Abstract
Oxidative cell damage contributes to neuronal degeneration in many central nervous system (CNS) diseases such as Alzheimer’s disease, Parkinson’s disease, and ischemia. Nrf2 signaling-mediated heme oxygenase (HO)-1 expression acts against oxidants that are thought to play a key role in the pathogenesis of neuronal diseases. Cudraflavone B is a prenylated flavone isolated from C. tricuspidata which has shown anti-proliferative activity, mouse brain monoamine oxidase (MAO) inhibitory effects, apoptotic actions in human gastric carcinoma cells and mouse melanoma cells, and hepatoprotective activity. In this study, cudraflavone B showed neuroprotective effects and reactive oxygen species (ROS) inhibition against glutamate-induced neurotoxicity by inducing the expression of HO-1 in mouse hippocampal HT22 cells. Furthermore, cudraflavone B caused the nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response elements (ARE) in mouse hippocampal HT22 cells. In addition, we found that the Nrf2-midiated HO-1 expression by cudraflavone B is involved in the cell protective response and ROS reductions, and cudraflavone B-induced expression of HO-1 was mediated through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in HT22 cells. Our results demonstrated the potential application of naturally occurring cudraflavone B as a therapeutic agent from neurodegenerative disease.
Highlights
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons
Our results indicate that phosphatidylinositol 3-kinase (PI3K)/Akt cascade pathways, which are activated by cudraflavone B, participate in an early stage of heme oxygenase (HO)-1expression in HT22 cells
The results of the present study suggest that cudraflavone B from Cudrania tricuspidata effectively prevents glutamate-induced oxidative damage, and HO-1 induction via PI3K/Akt and nuclear factor-E2-related factor 2 (Nrf2)/antioxidant response elements (ARE)
Summary
Neurodegeneration is the umbrella term for the progressive loss of structure or function of neurons, including death of neurons. HT22 cells have been used as an in vitro model for studying the mechanism of oxidative glutamate toxicity In this respect, naturally occurring compounds that have intrinsic anti-oxidative effects against glutamate-induced oxidative stress and which can trigger the intracellular cascade of protective pathways may offer a promising strategy for therapeutic applications. Nrf2/ARE pathways and phase 2 antioxidant enzymes, including HO-1 has emerged as a therapeutic target for neuronal protections [12,13]. In this respect, the identification of constituents in natural products that have neuroprotective effects through Nrf2/ARE-mediated HO-1 expression against glutamate-induced oxidative stress would be valuable for therapeutic applications from neurodegenerative disease. Neuroprotective effects on glutamate-induced oxidative toxicity in mouse hippocampal HT22 cells through Nrf2/ARE-dependent HO-1 expression via activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathways
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