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Tae-Joon Shin,황성희,최선혜,이병환,Jiyeon Kang,R. Suzanne Zukin,나승열,임혜원,김현중 대한약리학회 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.2
Ginsenosides are low molecular weight glycosides found in ginseng that exhibit neuroprotective effects through inhibition of N-methyl-D-aspartic acid (NMDA) receptor channel activity. Ginsenosides, like other natural compounds, are metabolized by gastric juices and intestinal microorganisms to produce ginsenoside metabolites. However, little is known about how ginsenoside metabolites regulate NMDA receptor channel activity. In the present study, we investigated the effects of ginsenoside metabolites, such as compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT), on oocytes that heterologously express the rat NMDA receptor. NMDA receptor-mediated ion current (INMDA) was measured using the 2-electrode voltage clamp technique. In oocytes injected with cRNAs encoding NMDA receptor subunits, PPT, but not CK or PPD, reversibly inhibited INMDA in a concentration-dependent manner. The IC50 for PPT on INMDA was 48.1±4.6 μM, was non-competitive with NMDA, and was independent of the membrane holding potential. These results demonstrate the possibility that PPT interacts with the NMDA receptor, although not at the NMDA binding site, and that the inhibitory effects of PPT on INMDA could be related to ginseng-mediated neuroprotection.
Gadd45b Acts as Neuroprotective Effector in Global Ischemia- Induced Neuronal Death
Chang Hoon Cho,Hyae-Ran Byun,Teresa Jover-Mengual,Fabrizio Pontarelli,Christopher Dejesus,조아랑,R. Suzanne Zukin,Jee-Yeon Hwang 대한배뇨장애요실금학회 2019 International Neurourology Journal Vol.23 No.S1
Purpose: Transient global ischemia arising in human due to cardiac arrest causes selective, delayed neuronal death in hippocampal CA1 and cognitive impairment. Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) is a wellknown molecule in both DNA damage-related pathogenesis and therapies. Emerging evidence suggests that Gadd45b is an anti-apoptotic factor in nonneuronal cells and is an intrinsic neuroprotective molecule in neurons. However, the mechanism of Gadd45b pathway is not fully examined in neurodegeneration associated with global ischemia. Methods: Rats were subjected to transient global ischemia by the 4-vessel occlusion or sham operation. The animals were sacrificed at 24 hours, 48 hours, and 7 days after ischemia. The hippocampal CA1 was microdissected and processed to examine mRNA and protein level. To assess neuronal death, tissue sections were cut and processed for Fluoro-Jade and Nissl staining. Results: Here we show that ischemic insults increase abundance of Gadd45b and brain-derived neurotrophic factor, a known target of Gadd45 mediated demethylation, in selectively-vulnerable hippocampal CA1 neurons. We further show that knockdown of Gadd45b increases abundance of a pro-apoptotic Bcl-2 family member Bax while decreasing the antiapoptotic protein Bcl-2, which together promote neuronal death. Conclusions: These findings document a protective role of Gadd45b against neuronal insults associated with global ischemia and identify Gadd45b as a potential therapeutic target for the amelioration of hippocampal neurodegeneration.
Shin, Tae-Joon,Hwang, Sung-Hee,Choi, Sun-Hye,Lee, Byung-Hwan,Kang, Ji-Yeon,Kim, Hyeon-Joong,Zukin, R. Suzanne,Rhim, Hye-Whon,Nah, Seung-Yeol The Korean Society of Pharmacology 2012 The Korean Journal of Physiology & Pharmacology Vol.16 No.2
Ginsenosides are low molecular weight glycosides found in ginseng that exhibit neuroprotective effects through inhibition of $N$-methyl-D-aspartic acid (NMDA) receptor channel activity. Ginsenosides, like other natural compounds, are metabolized by gastric juices and intestinal microorganisms to produce ginsenoside metabolites. However, little is known about how ginsenoside metabolites regulate NMDA receptor channel activity. In the present study, we investigated the effects of ginsenoside metabolites, such as compound K (CK), protopanaxadiol (PPD), and protopanaxatriol (PPT), on oocytes that heterologously express the rat NMDA receptor. NMDA receptor-mediated ion current ($I_{NMDA}$) was measured using the 2-electrode voltage clamp technique. In oocytes injected with cRNAs encoding NMDA receptor subunits, PPT, but not CK or PPD, reversibly inhibited $I_{NMDA}$ in a concentration-dependent manner. The $IC_{50}$ for PPT on $I_{NMDA}$ was $48.1{\pm}4.6\;{\mu}M$, was non-competitive with NMDA, and was independent of the membrane holding potential. These results demonstrate the possibility that PPT interacts with the NMDA receptor, although not at the NMDA binding site, and that the inhibitory effects of PPT on $I_{NMDA}$ could be related to ginseng-mediated neuroprotection.
신태준,나승열,Hyeon-Joong Kim,Byeong-Jae Kwon,최선혜,Hyun-Bum Kim,황성희,이병환,Sang-MokLee,R. Suzanne Zukin,박지호,Hyoung Chun KIM,Hyewhon Rhim,Joon-Hee Lee 한국분자세포생물학회 2012 Molecules and cells Vol.34 No.6
Ginseng has been shown to have memory-improving effects in human. However, little is known about the active components and the molecular mechanisms underlying its effects. Recently, we isolated novel lysophosphatidic acids (LPAs)-ginseng protein complex derived from ginseng, gintonin. Gintonin activates G protein-coupled LPA receptors with high affinity. Gintonin activated Ca2+-activated Cl- channels in Xenopus oocytes through the activation of endogenous LPA receptor. In the present study, we investigated whether the activation of LPA receptor by gintonin is coupled to the regulation of N-methyl-D-aspartic acid (NMDA) receptor channel activity in Xenopus oocytes expressing rat NMDA receptors. The NMDA receptor-media-ted ion current (INMDA) was measured using the two-elec-trode voltage-clamp technique. In oocytes injected with cRNAs encoding NMDA receptor subunits, gintonin enhanced INMDA in a concentration-dependent manner. Gintonin-mediated INMDA enhancement was blocked by Ki16425, an LPA1/3 receptor antagonist. Gintonin action was blocked by a PLC inhibitor, IP3 receptor antagonist, Ca2+ chelator, and a tyrosine kinase inhibitor. The site-directed mutation of Ser1308 of the NMDA receptor, which is phosphorylated by protein kinase C (PKC), to an Ala residue, or co-expression of receptor protein tyrosine phosphatase with the NMDA receptor attenuated gintonin action. Moreover, gintonin treatment elicited a transient elevation of [Ca2+]i in cultured hippocampal neurons and elevated long-term potentiation (LTP) in both concentration-dependent manners in rat hippocampal slices. Gintonin-mediated LTP induction was abolished by Ki16425. These results indicate that gintonin-mediated INMDA potentiation and LTP induction in the hippocampus via the activation of LPA receptor might be responsible for ginseng-mediated improvement of memory-related brain functions.