A trend over time study of hepatic Farnesoid-X-activated receptor and its downstream targets modulation by valproic acid in mice

Abstract

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.

Keywords:

• Sodium valproate
• oxidative stress
• FXR
• Nrf2
• hepatotoxicity

Acknowledgments

The Laboratory technical assistance staff of the Paramedicine School of Alborz University of Medical Sciences are gratefully acknowledged.

Author contributions

Conception or design of work, acquisition, analysis, or interpretation of data for the work, and drafting the work or revising it critically for important intellectual content: Gholamreza Bayat, Azadeh Khalili, Amir Saamaan Fattahi, Seyed Ali Hashemi, Roham Mazloom and Parvaneh Najafizadeh. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

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Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.