Acetylcholinesterase Inhibitor Donepezil Effects on Plasma β-Hydroxybutyrate Levels in the Treatment of Alzheimer’s Disease

摘要

Background: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterizedby a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesteraseinhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesteraseinhibitory effect, to act through other non-cholinergic mechanisms such as affecting mitochondrialbiogenesis through peroxisome proliferator-activated receptor gamma coactivator (PGC1α).Mitochondrial biogenesis and PGC-1α, at least in part, are associated with hepatic fatty acid oxidationand ketogenesis. Whether donepezil regulates ketogenesis in AD treatment remains unclear. Ketogenesisis important in the progression of AD and is a critical consideration during the therapeutic strategy selectionfor AD. Thus, our goals were to determine the differences in ketone bodies in patients with AD whowere taking donepezil treatment and those who were not, to elucidate the potential effect of AD anddonepezil therapy on ketone body metabolic parameters, and to discover the effect of donepezil therapyon ketogenesis in patients with AD.Methods: Cross-sectional analysis was performed on plasma collected from 145 individuals, namely,elderly adults as healthy controls (n=30), newly diagnosed patients with AD (n=30), patients with ADwho responded to donepezil therapy (n=48) and patients with AD who did not respond to donepeziltherapy (n=37). Gas chromatography-mass spectrometry was performed to quantify the lipids in theplasma. The level of β-hydroxybutyrate, a metabolite, was determined by liquid chromatographytandemmass spectrometry, and to gain further insight into the effect of donepezil on ketogenesis, theeffects of donepezil were investigated in a mouse model.Results: The level of β-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasmalevel of β-hydroxybutyrate. Donepezil increased the plasma and liver levels of β-hydroxybutyrate inmice as well as the hepatic expression of PGC-1α and the mitochondrial expression of HMG-CoA synthetase2 (HMGCS2) in response to fasting, causing a subsequent increase in ketogenesis.Conclusions: Our study revealed that impaired ketogenesis is a metabolic feature of AD. Donepezil hadeffects on ketogenesis in mice and reversed the decrease in the level of β-hydroxybutyrate found in patientswith AD.