Protective Role of Transduced Tat-Thioredoxin1 (Trx1) against Oxidative Stress-Induced Neuronal Cell Death via ASK1-MAPK Signal Pathway

Abstract

Oxidative stress plays a crucial role in the development of neuronal disorders including brain ischemic injury. Thioredoxin 1 (Trx1), a 12 kDa oxidoreductase, has anti-oxidant and anti-apoptotic functions in various cells. It has been highly implicated in brain ischemic injury. However, the protective mechanism of Trx1 against hippocampal neuronal cell death is not identified yet. Using a cell permeable Tat-Trx1 protein, protective mechanism of Trx1 against hydrogen peroxide-induced cell death was examined using HT-22 cells and an ischemic animal model. Transduced Tat-Trx1 markedly inhibited intracellular ROS levels, DNA fragmentation, and cell death in H 2 O 2 -treatment HT-22 cells. Tat-Trx1 also significantly inhibited phosphorylation of ASK1 and MAPKs in signaling pathways of HT-22 cells. In addition, Tat-Trx1 regulated expression levels of Akt, NF-κB, and apoptosis related proteins. In an ischemia animal model, Tat-Trx1 markedly protected hippocampal neuronal cell death and reduced astrocytes and microglia activation. These findings indicate that transduced Tat-Trx1 might be a potential therapeutic agent for treating ischemic injury.

The role of selenoproteins in neurodevelopment and neurological function: Implications in autism spectrum disorder

“…In contrast, overexpression of Trx1 significantly decreased levels of reactive oxygen species and improved motor function ( Liu et al, 2021 ), and may also protect from brain toxicity and addiction from drugs such as methamphetamine ( Yang et al, 2020 ). The mechanism through which Trx1 exhibits antioxidant activity is through inhibiting intracellular ROS levels, DNA fragmentation, and regulating apoptosis ( Yeo et al, 2021 ). Therefore, the thioredoxin reductases, like most other selenoproteins, play a neuroprotective role.…”