The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis.
alpha-Amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor-mediated excitotoxicity has been implicated in the selective motor neuron loss in amyotrophic lateral sclerosis (ALS). The extent to which excitotoxicity contributes to motor neuron death remains incompletely understood. We therefore tested the potent and selective AMPA/kainate receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) on motor neurons in culture and in the G93A mouse model for familial ALS. Kainate-induced currents and changes in intracellular Ca(2+) concentration were measured with the perforated patch clamp technique combined with Ca(2+) imaging, motor neuron death was quantified by counting experiments and G93A mice were treated with saline or 8 mg/kg NBQX. NBQX blocked kainate-induced currents and concomitant changes in intracellular Ca(2+), prevented the kainate-induced motor neuron death, and prolonged survival of G93A mice.
Van Damme
Philip
P
Laboratory for Neurobiology, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium.
Leyssen
Maarten
M
Callewaert
Geert
G
Robberecht
Wim
W
Van Den Bosch
Ludo
L
D000367:Age Factors; D000409:Alanine / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005552:Forelimb / Q000187:drug effects / Q000503:physiopathology; D005998:Glycine / Q000235:genetics; D018737:Hand Strength / Q000502:physiology; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects*; D011597:Psychomotor Performance / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology*; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D000409:Alanine; D007608:Kainic Acid; D002118:Calcium; D005998:Glycine