6-cyano-7-nitroquinoxaline-2-3-dione and gamma-glutamylaminomethylsulfonic-acid

The behavioural and convulsant effects of imipenem (Imi), a carbapenem derivative, were studied after intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. The anticonvulsant effects of some excitatory amino acid antagonists and muscimol (Msc), a GABAA agonist, against seizures induced by i.p. or i.c.v. administration of Imi were also evaluated. The present study demonstrated that the order of anticonvulsant activity in our epileptic model, after i.p. administration, was (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine maleate (MK-801) > (+/-)(E)-2-amino-4-methyl-5-phosphono-3-pentenoate ethyl ester (CGP 39551) > 3-((+/-)-2-carboxypiperazin-4-yl)propenyl-1-phosphonic acid (CPPene) > 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CCP) > 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline (NBQX). Ifenprodil, a compound acting on the polyamine site of NMDA receptor complex was unable to protect against seizures induced by Imi, suggesting that the poliamine site did not exert a principal role in the genesis of seizures induced by Imi. In addition, the order of anticonvulsant potency in our epileptic model, after i.c.v. administration, was CPPene > MK-801 > Msc > (-)-2-amino-7-phosphonic acid (AP7) > gamma-D-glutamylaminomethylsulphonate (gamma-D-GAMS) > NBQX > kynurenic acid (KYNA) > 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX). The relationship between the different site of action and the anticonvulsant activity of these derivatives was discussed. Although the main mechanism of Imi induced seizures cannot be easily determined, potential interactions with the receptors of the excitatory amino acid neurotransmitters exists. In fact, antagonists of excitatory amino acids are able to increase the threshold for the seizures or to prevent the seizures induced by Imi. In addition, Imi acts on the central nervous system by inhibition of GABA neurotransmission and Msc, a selective GABAA agonist, was able to protect against seizures induced by Imi.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Amino Acids; Animals; Anticonvulsants; Dizocilpine Maleate; Excitatory Amino Acids; Glutamine; Imipenem; Kynurenic Acid; Mice; Mice, Inbred DBA; Muscimol; Piperazines; Piperidines; Quinoxalines; Seizures

The (RS)-alpha-Amino-3-hydroxy-5-methyl-4-isoxazolopropionic acid (AMPA)/kainate receptor-channel complex mediates fast components of excitatory synaptic currents in the central nervous system. Distinguishing between these components is a difficult pharmacological task. As was recently reported, gamma-D-glutamylaminomethylsulfonic acid (GAMS) may be a selective kainate receptor antagonist. We have tested this possibility in experiments which were carried out on acutely isolated rat hippocampal neurons. It appeared that 1 mM GAMS first blocked 83 +/- 1% of the fast desensitizing 128 microM AMPA-gated current, but only 38 +/- 6% of the non-desensitizing current component and reached, at higher GAMS concentrations, a plateau at about 50% of the control steady state current level. In contrast to the blocking action of GAMS on AMPA-gated currents, 4-fold higher concentrations of GAMS were needed to block currents elicited by 256 microM kainate application. It is suggested that several subunit compositions of the AMPA-gated receptor could coexist on a single hippocampal cell. Furthermore, GAMS has a certain preference for subunit assemblies which could mediate fast desensitizing and, a portion of, the non-desensitizing current component.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glutamine; Hippocampus; In Vitro Techniques; Ion Channel Gating; Ion Channels; Kainic Acid; Neurons; Rats; Rats, Wistar; Receptors, AMPA

Recent studies have reported that microinjection of kynurenic acid (KYN 12.5 nmol), the nonselective Excitatory Amino acid (EAA) antagonist, into the rostral ventrolateral medulla of the cat decreases arterial blood pressure (BP) and inferior cardiac sympathetic nerve discharge. The purpose of our study was to confirm this finding and determine the subtypes of EAA receptor(s) responsible for mediating this effect. This was done by microinjecting various EAA antagonists bilaterally into the SRFN of chloralose-anesthetized animals while monitoring BP and HR. KYN (12.5 nmol; N = 5) produced a decrease in mean BP (31 +/- 9 mmHg, P < .05) with no significant change in HR. To determine the subtype of EAA receptor responsible for eliciting tonic sympathetic outflow from the SRFN, specific antagonists of N-methyl-D-aspartate (NMDA) and non-NMDA EAA receptors were tested. The NMDA receptor antagonist 3-(RS)-Carboxypiperazin-4-yl)-proyl- 1-phosphonic acid (CPP-2.25 nmol; N = 3) microinjected into the SRFN produced a small but significant decrease in BP (-13 +/- 1 mmHg; P < .05). This effect of CPP was significantly less than that seen with KYN. Two antagonists of the non-NMDA subtype of EAA receptor, 6-cyano-7-nitroquinoxaline-2,3-dione (0.05 nmol; N = 4) and gamma-D-glutamylaminomethyl sulphonic acid (2.5 nmol; N = 4), were microinjected into the SRFN. Both of these drugs produced decreases in BP (-29 +/- 4 and -23 +/- 3 mmHg, respectively; P < 0.05) similar to that observed with KYN. No significant changes in HR were noted with CPP, 6 cyano-7-nitroquinoxaline-2,3-dione or gamma-G-glutamylamino-methylsulfonate. These data indicate that a non-NMDA EAA receptor plays the major role in control of cardiovascular function by the SRFN.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Blood Pressure; Cardiovascular Physiological Phenomena; Cats; Female; Glutamine; Kynurenic Acid; Male; Medulla Oblongata; Microinjections; Neurons; Piperazines; Quinoxalines; Receptors, Amino Acid; Receptors, N-Methyl-D-Aspartate

The effects of the glutamate receptor antagonist gamma-D-glutamylaminomethyl sulfonic acid (GAMS) on inward currents induced by bath application of kainic acid (KA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) were studied with single-electrode voltage clamp methods in Xenopus oocytes injected 3-5 days previously with mRNA from the brain of E16-17 chick embryos. Both AMPA and KA induced smooth inward currents, with Hill coefficients of 1.5 (AMPA) and 2.1 (KA). GAMS, at concentrations up to 1 mM, produced no reliable antagonism of AMPA-induced currents but showed a consistent, dose-dependent and reversible antagonism of KA-induced responses; the slope of the Schild plot was 0.76 and the pA2 value 4.32. In the presence of GAMS, however, the Hill coefficient for AMPA is reduced significantly and approaches unity, suggesting that AMPA interacts with both KA and AMPA binding sites on chick brain glutamate receptors. The selectivities of three quinoxalinedione antagonists (6,7-dinitroquinoxaline-2,3-dione [DNQX], 6-cyano-7- nitroquinoxaline-2,3-dione [CNQX] and 6-nitro-7-sulfamoyl-benzo(F)quinoxaline-2,3-dione [NBQX]) were then compared with that shown by GAMS. DNQX, CNQX and NBQX all blocked the effects of both KA and AMPA completely, competitively, reversibly and dose-dependently, with Schild-plot slopes very close to 1.0. Against AMPA, observed pA2 values were 6.58 for DNQX, 6.43 for CNQX and 6.77 for NBQX. Against KA, pA2 values were 6.42 for DNQX, 6.56 for CNQX and 7.21 for NBQX.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Brain Chemistry; Chick Embryo; Electrophysiology; Glutamine; Kainic Acid; Kinetics; Oocytes; Quinoxalines; Receptors, Glutamate; RNA, Messenger; Xenopus

Extracellular single-neuron recordings were obtained from electrophysiologically identified nigrostriatal neurons in chloral hydrate anesthetized rats, in order to test the hypothesis that excitatory amino acid receptors are involved in responses of these neurons to electrical stimulation of the pontine region where the pedunculopontine nucleus (PPN) is located. The effects of iontophoretic application of excitatory amino acids and their antagonists as well as of cholinergic antagonists were tested on the fast orthodromic excitation of nigrostriatal neurons evoked by stimulation of the PPN region. The N-methyl-D-aspartate (NMDA) receptor antagonist D-alpha-aminoadipic acid as well as the cholinergic receptor antagonists mecamylamine and atropine failed to suppress the synaptic excitation of nigral neurons. The NMDA receptor antagonist DL-2-amino-5-phosphonovalerate exerted a weak depressant action on the synaptic response in a few neurons only. On the contrary, the broad spectrum antagonists of excitatory amino acid receptors kynurenic acid and gamma-D-glutamyl-amino-methyl-sulphonate were found to block simultaneously both the synaptic excitation and the neuronal responses to iontophoretic pulses of glutamate while leaving unaffected the neuronal responses to local application of acetylcholine or carbachol. The competitive antagonist of non-NMDA receptors 6-cyano-2,3-dihydroxy-7-nitro-quinoxaline suppressed the synaptic excitation at ejection currents which antagonized neuronal responses to quisqualate and kainate. These results suggest that PPN excitatory fibers synapsing onto pars compacta nigrostriatal neurons utilize an excitatory amino acid as a synaptic transmitter acting preferentially on non-NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; 2-Aminoadipic Acid; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Corpus Striatum; Dopamine; Electric Stimulation; Evoked Potentials; Glutamine; Iontophoresis; Kainic Acid; Kynurenic Acid; Male; N-Methylaspartate; Neurons; Pons; Quinoxalines; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Substantia Nigra; Synapses