Excitatory amino acid antagonists protect cochlear auditory neurons from excitotoxicity.
Since ischemic damage in the brain is linked to glutamate excitotoxicity, the effects of an acute exposure to glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) or N-methyl-D aspartate (NMDA) on the radial dendrites were compared with those occurring after a severe cochlear ischemia. Glutamate and AMPA, but not NMDA, produced a drastic swelling restricted to the radial dendrites below the inner hair cells (IHCs). At a concentration of 20 microM AMPA, a full electrophysiological recovery could be observed in some cochleas after washing the drug out. A prior perfusion of 6-7-dinitroquinoxaline-2,3-dione (DNQX, 50 microM) prevented the 25 microM AMPA-induced dendritic swelling. No protective effect of D-2-amino-5-phosphonopentanoate (D-AP5) could be observed. In the same way, ischemia (5-40 minutes) resulted in a clear swelling of the radial dendrites. While D-AP5 had no protective effects, 50 microM DNQX protected most of the radial dendrites from the ischemia-induced swelling, excepting those contacting the modiolar side of the IHCs. Finally, 50 microM DNQX + 50 microM D-AP5 resulted in a nearly complete protection of all the radial dendrites. Altogether, these results suggest that the acute swelling of radial dendrites primarily occurs via AMPA/kainate receptors. However, in radial dendrites contacting the inner hair cells on their modiolar side, NMDA receptors may be also involved.
Puel
J L
JL
INSERM--U.254 et Université de Montpellier, Laboratoire de Neurobiologie de l'Audition, CHR Hôpital St. Charles, France.
Pujol
R
R
Tribillac
F
F
Ladrech
S
S
Eybalin
M
M
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000596:Amino Acids / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology; D003051:Cochlea / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D003055:Cochlear Microphonic Potentials / Q000187:drug effects; D003712:Dendrites / Q000187:drug effects / Q000648:ultrastructure; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D005971:Glutamates / Q000633:toxicity; D018698:Glutamic Acid; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects; D008297:Male; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D009475:Neurons, Afferent / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000633:toxicity; D010477:Perfusion; D011810:Quinoxalines / Q000494:pharmacology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000037:antagonists & inhibitors / Q000633:toxicity
D000596:Amino Acids; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018377:Neurotransmitter Agents; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; C056723:FG 9041; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid