Effect of donepezil hydrochloride (E2020) on basal concentration of extracellular acetylcholine in the hippocampus of rats
Introduction
Alzheimer's disease is a progressive neurodegenerative disease characterized by deficits in memory and cognitive function. One of the most pronounced changes in the brain of Alzheimer's disease patients occurs in the cholinergic systems. Cholinesterase inhibitors are the only class of drugs currently approved for the treatment of Alzheimer's disease.
We have developed a novel, piperidine-based, acetylcholinesterase (AChE) inhibitor, donepezil hydrochloride (donepezil: E2020: (±)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride), for the treatment of Alzheimer's disease (Sugimoto et al., 1995). Donepezil was approved by the U.S. Food and Drug Administration (FDA) in 1996, and is now being prescribed world-wide. A large-scale multicenter, double-blind clinical study has demonstrated that donepezil is a well-tolerated drug that improves cognitive performance and global function in patients with mild to moderate Alzheimer's disease (Rogers and Friedhoff, 1998, Rogers et al., 1996, Rogers et al., 1998a, Rogers et al., 1998b). Pharmacological studies in vitro have revealed that donepezil is a reversible and non-competitive cholinesterase inhibitor, and is a far more selective inhibitor of AChE, relative to butyrylcholinesterase, than is tacrine or physostigmine. It produces marked and long-lasting inhibition of brain AChE and increases the brain content of acetylcholine in vivo. Moreover, donepezil significantly ameliorates performance deficits in several learning and memory tasks including eight-arm radial maze impairments after scopolamine, and passive avoidance deficits in nucleus basalis magnocellularis-lesioned rats Ogura et al., 1988, Yamanishi et al., 1988, Rogers et al., 1991. Other cholinesterase inhibitors available for the treatment of Alzheimer's disease are tacrine (9-amino-1,2,3,4-tetrahydroacridine hydrochloride) and ENA-713 (rivastigmine: (S)-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methyl-phenylcarbamate hydrogentartrate). Tacrine is the first drug approved by the U.S. FDA for the treatment of Alzheimer's disease, although it has adverse effects related to its actions on the peripheral nervous system and to hepatic toxicity (Beermann, 1993). ENA-713 is a pseudo-irreversible, carbamate-based cholinesterase inhibitor Weinstock et al., 1994, Anand and Gharabawi, 1996 and is currently available in some European countries.
Since the extracellular acetylcholine concentration measured by the intracerebral microdialysis technique reflects the acetylcholine concentration in the synaptic cleft, it is a useful parameter with which to compare the potential efficacy of various cholinesterase inhibitors in the central cholinergic system. The effects of donepezil, tacrine and ENA-713 on extracellular acetylcholine concentration have been studied by microdialysis. However, in those studies, the drug effects were evaluated after intraperitoneal or subcutaneous injection Kawashima et al., 1994, Giacobini et al., 1996, or in the presence of a second cholinesterase inhibitor, in the perfusion solution in order to increase extracellular acetylcholine to a detectable level (Ohara et al., 1997). In the present study, we compared the effects of orally administered donepezil, tacrine and ENA-713 on the basal concentration of extracellular acetylcholine in the hippocampus of rats under the same experimental conditions. Moreover, in order to validate the microdialysis data, we measured the inhibition of brain AChE and the brain concentrations of these drugs.
Section snippets
Subjects
Male Wistar rats (Charles River Japan, Kanagawa, Japan; 7 weeks of age, 210–290 g) were housed at a room temperature of 23±1°C and relative humidity of 55±10%, under a 12-h light/dark cycle (start at 0700 h) for at least 1 week before experiments. The animals were given free access to food and water. All experiments were approved by the Animal Care and Use Committee of Eisai.
Drugs
Donepezil hydrochloride (E2020: (±)-2-[(1-benzylpiperidin-4-yl)methyl]-5,6-dimethoxy-indan-1-one monohydrochloride) was
Effects of cholinesterase inhibitors on hippocampal extracellular acetylcholine concentration
We examined the effects of donepezil, tacrine and ENA-713 on the extracellular acetylcholine concentration in the hippocampus of rats. These cholinesterase inhibitors produced dose-dependent increases in the extracellular acetylcholine concentration (Fig. 1, Fig. 2, Fig. 3). Donepezil had a significant effect at a dose of 2.5 mg/kg. The maximum increase produced by this dose was seen at about 1.5 h, when acetylcholine reached 499% of the pre-treatment level. The duration of the acetylcholine
Discussion
The results in this study clearly demonstrate that donepezil has a more potent activity than tacrine and a longer-lasting effect than ENA-713 on the central cholinergic system, in terms of the basal concentration of extracellular acetylcholine in the hippocampus and the AChE activity in the brain of rats.
Oral administration of donepezil dose-dependently increased the basal concentration of extracellular acetylcholine in the hippocampus of rats. Previously, Kawashima et al. (1994) had examined
Conclusion
The findings of this study demonstrated that centrally acting cholinesterase inhibitors, donepezil, tacrine and ENA-713, potently increase the extracellular acetylcholine concentration in the synaptic cleft of the hippocampus of rats mostly through AChE inhibition, and that donepezil has a more potent activity than tacrine and a longer-lasting effect than ENA-713 on the central cholinergic system. Donepezil may be one of the more useful cholinesterase inhibitors for the treatment of Alzheimer's
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2018, Bioorganic ChemistryA comparison of cholinesterase inhibitors in the treatment of quinuclidinyl benzilate-induced behavioural deficit in rats performing the multiple T-maze
2014, Journal of Applied BiomedicineCitation Excerpt :Rivastigmine at a dose of 1.5 mg kg−1 effectively reverses the spatial memory deficit induced by 0.5 mg kg−1 scopolamine, which corresponds to almost 50% AChE inhibition in the cortex (Bejar et al., 1999). Another tested compound, donepezil, is a centrally-acting ChEI which selectively inhibits AChE (Kosasa et al., 1999; Ogura et al., 2000; Racchi et al., 2004). Moreover, donepezil also elevates ACh levels via stimulation of catecholamine release (Giacobini et al., 1996).