Pyruvic acid prevents Cu 2+ /Zn 2+ -induced neurotoxicity by suppressing mitochondrial injury

• Published in: Biochemical and biophysical research communications 2018-01, Vol.495 (1), p.1335
• Main Authors: Tanaka, Ken-Ichiro, Shimoda, Mikako, Kawahara, Masahiro
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Cell Survival - drug effects; Copper - toxicity; Dose-Response Relationship, Drug; Mice; Mitochondria - drug effects; Mitochondria - pathology; Neurons - drug effects; Neurons - pathology; Neuroprotective Agents - administration & dosage; Neurotoxins - toxicity; Pyruvic Acid - administration & dosage; Zinc - toxicity
• ISSN: 1090-2104

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. Furthermore, we recently found that copper (Cu ) significantly exacerbates Zn neurotoxicity in mouse hypothalamic neuronal cells, suggesting that Zn interaction with Cu is important for the development of neurological disease. Meanwhile, organic acids such as pyruvic acid and citric acid are reported to prevent neuronal cell death induced by various stresses. Thus, in this study, we focused on organic acids and searched for compounds that inhibit Cu /Zn -induced neurotoxicity. Initially, we examined the protective effect of various organic acids on Cu /Zn -induced neurotoxicity, and found that pyruvic acid clearly suppresses Cu /Zn -induced neurotoxicity in GT1-7 cells. Next, we examined the protective mechanisms of pyruvic acid against Cu /Zn -induced neurotoxicity. Specifically, we examined the possibilities that pyruvic acid chelates Cu and Zn or suppresses the ER stress response, but found that neither was suppressed by pyruvic acid treatment. In contrast, pyruvic acid significantly suppressed cytochrome c release into cytoplasm, an index of mitochondrial injury, in a dose-dependent manner. These results suggest that pyruvic acid prevents Cu /Zn -induced neuronal cell death by suppressing mitochondrial injury. Based on our results, we assume that pyruvic acid may be therapeutically beneficial for neurological diseases involving neuronal cell death such as vascular dementia.