Hepatoprotective Effects of Cilnidipine in Cholestatic Liver Disease: Role of FXR and NRF2 Signalling.

Q2 Medicine Journal of Experimental Pharmacology Pub Date : 2025-02-17 eCollection Date: 2025-01-01 DOI:10.2147/JEP.S504511

Thamer Abdulla Mohammed, Munaf H Zalzala

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Abstract

Background: Bile acid (BA) is a type of cholesterol derivative that has long been established for its crucial role in the breakdown and absorption of fat from food. Cholestasis occurs when the liver fails to transfer BAs to the intestines. Chronic cholestatic diseases can lead to liver cirrhosis.

Objective: Ursodeoxycholic acid (UDCA) treatment is ineffective for certain cholestatic diseases like benign recurrent intrahepatic cholestasis (BRIC), despite increasing the hydrophilic bile acid pool. Moreover, studies indicate that UDCA and other bile acids affect liver cell functions, such as biotransformation through CYP enzymes. In hepatitis B virus transgenic mice, a UDCA-rich diet promoted hepatocyte proliferation and tumor growth. Hepatologists advise against using UDCA in patients with severe obstructive cholangiopathies. Given the foregoing, new medications are required to treat these illnesses.

Methods: Twenty-four male Wistar albino rats were separated into three groups (8 rats for each group): negative control group I, positive control group II (ANIT-induced cholestasis), and treatment group III (Cil and ANIT). The mRNA and protein expression levels of FXR, small heterodimer partner (SHP), bile salt export pump (BSEP), nuclear factor erythroid 2-related factor 2 (NRF2), hepatocyte nuclear factor 1α (HNF1α), sirtuin 1 (SIRT1), NADPH dehydrogenase-quinone-1 (NQO-1), and heme oxygenase-1 (HO-1) were assessed post euthanasia. Additionally, other tissue oxidative stress markers were measured.

Results: Cil significantly increased the mRNA expression levels of FXR, SHP, BSEP, HNF1α, and NRF2 and the protein expression levels of FXR, BSEP, SIRT1, NQO-1, and HO-1 in the treatment group compared with those in the positive control group. Additionally, Cil decreased the oxidative stress level compared with that in the ANIT-treated group.

Conclusion: The results suggest that Cil effectively treats cholestasis by affecting the FXR signaling system and the NRF2 pathway.

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