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