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

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.

Lycopene Inhibits IL-6 Expression by Upregulating NQO1 and HO-1 via Activation of Nrf2 in Ethanol/Lipopolysaccharide-Stimulated Pancreatic Acinar Cells

“…Regarding the possible toxicity of THF, we used 0.01% of THF for a vehicle of lycopene. Even though THF is a toxic compound, THF (0.1%) did not decrease the cell viability of prostate cancer cell line DU145 and SH-SY5Y Neuroblastoma cell line SY5Y [73,74]. In addition, THF, up to the maximum concentration of 1.25% in the cell culture medium, did not affect the viability of the gastric cancer cell line HepG2 [75].…”

6,7,4′-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways

“…Following from a previous study from our group in which the treatment of SH-SY5y cells at a density of 1 × 10 4 /well with THF ( Figure 1 A) was not cytotoxic [ 27 ], we investigated whether THF leads to apoptosis in SH-SY5y cells at a lower density. Figure 1 B shows that THF up to a concentration of 40 μM did not induce cytotoxicity in SH-SY5y cells at densities of 5 × 10 3 /well or 1 × 10 4 /well.…”

“…The Nrf2/HO-1 signaling pathway is one of the most effective underlying mechanisms for the protection of cells against METH-induced cytotoxicity by small molecules [ 22 , 31 ]. In a recent study, our group reported that THF promotes the Nrf2/HO-1 pathway in SH-SY5y cells in a dose-dependent manner [ 27 ]. As such, we examined whether THF leads to the nuclear translocation of Nrf2 in a time-dependent manner.…”