Thioredoxin-1 blocks methamphetamine-induced injury in brain through inhibiting endoplasmic reticulum and mitochondria-mediated apoptosis in mice

Abstract

Methamphetamine (METH) has been reported to induce endoplasmic reticulum (ER) stress and neuronal apoptosis in the central nervous system (CNS) during the development of addiction. Thioredoxin-1 (Trx-1) is a redox regulating protein and plays an important role in inhibiting apoptosis and protects neurons from cytotoxicity through ER and mitochondria-mediated pathways. Our previous study has been reported that Trx-1 protects mice from METH-induced rewarding effect. However, whether Trx-1 plays the role in resisting METH injury is still unclear. Here, we aim to investigate whether Trx-1 participates in the regulation of METH-induced CNS injury via ER stress and mitochondria-mediated pathways. Our study first repeated the conditioned place preference expression induced by METH. Then we detected and found that METH increased the expression of N-methyl-d-asparate (NMDA) receptor subunit 2B (NR2B) and the level of glutamate (Glu) in the ventral tegmental area (VTA) and nucleus accumbens (NAc), while Trx-1 overexpression suppressed the increases. We further examined ER stress-related proteins and mitochondrial apoptosis pathway in the VTA and NAc, and found that METH increased the expressions of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Bax, as same time decreased the expressions of procaspase12, Bcl-2, and procaspase3, while Trx-1 overexpression blocked these changes. These results indicate that Trx-1 blocks METH-induced injury by suppressing ER stress and mitochondria-mediated apoptosis in the VTA and NAc via targeting glutamatergic system.

Keywords: Endoplasmic reticulum; Injury; Methamphetamine; Mitochondria; Thioredoxin-1.