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Modulation of N-Methyl-d-aspartate Receptors by Donepezil in Rat Cortical Neurons
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 recept...
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Published in: | The Journal of pharmacology and experimental therapeutics 2005-10, Vol.315 (1), p.125-135 |
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Main Authors: | , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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 â70 mV in Mg 2+ -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 (0.01â1 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. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.105.087908 |