Hippocampus mitochondrial MnSOD activation by a SIRT3 activator, honokiol, correlates with its deacetylation and upregulation of FoxO3a and PGC1α in a rat model of ammonia neurotoxicity

Abstract

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.

The restoration of hippocampal nerve de‐myelination by methylcobalamin relates with the enzymatic regulation of homocysteine level in a rat model of moderate grade hepatic encephalopathy

“…[55] Thus, the increase in Hcy levels associated with MoHE could also be correlated with the neurochemical derangements and atrophy of CA1 neurons recently reported during MoHE pathogenesis. [2,12,13] In line with this, MeCbl mediated recovery of neurodegeneration (decreased number of Nissl positive cells) in both the CA1 and CA3 regions and a similar decrease in the Hcy level in MeCbl-treated MoHE rats suggest for a causal relationship between Hcy levels and MoHE associated neurodegeneration during MoHE pathogenesis. Indeed, MeCbl has been found to inhibit apoptotic cell death in Hcy-induced excitotoxicity.…”

“…As reported recently [ 12 ] sections were dried and washed with PBS three times, for 5 min each. The excess fluid was blotted on Kim wipes and then the tissue sections were subsequently permeabilized in 0.1% Triton X‐100 for 10 min.…”

The role and therapeutic potential of SIRTs in sepsis

“…SIRTs such as SIRT1, SIRT2, and SIRT3 possess the capability to deacetylate the FOXO3a transcription factor, culminating in its activation ( 106 , 107 ). The activation of FOXO3a triggers the expression of antioxidative genes, including SOD and various antioxidative enzymes, thereby providing a robust defense against ROS-induced cellular damage.…”

Sirtuins in kidney diseases: potential mechanism and therapeutic targets

“…Sirt3 directly deacetylates and activates superoxide dismutase 2 (SOD2), promoting the transcription of SOD2 and peroxisomes [ 84 ]. Sirt3 also induces FOXO3a and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1ɑ) upregulation, restoring MnSOD activity and levels [ 85 ]. It also mediates Foxo3a deacetylation and nuclear localisation, which in turn leads to the activation of Foxo3a-dependent peroxidase expression; reduces Ang II-induced renal fibrosis, endothelial-to-mesenchymal transition (EndoMT), and oxidative stress; and maintains renal endothelial homeostasis [ 86 ].…”