fg-9041 and 7-chlorokynurenic-acid

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.

Topics: Animals; Cells, Cultured; Cerebral Cortex; Dizocilpine Maleate; Kynurenic Acid; N-Methylaspartate; Neurons; Quinoxalines; Quisqualic Acid; Rats; Receptors, N-Methyl-D-Aspartate

Experiments have been carried out using slices of olfactory cortex of the mouse perfused in solution containing Mg2+ (1 mM) and in which the lateral olfactory tract was stimulated at a frequency of 1 pulse/5 sec to avoid polysynaptic activity. Application of the N-methyl-D-aspartate antagonist D-(-)-2-amino-5-phosphonopentanoic acid (APP, 25 microM) suppressed a low amplitude component of the potential, the latency to onset of which corresponded with that of the monosynaptically evoked N-wave in 14 of the 17 slices tested and duration of which exceeded that of the N-wave. A residual potential, recorded in slices to which the quisqualate-/kainate-selective antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) had been applied at a concentration of 10microM, was identical to the potential suppressed by APP. The residual potential in the presence of DNQX was blocked by APP, 7-chlorokynurenate (25 microM) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK801, 0.125-2 microM). It was potentiated in area by exogenous D-serine (1 mM) and in slices preincubated and perfused with Mg(2+)-free solution. It is concluded that, in addition to receptors of the quisqualate/kainate categories, N-methyl-D-aspartate receptors also contribute to both mono- and di-synaptic excitations in the olfactory cortex.

Topics: 2-Amino-5-phosphonovalerate; Animals; Cerebral Cortex; Evoked Potentials; In Vitro Techniques; Kynurenic Acid; Magnesium; Male; Mice; N-Methylaspartate; Olfactory Bulb; Quinoxalines; Receptors, N-Methyl-D-Aspartate; Stereoisomerism; Synapses

HA-966 (1-hydroxy-3-amino-pyrrolid-2-one), an antagonist at the strychnine-insensitive glycine site on the N-methyl-D-aspartate (NMDA) receptor complex, only partially inhibits the binding of noncompetitive antagonists to the NMDA receptor but enhances the binding of the NMDA competitive antagonist CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid). Here we report that the IC50 of the active (R)-enantiomer of HA-966 for displacement of [3H]glycine binding is decreased in the presence of spermine, suggesting that spermine increases the affinity of (R)-HA-966 at the [3H]glycine binding site. The IC50 values of the agonist glycine and the partial agonist 1-aminocyclopropane-1-carboxylate are also decreased. The IC50 values of glycine antagonists 6,7-dinitroquinoxalin-2,3-dione and 7-chlorokynurenic acid are not significantly altered. The spermine shift represents the first demonstration of the agonist-like character of the (R)-enantiomer of HA-966 at the glycine site.

Topics: Amino Acids; Amino Acids, Cyclic; Animals; Binding, Competitive; Dose-Response Relationship, Drug; Glycine; Kynurenic Acid; Male; Pyrrolidinones; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Spermine; Stereoisomerism; Synaptosomes