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NEUROPHARMACOLOGY

Modulation of N-Methyl-D-aspartate Receptors by Donepezil in Rat Cortical Neurons

Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, Chicago, Illinois

Nicotinic acetylcholine receptors and N-methyl-D-aspartate (NMDA) receptors are known to be down-regulated in the brain of patients with Alzheimer's disease. It was previously shown that the nootropic drugs nefiracetam and galantamine potentiate the activity of both nicotinic and NMDA receptors. We hypothesized that donepezil, a nootropic with a potent anticholinesterase activity, might also affect the NMDA system. NMDA-induced currents were recorded from rat cortical neurons in primary culture using the whole-cell patch-clamp technique at a holding potential of –70 mV in Mg²⁺-free solutions. In multipolar neurons, NMDA currents were decreased by bath and U-tube applications of 1 to 10 µM donepezil but were increased by 30 to 100 µM donepezil. Donepezil suppression occurred in a manner independent of NMDA concentrations ranging from 3 to 1000 µM. The donepezil suppression of NMDA currents was prevented by inhibition of protein kinase C (PKC) but unaffected by protein kinase A (PKA) and G proteins. In bipolar neurons, however, NMDA currents were potently augmented by bath and U-tube applications of 0.01 to 100 µM donepezil. Donepezil potentiation occurred at high NMDA concentrations that evoked the saturating responses and in a manner independent of NMDA concentrations ranging from 3 to 1000 µM. The potentiation of NMDA currents by donepezil was decreased by inhibition of PKC and abolished by modulation of G proteins but not by PKA inhibition. It was concluded that donepezil at low therapeutic concentrations (0.01–1 µM) potentiated the activity of the NMDA system and that this action together with cholinesterase inhibition would contribute to the improvement of learning, memory, and cognition in patients with Alzheimer's disease.

Address correspondence to: Dr. Toshio Narahashi, Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611. E-mail: narahashi{at}northwestern.edu

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				T. Maurice, J. Meunier, B. Feng, J. Ieni, and D. T. Monaghan Interaction with {sigma}1 Protein, but Not N-Methyl-D-aspartate Receptor, Is Involved in the Pharmacological Activity of Donepezil J. Pharmacol. Exp. Ther., May 1, 2006; 317(2): 606 - 614. [Abstract] [Full Text] [PDF]