Takashi Kosasa, Yuka Kuriya and Yoshiharu Yamanishi
Tsukuba Research Laboratories, Eisai Co., Ltd., 5 - 1 - 3 Tokodai, Tsukuba,
Ibaraki 300 - 2635, Japan
Abstract: Donepezil hydrochloride (donepezil), a potent and selective
acetylcholinesterase inhibitor, has been developed for the treatment of
Alzheimer's disease. We studied the effect of oral administration of this
drug on the extracellular acetylcholine (ACh) concentration in the cerebral
cortex of rats using microdialysis. We also observed fasciculation, a peripheral
cholinergic sign induced by activation of neuromuscular transmission, after
oral administration of the drug as an index of peripheral cholinergic activation.
Other cholinesterase inhibitors, tacrine, ENA-713 and TAK-147, were used
as reference drugs. Donepezil significantly and dose-dependently increased
the extracellular ACh concentration in the rat cerebral cortex within the
dose range of 2.5 - 10 mg/kg. Tacrine, ENA-713 and TAK-147 also elevated
the extracellular concentration of ACh. The minimum effective doses of donepezil,
tacrine, ENA-713 and TAK-147 were ≦2.5, 10, 10 and ≦10 mg/kg, respectively.
Donepezil produced fasciculation at doses of 2.5 mg/kg and above, with a
dose-dependent increase in incidence and intensity. The reference compounds
also induced fasciculation in a dose-dependent manner. The threshold doses
of tacrine, ENA-713 and TAK-147 for fasciculation were 5, 2.5 and 2.5 mg/kg,
respectively. The values of the ratio of the minimum effective dose for
the ACh-increasing action to that for the fasciculation-producing action
were: donepezil, ≦1; tacrine, 2; ENA-713, 4; TAK-147, ≦4. These results
indicate that orally administered donepezil has a potent and selective activity
on the central cholinergic system.
Keywords: Donepezil hydrochloride (E2020), Acetylcholinesterase inhibitor,
Acetylcholine,
Microdialysis, Cerebral cortex