We have recently reported that honokiol (HKL), by activating mitochondrial SIRT3, normalizes reactive oxygen species level and mitochondrial integrity in hippocampus of the moderate grade hepatic encephalopathy (MoHE) rat model of ammonia neurotoxicity. To delineate the mechanism by which HKL does so, the present study describes activity versus level of the deacetylated mitochondrial Mn-superoxide dismutase (MnSOD) and expression of MnSOD versus levels of its main transcription regulators, FoxO3a and PGC1α, in the hippocampus of the MoHE rats. MoHE in rat was developed by administration of 100 mg/kg bw thioacetamide i.p. for 10 days. The study parameters were compared between the control, the MoHE rats and the MoHE rats treated with HKL (10 mg/Kg b.w.) for 7 days. As compared to control, the hippocampus mitochondria from MoHE rats showed a significantly declined activity of MnSOD vs enhanced lipid peroxidation coinciding with the increased level of its acetylated form. The HKL treatment could, however, normalize all these parameters in those MoHE rats. Also, a significantly reduced expression of MnSOD in the hippocampus of the MoHE rats coincided with a similar decline in transcript level of Foxo3a and Pgc1α. This was consistent with the reduced level of immuno-stained Foxo3a and Pgc1α proteins in hippocampus DG, CA1 and CA3 regions of those MoHE rats. However, all these factors were observed to be restored back to their normal levels due to the treatment with HKL. As HKL is a specific activator of mitochondrial SIRT3, these findings suggest involvement of Sirt3 activation led deacetylation of MnSOD and upregulation of its transcription activators, FoxO3a and PGC1α, in restoring mitochondrial MnSOD level in the hippocampus of the MoHE rat model of ammonia neurotoxicity.
Keywords: Foxo3a/Pgc1α; MnSOD; ammonia neurotoxicity; hepatic encephalopathy; hippocampus; mitochondrial SIRT3.
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