The Main Molecular Mechanisms Underlying Methamphetamine- Induced Neurotoxicity and Implications for Pharmacological Treatment

Abstract

Methamphetamine (METH) is a popular new-type psychostimulant drug with complicated neurotoxicity. In spite of mounting evidence on METH-induced damage of neural cell, the accurate mechanism of toxic effect of the drug on central nervous system (CNS) has not yet been completely deciphered. Besides, effective treatment strategies toward METH neurotoxicity remain scarce and more efficacious drugs are to be developed. In this review, we summarize cellular and molecular bases that might contribute to METH-elicited neurotoxicity, which mainly include oxidative stress, excitotoxicity, and neuroinflammation. We also discuss some drugs that protect neural cells suffering from METH-induced neurotoxic consequences. We hope more in-depth investigations of exact details that how METH produces toxicity in CNS could be carried out in future and the development of new drugs as natural compounds and immunotherapies, including clinic trials, are expected.

Keywords: excitotoxicity; immunotherapy; methamphetamine; neuroinflammation; neurotoxicity; oxidative stress.

FIGURE 1

The illustration summarizes the main mechanisms of Methamphetamine (METH)-elicited neurotoxic effects, which include DA oxidation, excessive glutamate production, generating a large amount of reactive oxygen species (ROS) and reactive nitrogen species (RNS), and subsequently leading to mitochondrial dysfunction and ER stress. The neuroinflammation mediated by microglial cells also contribute to the neuronal damage by attacking it with inflammatory cytokines. As a result of the suffering from METH, the neuronal cells may undergo terminal degeneration or apoptosis. In particular, due to the neurotoxicity of the drug, long time abuse of METH often cause the decrease of dopaminergic markers such as dopamine (DA), tyrosine hydroxylase (TH), and dopamine transporter (DAT).

FIGURE 2

This model illustrates the oxidative stress and mitochondrial dysfunction involved in METH-induced neurotoxic consequences. METH exposure produced a considerable amount of ROS and RNS, named OH^-, H₂O₂, O₂^-, NO, and ONOO^-. The excessive oxidative stress inhibits the key enzymes of the ETC, causing mitochondrial dysfunction that leads to mitochondrial fission and mitophagy. Particularly, the impaired mitochondria trigger the increase of Bax and decrease of Bcl-2 and sequential cytochrome c (Cyt c) release, inducing activation of executioner caspases-3 and apoptosis which might be regulated by some molecules such as p53-upregulated modulator of apoptosis (PUMA), protein kinase C delta (PKCδ), miRNAs, and long non-coding RNAs (lncRNAs) which are reviewed in the text.

FIGURE 3

The image shows the excitatory toxicity model of METH. METH-mediated increase in extracellular glutamate level leads to stimulation of mGluR1/5 or N-methyl-D-aspartate receptors (NMDARs). mGluR1/5-induced protein kinase C (PKC) activation phosphorylates and upregulates NMDAR function, leading to Ca²⁺ influx. The signaling results in enhancement of cytosolic Ca²⁺ level associated with nNOS activity, leading to NO production. NO acts as an ER stressor, and then, UPR signaling pathway would be initiated in response to ER stress through three ER transmembrane mediators [inositol requiring protein-1 (IRE1)α, activating transcription factor-6 (ATF6), and protein kinase RNA-like ER kinase (PERK)]. Subsequently, the mediators lead to special genes transcription as CHOP, GRP78, and Caspase 12 which triggering a series of cascade involving apoptosis and autophagy.

FIGURE 4

METH produces neuronal damage through microglia associated neuroinflammation in addition to direct actions on neurons. METH damages presynaptic terminals of neurons causing the production of DA-quinone (DAQ) and sequential ROS; these facilitate microglial activation. The activated microglia then increase production of nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 1β (IL-1β), monocyte chemo-attractant protein 1 (MCP-1), ICAM-1, ROS, and RNS, promoting neuroinflammation and neuronal injury. The damaged neurons release DAMPs that act on microglia, and aggravate the inflammation and eventual neurotoxicity through the positive feedback mechanism.