7,8,4’-Trihydroxyisoflavone, a Metabolized Product of Daidzein, Attenuates 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells
Yong-Hyun Ko1, Seon-Kyung Kim1, Seung-Hwan Kwon1, Jee-Yeon Seo1, Bo-Ram Lee1, Young-Jung Kim1, Kwang-Hyun Hur1, Sun Yeou Kim2, Seok-Yong Lee1 and Choon-Gon Jang1,*
1Department of Pharmacology, School of Pharmacy, Sungkyunkwan University, Suwon 16419,
2College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea
E-mail: jang@skku.edu
Tel: +82-31-290-7780, Fax: +82-31-292-8800
Received: October 31, 2018; Revised: December 11, 2018; Accepted: February 18, 2019; Published online: March 8, 2019.
© The Korean Society of Applied Pharmacology. All rights reserved.

Abstract
Daidzein isolated from soybean (Glycine max) has been widely studied for its antioxidant and anti-inflammatory activities. However, the protective effects of 7,8,4’-trihydroxyisoflavone (THIF), a major metabolite of daidzein, on 6-hydroxydopamine (OHDA)-induced neurotoxicity are not well understood. In the current study, 7,8,4’-THIF significantly inhibited neuronal cell death and lactate dehydrogenase (LDH) release induced by 6-OHDA in SH-SY5Y cells, which were used as an in vitro model of Parkinson’s disease (PD). Moreover, pretreatment with 7,8,4’-THIF significantly increased the levels of superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) and decreased malondialdehyde (MDA) activity in 6-OHDA-induced SH-SY5Y cells. In addition, 7,8,4’-THIF significantly recovered 6-OHDA-induced cleaved caspase-3, cleaved caspase-9, cleaved poly-ADP-ribose polymerase (PARP), increased Bax, and decreased Bcl-2 levels. Additionally, 7,8,4’-THIF significantly restored the expression levels of phosphorylated c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2), phosphatidylinositol 3-kinases (PI3K)/Akt, and glycogen synthase kinase-3 beta (GSK-3β) in 6-OHDA-induced SH-SY5Y cells. Further, 7,8,4’-THIF significantly increased the reduced tyrosine hydroxylase (TH) level induced by 6-OHDA in SH-SY5Y cells. Collectively, these results suggest that 7,8,4’-THIF protects against 6-OHDA-induced neuronal cell death in cellular PD models. Also, these effects are mediated partly by inhibiting activation of the MAPK and PI3K/Akt/GSK-3β pathways.
Keywords: 7,8,4’-Trihydroxyisoflavone, 6-Hydroxydopamine, Neurotoxicity, Apoptosis, Parkinson’s disease


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