Abstract
Galantamine, a new Alzheimer's drug approved in the United States, is known to inhibit acetylcholinesterase and potentiate acetylcholine-induced currents in brain neurons. However, because both cholinergic and N-methyl-d-aspartate (NMDA) systems are down-regulated in the brain of Alzheimer's patients, we studied the effects of galantamine on NMDA receptors. NMDA-induced whole-cell currents were recorded from the rat multipolar cortical neurons in primary culture. NMDA currents recorded in Mg2+-free media without addition of glycine were reversibly potentiated by bath and U-tube applications of galantamine at 10 to 10,000 nM, showing a bell-shaped dose-response relationship. However, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate currents were not affected by galantamine. The maximum potentiation of NMDA currents to ∼130% of the control was obtained at 1 μM galantamine. The potentiation was due to a shift of the NMDA dose-response curve in the direction of lower NMDA concentrations. Glycine at 1 to 3000 nM enhanced NMDA currents, and potentiation by 1 μM galantamine and 1 to 300 nM glycine was additive. The glycine site antagonist 7-chlorokynurenic acid did not prevent the galantamine action. These results suggested that galantamine did not interact with the glycine binding site. Experiments with various concentrations of Mg2+ indicated that galantamine did not affect the Mg2+ blocking site of the NMDA receptor. PKC was involved in galantamine potentiation of NMDA currents, but protein kinase A, Gi/Go proteins, and Gs proteins were not involved. Potentiation of the activity of NMDA receptors is deemed partially responsible for the improvement of cognition, learning, and memory in Alzheimer's patients.
Footnotes
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This work was supported in part by Janssen Pharmaceutica.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.067603.
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ABBREVIATIONS: nAChR; nicotinic acetylcholine receptor; NMDA, N-methyl-d-aspartate; PKC, protein kinase C; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; 7-ClKN, 7-chlorokynurenic acid; PKA, protein kinase A; H-89, N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride.
- Received February 25, 2004.
- Accepted April 29, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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