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

• Published in: Molecules (Basel, Switzerland) Switzerland), 2018-11, Vol.23 (11), p.2919
• Main Authors: Paudel, Pradeep, Seong, Su Hui, Zhou, Yajuan, Park, Chan Hum, Yokozawa, Takako, Jung, Hyun Ah, Choi, Jae Sue
• Format: Article
• Language: English
• Subjects: Acids; Alkenes - chemistry; Alkenes - pharmacology; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer's disease; ATP; Benzofurans - chemistry; Benzofurans - pharmacology; Binding sites; Brain; Caffeic Acids - chemistry; Caffeic Acids - pharmacology; Cinnamates - chemistry; Cinnamates - pharmacology; Cognitive ability; Competition; Computer Simulation; Constituents; Depsides - chemistry; Depsides - pharmacology; Diabetes; Dose-Response Relationship, Drug; Drugs, Chinese Herbal - chemistry; Drugs, Chinese Herbal - pharmacology; Enzyme kinetics; Glycogen; Glycogen synthase kinase 3; Glycogen Synthase Kinase 3 beta - antagonists & inhibitors; Glycogen Synthase Kinase 3 beta - chemistry; Glycogens; GSK-3β; Herbal medicine; Humans; Hydrophobicity; Hypotheses; Inhibition; Inhibition (psychology); Kangen-karyu; Kinases; Lactates - chemistry; Lactates - pharmacology; Magnesium; Metabolism; Metabolites; Modelling; Molecular Docking Simulation; Molecular Structure; Pathogenesis; Pharmacology; Phosphorylation; Plant Roots - chemistry; Polyphenols - chemistry; Polyphenols - pharmacology; Proteins; Rosmarinic Acid; Salvia miltiorrhiza; salvianolic acids
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules23112919

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 (IC : 17.05 ± 1.14 μg/mL) when compared with the reference drug luteolin (IC : 2.18 ± 0.13 μM). Among the six components of KK, extracts of Cyperi Rhizoma and Salviae Miltiorrhizae Radix significantly inhibited GSK-3β with IC values of 20.68 ± 2.50 and 7.77 ± 1.38 μg/mL, respectively. Among the constituents of the roots of water extract, rosmarinic acid, magnesium lithospermate B, salvianolic acid A, salvianolic acid B, and salvianolic acid C inhibited GSK-3β with IC 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 IC 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 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.