In Vitro BACE1 Inhibitory Activity of Geraniin and Corilagin from Geranium thunbergii

Generation of amyloid beta peptide through the proteolytic process of amyloid precursor protein by beta-secretase and gamma-secretase is a main casual factor of Alzheimer's disease, since amyloid beta peptide is a major and crucial component of senile plaques in Alzheimer's disease brains. In the process of searching for beta-secretase inhibitors from natural resources, the EtOAc soluble fraction of Geranium thunbergii exhibited significant beta-secretase inhibitory activity. Two compounds, geraniin and corilagin, isolated from the most active EtOAc fraction of G. thunbergii, exhibited predominant inhibition against beta-secretase with IC50 values of 4.0 x 10(-6) M and 3.4 x 10(-5) M, respectively. Dixon plot of geraniin and corilagin demonstrated that the beta-secretase inhibition was noncompetitive with the substrate, thus clearly suggesting that these compounds might bind either to the beta-secretase subsites or to another regulatory domain with Ki values of 2.8 x 10(-6) M and 7.9 x 10(-5) M, respectively. Both compounds exhibited no significant inhibition against alpha-secretase and other serine proteases including trypsin and chymotrypsin, showing that they were relatively specific and selective inhibitors of beta-secretase. These novel findings suggest that geraniin and corilagin from G. thunbergii may be effective therapeutic agents for further drug development in Alzheimer's disease.