Effects of Molecular Hydrogen on Methamphetamine-Induced Neurotoxicity and Spatial Memory Impairment.

Di Wen,Bin Cong,Xi Shen,Rongji Hui,Miao Gong,Feng Yu,Chunling Ma,Jian Wang,Bing Xie

doi:10.3389/fphar.2019.00823

Abstract

Methamphetamine (METH) is a highly addictive stimulant, and METH exposure can induce irreversible neuronal damage and cause neuropsychiatric and cognitive disorders. The ever-increasing levels of METH abuse worldwide have necessitated the identification of effective intervention strategies to protect the brain against METH-induced neurotoxicity. The protective effects of molecular hydrogen on oxidative stress and related neurodegenerative diseases have been recently elucidated. Herein, we investigated whether treatment with molecular hydrogen ameliorated the METH-induced neurotoxicity and spatial learning and memory impairments. Male C57BL/6 mice received four intraperitoneal METH injections (10 mg/kg, 3-h interval), and stereotypic behaviors and hyperthermia were observed. After METH treatment and behavioral observation, the mice were returned to their home cages, where they received water or hydrogen-rich water (HRW) ad libitum for 7 days. We found that the molecular hydrogen delivered by ad libitum HRW consumption significantly inhibited the METH-induced spatial learning impairment and memory loss evidenced in the Barnes maze and Morris water maze tests. Furthermore, molecular hydrogen significantly restrained the neuronal damage in the hippocampus after high-dose METH exposure. Ad libitum HRW consumption also had an inhibitory effect on the METH-induced increase in the expression of Bax/Bcl-2, cleaved caspase-3, glucose-related protein 78 (GRP 78), CCAAT/enhancer-binding protein homologous protein (CHOP), and p-NF-kB p65 expression and elevation of interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the hippocampus. These are the first findings to indicate that hydrogen might ameliorate METH-induced neurotoxicity and has a potential application in reducing the risk of neurodegeneration frequently observed in METH abusers.

Highlights

Methamphetamine (METH) is one of the most frequently abused pharmacologic psychostimulant illicit drugs with strong neurotoxic effects on the central nervous system (CNS)
Three mice died after the last METH injection, and two mice were excluded from the statistical analysis because of low mobility in behavioral test
Saline- or METH-treated mice were returned to their home cages for the subsequent ad libitum water or hydrogen-rich water (HRW) consumption treatment

Summary

Introduction

Methamphetamine (METH) is one of the most frequently abused pharmacologic psychostimulant illicit drugs with strong neurotoxic effects on the central nervous system (CNS). METH abusers are more likely to develop schizophrenia, depression, Parkinson’s disease, and other neuropsychiatric and cognitive disorders; these are mostly attributed to METHinduced neurotoxicity (Schroder et al, 2003; Hruba et al, 2010; Kuehn, 2011). METH intake elicits a massive release of dopamine (DA) and excessive glutamate production in the brain, generating a large amount of reactive oxygen species (ROS), and subsequently leading to mitochondrial dysfunction and endoplasmic reticulum (ER) stress (Beauvais et al, 2011; Irie et al, 2011; Dang et al, 2018; Shin et al, 2018). METH can cause terminal damage and neurodegeneration of the neuronal cells in the hippocampus, eventually resulting in cognitive disorder

Objectives

Results

Conclusion