title: Dextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons.
abstract: The effect of dextromethorphan on several types of cation currents in cultured rat cortical neurons and PC12 cells was studied by using the whole-cell configuration of the patch-clamp technique. The Ba2+ current through L- and N-type Ca2+ channels was blocked with similar potencies (52-71 microM) in both types of cells. The effect was not voltage-dependent, in contrast to that of amlodipine (a dihydropyridine). Dextromethorphan was able to block the Ba2+ current completely unlike amlodipine and omega-conotoxin (an N-type channel blocker) which produced only partial inhibition. The voltage-activated Na+ and Ca2+ channels in cortical neurons were inhibited by similar concentrations of dextromethorphan (IC50 approximately 80 microM). The morphinan was at least 100 times more potent (IC50 = 0.55 microM) as a blocker of the current induced by N-methyl-D-aspartate (NMDA) in cortical neurons. Currents induced by (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ((RS)-AMPA) or kainic acid were not significantly affected even at 1 mM. The results suggest that the neuroprotective effect of dextromethorphan, previously found to occur in a concentration range of 10-100 microM, may be due to a complete blockade of the NMDA receptor channel and a partial inhibition of voltage-dependent Ca2+ and Na+ channels.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Netzer
authors.forename: P
authors.initials: P
authors.lastname: Pflimlin
authors.forename: G
authors.initials: G
authors.lastname: Trube
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D017311:Amlodipine / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D003915:Dextromethorphan / Q000494:pharmacology*; D004594:Electrophysiology; D005260:Female; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D015220:Calcium Channels; D016194:Receptors, N-Methyl-D-Aspartate; D015222:Sodium Channels; D017311:Amlodipine; D001464:Barium; D016202:N-Methylaspartate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D003915:Dextromethorphan; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007608:Kainic Acid