An active compound Kempferia parviflora with inhibitory activity against GSK-3 kinase implicated in type II Diabetes and Alzheimer's disease

Abstract

Calcium signaling pathways play pivotal roles in regulation of various important biological processes in eukaryotes ranging from yeast to human. Because of the high degree in gene conservation from yeast to human, the small molecule inhibitors discovered in the yeast based-drug screening system can be expected to exert their function in human as well. The immunosuppressive agents, FK506 and cyclosporine A, are an example. Our previous studies using a zds1 yeast-based assay to search for inhibitors in the calcium signaling pathway in Saccharomyces cerevisae mutant strain from the crude extract of Thai medicinal plants found the crude extract of Kaempferia parviflora as one of the strong positive candidates. Using zds1 proliferation assay to guide fractionation and purification, a compound 5-hydroxy-3,7-dimethoxyflavone (here designated as Cpd1) was obtained and showed inhibitory activity against the calcium signals in yeast. This study aimed to learn more on its biological activity related to the calcium signal inhibition. Genetic and biochemical analyses in yeast revealed that Mck1 kinase, a protein in the calcium signaling pathway was inhibited by Cpd1. Yeast MCK1 is an ortholog gene coding for GSK3β. High level of GSK3β causes several pathogenesis including type II Diabetes and Alzheimer’s disease. In addition, Cpd1 showed no cytotoxicity to the yeast cells.