RT Journal Article
SR Electronic
T1 Mechanism of Action of Galantamine on <em>N</em>-Methyl-<span class="sc">d</span>-Aspartate Receptors in Rat Cortical Neurons
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 933
OP 942
DO 10.1124/jpet.104.067603
VO 310
IS 3
A1 Shigeki Moriguchi
A1 William Marszalec
A1 Xilong Zhao
A1 Jay Z. Yeh
A1 Toshio Narahashi
YR 2004
UL http://jpet.aspetjournals.org/content/310/3/933.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics