Dextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons.
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.
Netzer
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R
Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Pflimlin
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P
Trube
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G
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
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