Honokiol, a SIRT3 activator, activates hippocampus mitochondrial MnSOD by deacetylating the enzyme and upregulating FoxO3a-PGC1α axis in a rat model of ammonia neurotoxicity

Abstract We have recently reported that honokiol (HKL), by activating mitochondrial SIRT3, restored ROS led deranged mitochondrial integrity associated with the pathogenesis of ammonia neurotoxicity induced moderate grade hepatic encephalopathy (MoHE). To delineate mechanism by which HKL does so, the present study describes activity vs acetylation level of the mitochondrial MnSOD and its expression vs levels of its main transcription regulators; FOXO3a, PGC1α, in the hippocampus of the MoHE rat model of ammonia neurotoxicity, developed by administration of 100 mg/kg bw of thioacetamide i.p. for 10 days, and in the MoHE rats treated with HKL (10 mg/Kg b.w.) for 7 days. As compared to the control, the hippocampus mitochondria from MoHE rats showed a significantly declined activity of MnSOD coinciding with the increased level of its acetylated form which however, could be restored back due the HKL treatment. Also, a significantly reduced expression of MnSOD in the hippocampus of those MoHE rats coincided with a similar decline in transcript level of FOXO3a and PGC1α. This was consistent with the reduced immunoreactivity of FOXO3a and PGC1α in the hippocampus DG, CA1 and CA3 regions of the MoHE rats. However, all these factors were observed to be restored back to their normal levels in the hippocampus of the MoHE rats treated with HKL. As HKL activates mitochondrial SIRT3, these findings suggest involvement of Sirt3 activation led deacetylation of MnSOD and upregulation of its transcription activators; FOXO3a and PGC1α in activating mitochondrial MnSOD in the hippocampus of the MoHE rat model of ammonia neurotoxicity.