| Autor: |
Fattahi AS; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran., Khalili A; Evidence-based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences, Karaj, Iran.; Department of Physiology-Pharmacology-Medical Physics, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran., Hashemi SA; Department of Pathology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran., Najafizadeh P; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.; Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran., Mazloom R; Department of Physiology-Pharmacology-Medical Physics, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran., Khodayar S; Department of Microbiology and Virology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran., Bayat G; Evidence-based Phytotherapy and Complementary Medicine Research Center, Alborz University of Medical Sciences, Karaj, Iran.; Department of Physiology-Pharmacology-Medical Physics, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran. |
| Abstrakt: |
Valproic acid (VA) is a broad-spectrum anticonvulsant agent that acts through several molecular mechanisms to control different types of seizures. The main concern of the drug is its liver toxicity. Considering the regulatory roles of the Farnesoid nuclear receptors and the nuclear transcription factor Nrf2 in modifying and neutralizing the harmful effects of oxidative damage, the present study was designed to evaluate the role of FXR-Nrf2 and some downstream target gene alterations in hepatotoxicity induced by VA. Thirty-five eight-week-old male albino mice were randomly divided into five groups, including a control group, and four groups were assigned to receive VA (300 mg/kg/day; oral) for 3, 7, 10, and 14 days. Serum levels of ALT, AST, ALP, and total and direct bilirubin (TB, DB) were measured. Liver histology and the expression of FXR, Nrf2, α-GST, SOD, and TNF-α were assessed using H&E staining and real-time RT-PCR techniques. Maximum extent of biochemical and histopathological damage was observed on the 14th day, but changes in the expression of FXR, Nrf2, α-GST, and SOD were seen at three points: a significant upregulation on the 3rd day, a remarkable downregulation on the 10th day, and a second-time upregulation on the 14th day. In conclusion, considering the observed dysregulation in FXR-Nrf2 cascade expression during VA administration, it seems that downregulation in this pathway and consequently its downstream detoxification and antioxidant genes may play a role in liver toxicity. |
