Involvement of SIRT3 downstream targets ANT1, VDAC, CYPD, and Drp1 in a rat model of hepatic encephalopathy: Therapeutic role of thymoquinone

Document Type : Original Article

Authors

1 Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Department of Toxicology, School of Pharmacy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

10.22038/ijbms.2026.93478.20159

Abstract

Objective(s): Hepatic encephalopathy (HE) is a brain disorder linked to hyperammonemia from liver injury. Elevated ammonia levels are known to impair mitochondrial function, the primary energy source for cells. Therefore, this study aimed to evaluate energy-related signaling pathways enhancing mitochondrial biogenesis using thymoquinone (TQ) in an HE model.
Materials and Methods: Wistar rats were randomly divided into three groups: sham, HE (200 mg/kg thioacetamide (TAA) in 2ml saline, administered intraperitoneally (IP) once every 48 hr for 14 consecutive days), and HE + TQ (20 mg/kg, IP, in 2 ml DMSO 5% administered once daily for seven consecutive days). Mitochondrial biomarkers (membrane potential [MMP], oxidative stress), gene expression (AMPK, PGC-1α), and protein expression (AMPK, P-AMPK, SIRT3, ANT1, CYPD, DRP1, VDAC, and P53) were measured in brain tissue. Additionally, electroencephalogram (EEG) recordings were obtained from the dentate gyrus (DG).
Results: Our findings indicate that TQ was associated with a significant increase in MMP and a concomitant decrease in mitochondrial oxidative stress. Furthermore, TQ appeared to augment the AMPK/PGC-1α/SIRT3 signaling pathway, and was associated with the reversal of HE-induced down-regulation of ANT1 and VDAC, as well as up-regulation of CYPD, DRP1, and P53. Besides, TQ treatment was also linked to increased power recorded in the EEG from the DG region of the rat hippocampus.
Conclusion: The AMPK/PGC-1α/SIRT3 signaling pathway appears to function as a key energy sensor that may help revitalize the metabolic machinery in mitochondria, potentially facilitating metabolic exchanges and energy production, particularly in response to neurodegenerative diseases such as HE.

Keywords

Main Subjects


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