivative of amphetamine, is one of the most widely abused illegal drugs with over 17.2 million users worldwide and is a major contributor to public health problem and economic consequences [1, 2]. E recent postmortem study indicated that pathological cardiovascular damage was found in 68% of Meth abusers [6]. The underlying crosstalk between CNS and cardiotoxicity of Meth dependence is still unclear and the effect of currently available medications for Meth addiction is far from ideal. Traditional Chinese Medicine (TCM), which is a holistic medicine and emphasizes the integrity of body on the internal homeostasis, has historically been used to treat drug addiction up till today in clinical practice, in Asia [7]. Rhynchophylline (Rhy), a major ingredient extracted from the traditional Chinese herb Uncaria rhynchophylla (Miq.) Miq. ex Havil., exerts strong inhibitory effects on drug addiction. In addition to antiaddictive effect, Rhy is often used to treat cardiovascular diseases. In addition to antiaddictive effect, Rhy is often used to treat cardiovascular diseases. e preclinical studies show that Rhy could prevent cardiac dysfunction and ameliorates myocardial ischemia/reperfusion injury [10, 11]

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Conclusion