Sirtuin-3 activation by honokiol restores mitochondrial dysfunction in the hippocampus of the hepatic encephalopathy rat model of ammonia neurotoxicity.

Abstract

The neurotoxic level of ammonia in the brain during liver cirrhosis causes a nervous system disorder, hepatic encephalopathy (HE), by affecting mitochondrial functions. Sirtuin-3 (SIRT3) is emerging as a master regulator of mitochondrial integrity, which is currently being focused as a pathogenic hotspot for HE. This article describes SIRT3 level versus mitochondrial dysfunction markers in the hippocampus of the control, the moderate-grade hepatic encephalopathy (MoHE), developed in thioacetamide-induced (100 mg/kg bw ip for 10 days) liver cirrhotic rats, and the MoHE rats treated with an SIRT3 activator, honokiol (HKL; 10 mg/kg bw ip), for 7 days from 8th day of the thioacetamide schedule. As compared with the control group rats, hippocampus mitochondria of MoHE rats showed a significant decline in SIRT3 expression and its activity with concordant enhancement of ROS and declined membrane permeability transitionand organelle viability scores. This was consistent with the declined mitochondrial thiol level and thiol-regenerating enzyme, isocitrate dehydrogenase 2. Also, significantly declined activities of electron transport chain complexes I, III, IV, and Q10 , decreased NAD+ /NADH and ATP/AMP ratios, and enhanced number of the shrunken mitochondria were recorded in the hippocampus of those MoHE rats. However, all these mitochondrial aberrations were observed to regain their normal profiles/levels, concordant to the enhanced SIRT3 expression and its activity due to treatment with HKL. The findings suggest a role of SIRT3 in mitochondrial structure-function derangements associated with MoHE pathogenesis and SIRT3 activation by HKL as a relevant strategy to protect mitochondrial integrity during ammonia neurotoxicity.