Abstract
Screening phenolic and polyphenolic compounds for inhibitory activity against electric eels acetylcholinesterase (AChE) identified baicalein, a major flavone derived from the roots of Scutellaria baicalensis, as the most potent inhibitor with IC50 (concentration required for 50% inhibition) of 0.61 µM. None of the hydroxybenzoic and hydroxycinnamic acids screened showed inhibitory activity measured at 100 µM. Structure-activity relationships based on IC50 values of the active flavonoids showed that inhibitory activity (a) required the unsaturated 2-phenyl-chroman structure, (b) has strong requirement for the A-ring A5-OH, A6-OH and A7-OH groups (b) does not depend on B-ring hydroxyl groups, and (d) was reduced by bulky sugar substitution of the saturated C-ring C3-OH. Enzyme kinetic analysis showed that baicalein is a mixed inhibitor of AChE with K1 (equilibrium constant of dissociation of the inhibitor bound enzyme complex) and K2 (equilibrium constant of dissociation of the inhibitor bound enzyme-substrate complex) of 0.91 and 1.98 µM, respectively.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most prevalent form of dementia in elderly people
Screening phenolic and polyphenolic compounds for inhibitory activity against electric eels acetylcholinesterase (AChE) identified baicalein, a major flavone derived from the roots of Scutellaria baicalensis, as the most potent inhibitor with inhibiting AChE activity by 50% (IC50) of 0.61 μM
Structure-activity relationships based on IC50 values of the active flavonoids showed that inhibitory activity (a) required the unsaturated 2-phenyl-chroman structure, (b) has strong requirement for the A-ring A5-OH, A6-OH and A7-OH groups (b) does not depend on B-ring hydroxyl groups, and (d) was reduced by bulky sugar substitution of the saturated C-ring C3-OH
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and is the most prevalent form of dementia in elderly people. The hall marks of AD are cholinergic system dysfunction, accelerated aggregation of -amyloid peptides (A ) and loss of cognitive function (Hardy & Selkoe, 2002; Holtzman, John, & Goate, 2011). These factors provide a basis for the cholinergic and amyloid hypotheses for AD pathology, respectively. The amyloid cascade hypothesis attributes the pathogenesis of AD to the accelerated aggregation of A peptide in the brain resulting in the formation of senile plaques that contributes to neuronal cell death and, dementia (Racchi, Mazzuccelli, Porrello, Lanni, & Govoni, 2004; Holtzman et al, 2011). Elevated AChE activity in brain has been linked to increased plague deposition (Geula & Darvesh, 2004)
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