Preventive effect of Thioredoxin-Albumin Fusion Protein against Copper enhanced Zinc-induced Neurotoxicity

Zinc (Zn) is known as a co-factor for over 300 metalloproteins or enzymes, and has essential roles in many physiological functions. However, excessively high Zn concentrations are induced in pathological conditions such as interruption of blood flow in stroke or transient global ischemia-induced neuronal cell death. Previously, we found that copper (Cu2+) significantly exacerbates Zn2+ neurotoxicity in mouse hypothalamic neuronal cells, suggesting that Zn2+ interaction with Cu2+ is important for the development of neurological disease. Development of a therapeutic agent for the ischemia-induced neurotoxicity, taking into account of the delicate neuronal cells is warranted. Thioredoxin (Trx) is an antioxidative protein that showed protective effects for various diseases caused by oxidative stress. Trx short plasma half-life limits its clinical effectiveness, hence we employed albumin fusion technology to improve the pharmacokinetics of Trx. We have shown previously in numerous studies that a single intravenous administration of Trx-Albumin fusion (HSA-Trx) showed protective effects in various diseases, including ovalbumin-induced lung injury. In this study, at a constant Zn concentration, increasing Cu concentrations reduced the viability of hypothalamic neuronal GT1-7 cells. HSA-Trx was proven to have alleviated the neurotoxicity by Zn and Cu, possibly via inhibiting the reactive oxygen species generated but no evidence suggested a direct interaction of the fusion protein with the two metals. Interestingly, HSA-Trx significantly suppressed ER stress response in a dose dependent manner. These findings suggested that HSA-Trx may be beneficial for treating for refractory neurological diseases.