Protective Effects of 6,7,4'-Trihydroxyflavanone on Hypoxia-Induced Neurotoxicity by Enhancement of HO-1 through Nrf2 Signaling Pathway.

Gil-Saeng Jeong,Hyun-Su Lee

doi:10.3390/antiox10030341

Abstract

Since hypoxia-induced neurotoxicity is one of the major causes of neurodegenerative disorders, including the Alzheimer’s disease, continuous efforts to find a novel antioxidant from natural products are required for public health. 6,7,4′-trihydroxyflavanone (THF), isolated from Dalbergia odorifera, has been shown to inhibit osteoclast formation and have an antibacterial activity. However, no evidence has reported whether THF has a protective role against hypoxia-induced neurotoxicity. In this study, we found that THF is not cytotoxic, but pre-treatment with THF has a cytoprotective effect on CoCl2-induced hypoxia by restoring the expression of anti-apoptotic proteins in SH-SY5y cells. In addition, pre-treatment with THF suppressed CoCl2-induced hypoxia-related genes including HIF1α, p53, VEGF, and GLUT1 at the mRNA and protein levels. Pre-treatment with THF also attenuated the oxidative stress occurred by CoCl2-induced hypoxia by preserving antioxidant proteins, including SOD and CAT. We revealed that treatment with THF promotes HO-1 expression through Nrf2 nuclear translocation. An inhibitor assay using tin protoporphyrin IX (SnPP) confirmed that the enhancement of HO-1 by pre-treatment with THF protects SH-SY5y cells from CoCl2-induced neurotoxicity under hypoxic conditions. Our results demonstrate the advantageous effects of THF against hypoxia-induced neurotoxicity through the HO-1/Nrf2 signaling pathway and provide a therapeutic insight for neurodegenerative disorders.

Highlights

Our results demonstrate the advantageous effects of THF against hypoxia-induced neurotoxicity through the heme oxygenase1 (HO-1)/nuclear transcription factor erythroid 2-like factor 2 (Nrf2) signaling pathway and provide a therapeutic insight for neurodegenerative disorders
Since the expression of induced HO-1 by antioxidants has been reported to protect cells against cytotoxic conditions, including hypoxia, we investigated whether HO-1 induction by THF treatment is involved in the protective role of THF under hypoxic conditions
It has been widely studied that the expression of vascular endothelial growth factor (VEGF) and GLUT1 are regulated by Hypoxia inducible factor 1α (HIF1α) under hypoxic conditions

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Since continuous provision of enormous amounts of oxygen to the brain is required for its proper function, the brain is affected by the limited oxygen condition called hypoxia. Neuronal cytotoxicity is generally induced under hypoxic condition because insufficient supply of oxygen to the brain enhances the mortality and disability of neurons [1,2]. It has been reported that hypoxia-induced neurotoxicity causes brain damage and leads to neurodegenerative diseases, including Alzheimer’s disease, vascular dementia, and Parkinson’s disease [3,4]

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