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Molecules 2018, 23(11), 2919;

Rosmarinic Acid Derivatives’ Inhibition of Glycogen Synthase Kinase-3β Is the Pharmacological Basis of Kangen-Karyu in Alzheimer’s Disease

Department of Food and Life Science, Pukyong National University, Busan 48513, Korea
Department of Medicinal Crop Research National Institute of Horticultural and Herbal Science Rural Development Administration, Eumseong 27709, Korea
Graduate School of Science and Engineering for Research University of Toyama, Toyama 930-8555, Japan
Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 54896, Korea
Authors to whom correspondence should be addressed.
Received: 4 October 2018 / Revised: 25 October 2018 / Accepted: 6 November 2018 / Published: 8 November 2018
PDF [2192 KB, uploaded 8 November 2018]


Inhibition of glycogen synthase kinase 3β (GSK-3β) is considered to be the central therapeutic approach against Alzheimer’s disease (AD). In the present study, boiled water extracts of the Kangen-karyu (KK) herbal mixture and its constituents were screened for GSK-3β inhibitory activity. KK is used in traditional Kampo and Chinese medicines for improving cognitive function. The GSK-3β inhibition potential was evaluated by using the Kinase-Glo luminescent kinase assay platform. Furthermore, enzyme kinetics and in silico modeling were performed by using AutoDockTools to demonstrate the mechanism of enzyme inhibition. KK extract significantly inhibited GSK-3β in a concentration-dependent manner (IC50: 17.05 ± 1.14 μg/mL) when compared with the reference drug luteolin (IC50: 2.18 ± 0.13 μM). Among the six components of KK, extracts of Cyperi Rhizoma and Salviae Miltiorrhizae Radix significantly inhibited GSK-3β with IC50 values of 20.68 ± 2.50 and 7.77 ± 1.38 μg/mL, respectively. Among the constituents of the roots of S. miltiorrhiza water extract, rosmarinic acid, magnesium lithospermate B, salvianolic acid A, salvianolic acid B, and salvianolic acid C inhibited GSK-3β with IC50 values ranging from 6.97 to 135.5 μM. Salvianolic acid B was found to be an ATP-competitive inhibitor of GSK-3β and showed the lowest IC50 value (6.97 ± 0.96 µM). In silico modeling suggested a mechanism of action by which the hydrophobic, π–cation, and hydrophilic interactions of salvianolic acid B at ATP and substrate sites are critical for the observed GSK-3β inhibition. Therefore, one of the mechanisms of action of KK against AD may be the inhibition of GSK-3β and one of the active components of KK is the root of S. miltiorrhiza and its constituents: rosmarinic acid, magnesium lithospermate B, and salvianolic acids A, B, and C. Our results demonstrate the pharmacological basis for the use of KK against AD. View Full-Text
Keywords: Alzheimer’s disease; GSK-3β; Kangen-karyu; Salvia miltiorrhiza; salvianolic acids Alzheimer’s disease; GSK-3β; Kangen-karyu; Salvia miltiorrhiza; salvianolic acids

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Paudel, P.; Seong, S.H.; Zhou, Y.; Park, C.H.; Yokozawa, T.; Jung, H.A.; Choi, J.S. Rosmarinic Acid Derivatives’ Inhibition of Glycogen Synthase Kinase-3β Is the Pharmacological Basis of Kangen-Karyu in Alzheimer’s Disease. Molecules 2018, 23, 2919.

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