Quisqualate neurotoxicity in rat cortical cultures: pharmacology and mechanisms.
Quisqualate is a potent neurotoxin in cortical cultures of the rat. Unlike N-methyl-D-aspartate (NMDA), the toxicity of quisqualate is due to overstimulation of a membrane receptor after the agonist has been removed. This receptor appears to be the 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor since 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) are potent antagonists when added to the post incubation media. NBQX and DNQX are ineffective when present only during quisqualate exposure, indicating the AMPA receptor is not involved in the initial event. Transfer of culture media 30 min after quisqualate exposure to either neuronal or non-neuronal cells was found to cause toxicity in previously untreated neuronal cells. This effect could not be reproduced with NMDA. The neurotoxic chain of events could be interrupted during quisqualate exposure by removal of sodium from the incubation media, suggesting the involvement of a sodium-dependent plasma membrane uptake mechanism. Quisqualate may be continually recycled by internalization and release, causing neurotoxicity by persistent stimulation of the AMPA receptor.
Zinkand
W C
WC
CNS Pharmacology Section, ICI Pharmaceuticals Group, Wilmington, DE 19897.
DeFeo
P A
PA
Thompson
C
C
Hargrove
H
H
Salama
A I
AI
Patel
J
J
D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D016318:Quisqualic Acid / Q000633:toxicity*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C056723:FG 9041; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D016318:Quisqualic Acid; D007736:Kynurenic Acid; C057013:7-chlorokynurenic acid