Involvement of SIRT۳ downstream targets ANT۱, VDAC, CYPD, and Drp۱ in a rat model of hepatic encephalopathy: Therapeutic role of thymoquinone

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 (۲۰۰ mg/kg thioacetamide (TAA) in ۲ml saline, administered intraperitoneally (IP) once every ۴۸ hr for ۱۴ consecutive days), and HE + TQ (۲۰ mg/kg, IP, in ۲ ml DMSO ۵% administered once daily for seven consecutive days). Mitochondrial biomarkers (membrane potential [MMP], oxidative stress), gene expression (AMPK, PGC-۱α), and protein expression (AMPK, P-AMPK, SIRT۳, ANT۱, CYPD, DRP۱, VDAC, and P۵۳) 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-۱α/SIRT۳ signaling pathway, and was associated with the reversal of HE-induced down-regulation of ANT۱ and VDAC, as well as up-regulation of CYPD, DRP۱, and P۵۳. 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-۱α/SIRT۳ 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.

کلیدواژه ها:

ANT۱ ، CYPD ، DRP۱ ، Hepatic encephalopathy ، Local EEG ، VDAC