Abstract
Oxidative stress-induced neuronal cell damage is a crucial factor in the pathogenesis of mitochondria-associated neurological diseases. Therefore, elimination of overproduction of mitochondrial reactive oxygen species (mtROS) may be a potential strategy for prevention and treatment of neurological diseases. In the present study, the neuroprotective effects of trilobatin (TLB), a novel small molecule monomer derived from Lithocarpus polystachyus Rehd, and its underlying mechanisms were investigated in vitro using hydrogen peroxide (H2O2)-induced oxidative stress model in a neuron-like PC12 cell. The findings revealed that pre-treatment with TLB dramatically concentration-dependently suppressed H2O2-induced PC12 cells damage by enhancing cell viability, repressed reduction of mitochondrial membrane potential (MMP) and decreased mtROS overgeneration, thereby deferring cell apoptosis. Further study demonstrated that TLB not only increased the enzymatic activities of glutathione peroxidase (GPx), isocitrate dehydrogenase 2 (IDH2),superoxide dismutase 2 (SOD2) and deacetylation of SOD2, but also activated silent mating-type information regulation 2 homolog 3 (Sirt3) within the mitochondria and thereby upregulating forkheadboxO3a (FoxO3a), which regulated mitochondrial DNA genes, then led to improving complex I activity and adenosine triphosphate (ATP) synthesis. What’s more, TLB up-regulated p-adenosine monophosphate-activated protein kinase (AMPK) level, the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α), and ERRα. Intriguingly, TLB failed to mitigate H2O2-induced PC12 injury in the presence of the AMPK inhibitor (Compound C), indicating that the beneficial effects of TLB on the regulation of mtROS homeostasis were reliance on AMPK -Sirt3 signaling pathway. Moreover, TLB also facilitated nuclear factor erythroid 2-related factor 2 (Nrf2) and promoted antioxidant gene expression in turn, and knockdown of Nrf2 by siRNA dramatically reduced the neuroprotective effects of TLB. Notably, AMPK inhibitor abolished the activation of Nrf2 and Sirt3, whereas, knockdown of Nrf2 blocked the upregulation of Sirt3, but it did not affect p-AMPK level. In conclusion, our findings demonstrate that TLB protects against oxidative injury in neuronal PC12 cells through regulating mtROS homeostasis in the first time, which is, at least partly, mediated through the AMPK/Nrf2/Sirt3 signaling pathway.
Highlights
There is general recognition that considerable neurological diseases are characterized by a progressive death of neurons, accompanied with a decrease in antioxidant ability and/or an augment in oxidative stress, which is termed as a disequilibrium between the antioxidant enzymes system and the production of reactive oxygen species (ROS; Li et al, 2017)
We found, for the first time, that TLB protected against H2O2-induced PC12 cell injury was through reducing mitochondrial ROS (mtROS) production and apoptosis, which, at least in part, was via activation of AMPK/nuclear factor erythroid 2-related factor 2 (Nrf2)/silent mating-type information regulation homolog 3 (Sirt3) signaling pathway
Previous study confirmed that the treatment of 400 μM H2O2 for 48 h resulted in significantly PC12 cell death, such concentration and incubation time were used for the following experiments
Summary
There is general recognition that considerable neurological diseases are characterized by a progressive death of neurons, accompanied with a decrease in antioxidant ability and/or an augment in oxidative stress, which is termed as a disequilibrium between the antioxidant enzymes system and the production of reactive oxygen species (ROS; Li et al, 2017). Application of antioxidant which is termed as ‘‘a substance that, when present at a low concentration compared with that of an oxidizable substrate, inhibits oxidation of the substrate’’ to deter oxidative stress-induced neuron demise may be a potential strategy to fight neurological diseases (Halliwell and Gutteridge, 1995). The exploitation of natural or synthetic antioxidant was considered promising therapeutic candidates for neurological diseases has been challenged in spite of promising preclinical data and a great deal of public interests
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