Citicoline Ameliorates Arsenic-Induced Hepatotoxicity and Diabetes in Mice by Overexpression of VAMP2, PPAR-γ, As3MT, and SIRT3

Abstract

The use of arsenic in arsenic-based pesticides has been common in many countries in the past and today. There is considerable evidence linking arsenic exposure to hepatotoxicity and diabetes. Destructive phenomena such as hepatic oxidative stress and inflammation can interfere with glucose uptake and insulin function. In the present study, the antioxidant, anti-inflammatory, and molecular mechanism of citicoline against sodium arsenite induced hepatotoxicity and glucose intolerance were investigated in mice. Citicoline improved glucose tolerance impaired by sodium arsenite. Citicoline increased the hepatic activity of catalase, superoxide dismutase, and glutathione peroxidase enzymes. Moreover, we found that citicoline prevents an increase in the levels of thiobarbituric acid reactive substances. Citicoline reduced levels of caspase 3, tumor necrosis factor alpha, and interleukin 6 in sodium arsenite intoxicated groups. It was shown that citicoline increased the expression of arsenite methyltransferase, vesicle associated membrane protein 2, peroxisome proliferator-activated receptor gamma, and sirtuin 3 to combat sodium arsenite toxicity. Citicoline reduced glucose intolerance, which was disrupted by sodium arsenite, by affecting the pancreatic and extra-pancreatic pathways involved in insulin production, secretion, and action. Based on our results, citicoline can be considered as a modulating agent against arsenic induced hepatotoxicity and hyperglycemia. Considering the relationship between arsenic exposure and the occurrence of side effects such as liver toxicity and diabetes, it is necessary to monitor and awareness about arsenic residues from sources such as drinking water.

Note:
Funding declaration: This work was supported by Toxicology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (Grant number TRC-9926). This paper is taken from the Ph.D thesis of Mehrad Nikravesh. The authors grateful to the Vice-Chancellor of Research, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran, for financial support through a grant allocated to the Toxicology Research Center in Medical Basic Sciences Research Institute.

Conflicts of Interest: None

Ethical Approval: The Institutional Animal Ethics Committee duly approved the experimental protocol (Permission no. IR.AJUMS.ABHC.REC.1399.055).

Keywords: Arsenic, Hepatotoxicity, Glucose intolerance, Citicoline, Mice