Mechanism of Action of Galantamine on N-Methyl-d-Aspartate Receptors in Rat Cortical Neurons

• Published in: The Journal of pharmacology and experimental therapeutics 2004-09, Vol.310 (3), p.933-942
• Main Authors: Moriguchi, Shigeki, Marszalec, William, Zhao, Xilong, Yeh, Jay Z, Narahashi, Toshio
• Format: Article
• Language: English
• Subjects: Animals; Binding Sites; Cells, Cultured; Cerebral Cortex - cytology; Cyclic AMP-Dependent Protein Kinases - physiology; Drug Synergism; Galantamine - pharmacology; Glycine - metabolism; GTP-Binding Proteins - physiology; N-Methylaspartate - pharmacology; Neurons - drug effects; Neurons - metabolism; Protein Kinase C - physiology; Rats; Rats, Sprague-Dawley; Receptors, AMPA - physiology; Receptors, Kainic Acid - physiology; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.104.067603

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 Mg 2+ -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 Mg 2+ indicated that galantamine did not affect the Mg 2+ blocking site of the NMDA receptor. PKC was involved in galantamine potentiation of NMDA currents, but protein kinase A, G i /G o proteins, and G s 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.