Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity.

Abstract

Zinc (Zn) is a co-factor for a vast number of enzymes, and functions as a regulator for immune mechanism and protein synthesis. However, excessive Zn release induced in pathological situations such as stroke or transient global ischemia is toxic. Previously, we demonstrated that the interaction of Zn and copper (Cu) is involved in the pathogenesis of Alzheimer's disease and vascular dementia. Furthermore, oxidative stress has been shown to play a significant role in the pathogenesis of various metal ions induced neuronal death. Thioredoxin-Albumin fusion (HSA-Trx) is a derivative of thioredoxin (Trx), an antioxidative protein, with improved plasma retention and stability of Trx. In this study, we examined the effect of HSA-Trx on Cu2+/Zn2+-induced neurotoxicity. Firstly, HSA-Trx was found to clearly suppress Cu2+/Zn2+-induced neuronal cell death in mouse hypothalamic neuronal cells (GT1-7 cells). Moreover, HSA-Trx markedly suppressed Cu2+/Zn2+-induced ROS production and the expression of oxidative stress related genes, such as heme oxygenase-1. In contrast, HSA-Trx did not affect the intracellular levels of both Cu2+ and Zn2+ after Cu2+/Zn2+ treatment. Finally, HSA-Trx was found to significantly suppress endoplasmic reticulum (ER) stress response induced by Cu2+/Zn2+ treatment in a dose dependent manner. These results suggest that HSA-Trx counteracted Cu2+/Zn2+-induced neurotoxicity by suppressing the production of ROS via interfering the related gene expressions, in addition to the highly possible radical scavenging activity of the fusion protein. Based on these findings, HSA-Trx has great potential as a promising therapeutic agent for the treatment of refractory neurological diseases.

• Authors: Ken-Ichiro Tanaka, Mikako Shimoda, Victor T G Chuang, Kento Nishida, Masahiro Kawahara, Tatsuhiro Ishida, Masaki Otagiri, Toru Maruyama, Yu Ishima
• Journal: International journal of pharmaceutics (Int J Pharm) Vol. 535 Issue 1-2 Pg. 140-147 (Jan 15 2018) ISSN: 1873-3476 [Electronic] Netherlands
• PMID: 29122608 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier B.V. All rights reserved.

Chemical References

• Antioxidants
• Reactive Oxygen Species
• Recombinant Fusion Proteins
• TXN protein, human
• Thioredoxins
• Copper
• Zinc
• Serum Albumin, Human

Topics

• Animals
• Antioxidants (pharmacology)
• Cell Culture Techniques
• Cell Line
• Cell Survival (drug effects)
• Copper (metabolism, toxicity)
• Dose-Response Relationship, Drug
• Drug Synergism
• Hypothalamus (drug effects, metabolism, pathology)
• Mice
• Neurons (drug effects, metabolism, pathology)
• Reactive Oxygen Species (metabolism)
• Recombinant Fusion Proteins (genetics, pharmacology)
• Serum Albumin, Human (genetics, pharmacology)
• Thioredoxins (genetics, pharmacology)
• Zinc (metabolism, toxicity)