Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2020.154
Protective Role of Transduced Tat-Thioredoxin1 (Trx1) against Oxidative Stress-Induced Neuronal Cell Death via ASK1-MAPK Signal Pathway
Eun Ji Yeo1,†, Won Sik Eum1,†, Hyeon Ji Yeo1, Yeon Joo Choi1, Eun Jeong Sohn1, Hyun Jung Kwon2, Dae Won Kim2, Duk-Soo Kim3, Sung-Woo Cho4, Jinseu Park1, Kyu Hyung Han1, Keun Wook Lee1, Jong Kook Park1, Min Jea Shin1,* and Soo Young Choi1,*
1Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon 24252,
2Department of Biochemistry and Molecular Biology, Research Institute of Oral Sciences, College of Dentistry, Gangneung-Wonju National University, Gangneung 25457,
3Department of Anatomy and BK21 Plus Center, College of Medicine, Soonchunhyang University, Cheonan 31538,
4Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
*E-mail: wehome3@hallym.ac.kr (Shin MJ), sychoi@hallym.ac.kr (Choi SY)
Tel: +82-33-248-2112 (Shin MJ), +82-33-248-2112 (Choi SY)
Fax: +82-33-241-1463 (Shin MJ), +82-33-241-1463 (Choi SY)
The first two authors contributed equally to this work.
Received: September 3, 2020; Revised: November 23, 2020; Accepted: December 10, 2020; Published online: January 13, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 H2O2-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.
Keywords: Tat-Trx1, ASK1, ROS, Apoptosis, Ischemia, Protein therapy


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