fg-9041 and Seizures

Interictal spikes in models of focal seizures and epilepsies are sustained by the synchronous activation of glutamatergic and GABAergic networks. The nature of population spikes associated with seizure initiation (pre-ictal spikes; PSs) is still undetermined. We analyzed the networks involved in the generation of both interictal and PSs in acute models of limbic cortex ictogenesis induced by pharmacological manipulations. Simultaneous extracellular and intracellular recordings from both principal cells and interneurons were performed in the medial entorhinal cortex of the in vitro isolated guinea pig brain during focal interictal and ictal discharges induced in the limbic network by intracortical and brief arterial infusions of either bicuculline methiodide (BMI) or 4-aminopyridine (4AP). Local application of BMI in the entorhinal cortex did not induce seizure-like events (SLEs), but did generate periodic interictal spikes sensitive to the glutamatergic non-NMDA receptor antagonist DNQX. Unlike local applications, arterial perfusion of either BMI or 4AP induced focal limbic SLEs. PSs just ahead of SLE were associated with hyperpolarizing potentials coupled with a complete blockade of firing in principal cells and burst discharges in putative interneurons. Interictal population spikes recorded from principal neurons between two SLEs correlated with a depolarizing potential. We demonstrate in two models of acute limbic SLE that PS events are different from interictal spikes and are sustained by synchronous activation of inhibitory networks. Our findings support a prominent role of synchronous network inhibition in the initiation of a focal seizure.

Topics: 4-Aminopyridine; Action Potentials; Animals; Bicuculline; Computer Simulation; Convulsants; Disease Models, Animal; Electric Stimulation; Entorhinal Cortex; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; Female; Guinea Pigs; In Vitro Techniques; Models, Biological; Neural Inhibition; Potassium Channel Blockers; Quinoxalines; Seizures

Glutamate is the major excitatory neurotransmitter of the central nervous system in vertebrates. Excitotoxicity, caused by over-stimulation of the glutamate receptors, is a major cause of neuron death in several brain diseases, including epilepsy. We describe here how behavioural seizures can be triggered in adult zebrafish by the administration of kainate and are very similar to those observed in rodent models. Kainate induced a dose-dependent sequence of behavioural changes culminating in clonus-like convulsions. Behavioural seizures were suppressed by DNQX (6,7-dinitroquinoxaline-2,3-dione) dose-dependently, whilst MK-801 (a non-competitive NMDA receptor antagonist) had a lesser effect. Kainate triggers seizures in adult zebrafish, and thus this species can be considered as a new model for studying seizures and subsequent excitotoxic brain injury.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Kainic Acid; Quinoxalines; Rats; Receptors, Glutamate; Seizures; Zebrafish

In vitro studies performed on brain slices demonstrate that the potassium channel blocker 4-aminopyridine (4AP, 50 microM) discloses electrographic seizure activity and interictal discharges. These epileptiform patterns have been further analyzed here in a isolated whole guinea pig brain in vitro by using field potential recordings in olfactory and limbic structures. In 8 of 13 experiments runs of fast oscillatory activity (fast runs, FRs) in the piriform cortex (PC) propagated to the lateral entorhinal cortex (EC), hippocampus and occasionally to the medial EC. Early and late FRs were asynchronous in the hemispheres showed different duration [1.78 +/- 0.51 and 27.95 +/- 4.55 (SD) s, respectively], frequency of occurrence (1.82 +/- 0.49 and 34.16 +/- 6.03 s) and frequency content (20-40 vs. 40-60 Hz). Preictal spikes independent from the FRs appeared in the hippocampus/EC and developed into ictal-like discharges that did not propagate to the PC. Ictal-like activity consisted of fast activity with onset either in the hippocampus (n = 6) or in the mEC (n = 2), followed by irregular spiking and sequences of diffusely synchronous bursts. Perfusion of the N-methyl-d-aspartate receptor antagonist 2-amino-5-phosphonopentanoic acid (100 microM) did not prevent FRs, increased the duration of limbic ictal-like discharges and favored their propagation to olfactory structures. The AMPA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (50 microM) blocked ictal-like events and reduced FRs. In conclusion, 4AP-induced epileptiform activities are asynchronous and independent in olfactory and hippocampal-entorhinal regions. Epileptiform discharges in the isolated guinea pig brain show different pharmacological properties compared with rodent in vitro slices.

Topics: 2-Amino-5-phosphonovalerate; 4-Aminopyridine; Animals; Brain; Cerebral Cortex; Entorhinal Cortex; Epilepsy; Excitatory Amino Acid Antagonists; Guinea Pigs; Hippocampus; In Vitro Techniques; Limbic System; Periodicity; Quinoxalines; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Time Factors

The mechanism of anticonvulsant action of topiramate includes inhibition of glutamate-activated ion channels. The evidence is most convincing for direct inhibitory action at the ionotropic AMPA (alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate ((2S,3S,4S)-3-(Carboxymethyl)-4-prop-1-en-2-ylpyrrolidine-2-carboxylic acid) glutamate receptor subtypes. Less direct connection has been made to the NMDA (N-Methyl-d-aspartate) subtype. In the present study, we demonstrate that NMDA and AMPA produce concentration-dependent seizure-like activity in planarians, a type of flatworm which possesses mammalian-like neurotransmitters. In contrast, planarians exposed to the inhibitory amino acid, glycine, did not display pSLA. For combination experiments, topiramate significantly reduced planarian seizure-like activity (pSLA) produced by NMDA or AMPA. Additionally, NMDA-induced pSLA was antagonized by either an NMDA receptor antagonist (MK-801) or AMPA receptor antagonist (DNQX), thus suggesting that NMDA-induced pSLA was mediated by NMDA and non-NMDA receptors. The present results provide pharmacologic evidence of a functional inhibitory action of topiramate on glutamate receptor activity in invertebrates and provide a sensitive, quantifiable end-point for studying anti-seizure pharmacology.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Behavior, Animal; Dizocilpine Maleate; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Fructose; N-Methylaspartate; Neuroprotective Agents; Planarians; Quinoxalines; Seizures; Topiramate

This study investigated the anticonvulsant effect of 3-alkynyl selenophene (3-ASP) on pilocarpine (PC)-, pentylenetetrazole (PTZ)- and kainic acid (KA)-induced seizures and mortality in 21-day-old rats. Rats were pretreated by oral route (p.o.) with 3-ASP (10, 25 and 50mg/kg) before intraperitoneal (i.p.) administration of PC (400mg/kg), PTZ (80 mg/kg) or KA (45 mg/kg). 3-ASP increased the latency to the seizure onset on PTZ and KA models. At the dose of 50mg/kg, 3-ASP avoided the death caused by PTZ and KA. 3-ASP (50mg/kg) abolished seizures and death induced by PC in rats. To investigate the antioxidant effect of 3-ASP on rats exposed to PC, the activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), acetylcholinesterase (AChE), Na(+)K(+)ATPase, superoxide dismutase (SOD) and catalase (CAT) as well as the levels of reactive species (RS) and ascorbic acid (AA) were determined in brains of rats. 3-ASP protected against the increase in RS levels and CAT activity induced by PC in brains of rats. The decrease in the levels of AA and inhibition of Na(+)K(+)ATPase, SOD and AChE activities caused by PC were protected by 3-ASP. Subeffective doses of 3-ASP plus diazepam, 5S,10R-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) increased the latency to the seizure onset induced by PC, suggesting the involvement of ionotropic glutamatergic and GABAergic receptors in anticonvulsant action of 3-ASP. The anticonvulsant and antioxidant effects of 3-ASP in 21-day-old rats on PC model were demonstrated.

Topics: Animals; Anticonvulsants; Antioxidants; Brain; Diazepam; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Kainic Acid; Male; Organoselenium Compounds; Pentylenetetrazole; Pilocarpine; Quinoxalines; Rats; Rats, Wistar; Seizures; Time Factors; Treatment Outcome

Methotrexate (MTX)-induced neurotoxicity may occur after intrathecal or systemic administration at low, intermediate and high doses for the treatment of malignant or inflammatory diseases. The mechanisms of MTX neurotoxicity are not totally understood, and appear to be multifactorial. In this study we characterized a model of MTX-induced seizures in mice to evaluate the convulsive and toxic MTX properties. Additionally, the effect of MTX-induced seizures on the activity of glutamate transporters, as well as the anticonvulsant role of MK-801, DNQX and adenosine on glutamate uptake in brain slices was investigated . MTX induced tonic-clonic seizures in approximately 95% of animals and pre-treatment with MK-801, DNQX and adenosine prevented seizure in 80%, 62% and 50% of animals, respectively. Moreover, MTX leads 59% of mice to death, which was prevented in 100% and 94% when animals received MK-801 and DNQX, respectively. Glutamate uptake decreased by 20% to 30% in cortical slices after MTX-induced seizures. Interestingly, when seizures were prevented by MK-801, DNQX or adenosine, glutamate uptake activity remained at the same level as the control group. Thus, our results demonstrate the involvement of the glutamatergic system in MTX-induced seizures.

Topics: Adenosine; Animals; Brain; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Methotrexate; Mice; Neuroprotective Agents; Quinoxalines; Seizures

The effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, on Ca(2+) and Na(+) influx induced by various stimulants were investigated in cultured rat cerebellar granule cells by single-cell fura-2 or SBFI microfluorimetry. Honokiol and magnolol blocked the glutamate- and KCl-evoked Ca(2+) influx with similar potency and efficacy, but did not affect KCl-evoked Na(+) influx. However, honokiol was more specific for blocking NMDA-induced Ca(2+) influx, whereas magnolol influenced with both NMDA- and non-NMDA activated Ca(2+) and Na(+) influx. Moreover, the anti-convulsant effects of these two compounds on NMDA-induced seizures were also evaluated. After honokiol or magnolol (1 and 5 mg/kg, i.p.) pretreatment, the seizure thresholds of NMRI mice were determined by tail-vein infusion of NMDA (10 mg/ml). Data showed that both honokiol and magnolol significantly increased the NMDA-induced seizure thresholds, and honokiol was more potent than magnolol. These results demonstrated that magnolol and honokiol have differential effects on NMDA and non-NMDA receptors, suggesting that the distinct therapeutic applications of these two compounds for neuroprotection should be considered.

Topics: Analysis of Variance; Animals; Anti-Anxiety Agents; Biphenyl Compounds; Calcium; Cells, Cultured; Cerebellum; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Ion Channels; Lignans; Mice; N-Methylaspartate; Neurons; Platelet Aggregation Inhibitors; Potassium Chloride; Quinoxalines; Rats; Rats, Sprague-Dawley; Seizures; Sodium

Electroconvulsive seizure (ECS) induces structural remodelling in the adult mammalian brain, including an increase in adult hippocampal neurogenesis. The molecular mechanisms that underlie this increase in the proliferation of adult hippocampal progenitors are at present not well understood. We hypothesized that ECS may recruit the Sonic hedgehog (Shh) pathway to mediate its effects on adult hippocampal neurogenesis, as Shh is known to enhance the proliferation of neuronal progenitors and is expressed in the adult basal forebrain, a region that sends robust projections to the hippocampus. Here we demonstrate that the ECS-induced increase in proliferation of adult hippocampal progenitors was completely blocked in animals treated with cyclopamine, a pharmacological inhibitor of Shh signalling. Our results suggest that both acute and chronic ECS enhance Shh signalling in the adult hippocampus, as we observed a robust upregulation of Patched (Ptc) mRNA, a component of the Shh receptor complex and a downstream transcriptional target of Shh signalling. This increase was rapid and restricted to the dentate gyrus, where the adult hippocampal progenitors reside. In addition, both acute and chronic ECS decreased Smoothened (Smo) mRNA, the other component of the Shh receptor complex, selectively within the dentate gyrus. However, ECS did not appear to influence Shh expression within the basal forebrain, the site from which it has been suggested to be anterogradely transported to the hippocampus. Together, our findings demonstrate that ECS regulates the Shh signalling cascade and indicate that the Shh pathway may be an important mechanism through which ECS enhances adult hippocampal neurogenesis.

Topics: Animals; Autoradiography; Bromodeoxyuridine; Cell Count; Dizocilpine Maleate; Electroshock; Excitatory Amino Acid Antagonists; Gene Expression Regulation; Hedgehog Proteins; Hippocampus; Immunohistochemistry; In Situ Hybridization; Male; Neurons; Organogenesis; Patched Receptors; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Receptors, G-Protein-Coupled; RNA, Messenger; Seizures; Signal Transduction; Smoothened Receptor; Stem Cells; Time Factors; Trans-Activators; Veratrum Alkaloids

Seizures have been shown to promote the proliferation of granule cell precursors in the adult brain, but the underlying mechanisms remain largely unknown. Using systemic bromodeoxyuridine (BrdU) to label dividing cells, we examined the effects of selective ionotropic glutamate receptor antagonists on granule cell precursor proliferation in adult rats after pentylenetrazol (PTZ)-induced generalized clonic seizures. We found that the NMDA receptor antagonist MK-801 significantly inhibited behavioral and EEG seizures and completely blocked seizure-induced increase in the number of BrdU-labeled cells in the dentate gyrus. Although the AMPA/KA receptor antagonist DNQX was not observed to affect seizures, it significantly suppressed the number of BrdU-labeled cells in the dentate gyrus. Double immunohistochemical staining showed that both the mature granule cells and the majority of BrdU-labeled, mitotically active cells expressed the NMDA receptor subunit NR1 and the AMPA/KA receptor subunit GluR2. Because accumulated evidence showed that mild seizures are sufficient to promote precursor cell proliferation, the present findings that MK-801 inhibited seizures and completely blocked seizure-induced increase in precursor cell proliferation suggest that the direct blockade action of MK-801 on NMDA receptors on the granule cell precursors may play an important role in blocking seizure-induced precursor cell proliferation. The suppression of seizure-induced proliferation of granule cell precursors by DNQX may be achieved by the direct action of DNQX on AMPA/KA receptors on the granule cell precursors. Thus, our findings indicate that seizures may promote cell proliferation in the adult rat dentate gyrus through glutamatergic mechanisms acting on both NMDA and AMPA/KA receptors.

Topics: Animals; Cell Count; Cell Proliferation; Dentate Gyrus; Dizocilpine Maleate; Down-Regulation; Excitatory Amino Acid Antagonists; Male; Neurons; Pentylenetetrazole; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Seizures; Stem Cells

This study investigated whether D,L-cis-2,3-Pyrrolidine dicarboxylate (D,L-cis-2,3-PDC), a new glutamate analogue, alters glutamate binding to cerebral plasma membranes and whether N-methyl-D-aspartate (NMDA) receptors are involved in the convulsant effect of this compound. D,L-cis-2,3-PDC reduced sodium-independent [3H]-L-glutamate binding to lysed membrane preparations from adult rat cortex and had no effect on sodium-dependent glutamate binding. Intracerebroventricular administration of D,L-cis-2,3-PDC (7.5-25 nmol/5 microl) induced generalized tonic-clonic convulsions in mice in a dose-dependent manner. The coadministration of MK-801 (7 nmol/2.5 microl), with D,L-cis-2,3-PDC (16.5 nmol/2.5 microl), fully protected the animals against D,L-cis-2,3-PDC-induced convulsions, while the coadministration of DNQX (10 nmol/2.5 microl) increased the latency to convulsions but did not alter the percentage of animals that had convulsions. These results suggest that D,L-cis-2,3-PDC-induced effects are mediated predominantly by NMDA receptors.

Topics: Animals; Behavior, Animal; Brain Chemistry; Convulsants; Dicarboxylic Acids; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Membranes; Mice; Neuroprotective Agents; Pyrrolidines; Quinoxalines; Rats; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism; Structure-Activity Relationship

Benign familial neonatal convulsions (BFNC), a hereditary epilepsy, occurs specifically in newborns and remits spontaneously after this period. Several mutations of either KCNQ2 or KCNQ3, members of the KCNQ-related K+-channel (KCNQ-channel) family, were identified as a cause of BFNC. Such mutations impair KCNQ-related M- current, an element of the inhibitory system in the central nervous system (CNS), and therefore are thought to result in neuronal hyperexcitability.. To clarify the pathogenesis of BFNC, this study investigated the effects of the KCNQ channel on propagation of neuronal excitability using a 64-channel multielectrode dish (MED64) system for novel two-dimensional monitoring of evoked field potentials including fiber volley (FV) and field excitatory postsynaptic potential (fEPSP).. Dup996, a selective KCNQ-channel inhibitor, did not affect the amplitude of FV or fEPSP, but enhanced the FV and fEPSP propagation. The gamma-aminobutyric acid (GABA)A-receptor antagonist, bicuculline, enhanced their propagation, whereas alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/glutamate-receptor antagonist, DNQX, reduced both amplitude and propagation of fEPSP without affecting those of FV. Under the condition of GABAA-receptor blockade by bicuculline, Dup996 enhanced the amplitude of fEPSP and propagation of FV and fEPSP without affecting the amplitude of FV. Dup996 enhanced the stimulating effects of bicuculline on the propagation and amplitude of FV and fEPSP, but it did not affect the inhibiting effects of DNQX.. These results suggest that the occurrence of BFNC cannot be produced by KCNQ-channel dysfunction alone but by reciprocal action between impaired KCNQ channel and the other unknown.

Topics: Age Factors; Animals; Bicuculline; Central Nervous System; Data Interpretation, Statistical; Electroencephalography; Epilepsy, Benign Neonatal; Excitatory Amino Acid Antagonists; Excitatory Postsynaptic Potentials; GABA Antagonists; Hippocampus; Humans; Indoles; Infant, Newborn; Male; Mice; Mice, Knockout; Microdialysis; Mutation; Neurons; Potassium Channel Blockers; Potassium Channels; Pyridines; Quinoxalines; Rats; Rats, Wistar; Seizures; Synaptic Transmission

Our previous studies have shown a local decrease in glutamate and aspartate levels during seizures, induced by picrotoxin microdialysis in the hippocampus of chronic freely moving rats. In this paper, we study the effect of continuous hippocampal microperfusion of the NMDA, AMPA and kainate glutamate receptor inhibitors 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801); 6,7-dinitroquinoxaline-2,3-dione (DNQX), and 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466). We also examine the action of L(-)-threo-3-hydroxyaspartic acid (THA), a glutamate and aspartate reuptake blocker, on the modification of extracellular glutamate and aspartate levels induced by picrotoxin, using the microdialysis method in freely moving rats. We found that changes in extracellular hippocampal concentrations in both amino acids are prevented by NMDA, AMPA and kainate receptor inhibitors. Seizures elicited under DNQX also induce a transient increase in aspartate extracellular levels coincident with seizure time. L(-)-threo-3-hydroxyaspartic acid increased the basal extracellular concentrations of both amino acids, but did not prevent the seizure-related decrease. Our results suggest that glutamate, the major neurotransmitter at the synaptic level, may also play an important role in non-synaptic transmission during seizures.

Topics: Animals; Anti-Anxiety Agents; Aspartic Acid; Benzodiazepines; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Extracellular Space; Glutamic Acid; Hippocampus; Male; Microdialysis; Picrotoxin; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Seizures

Under conditions of low [Ca(2+)](o) and high [K(+)](o), the rat dentate granule cell layer in vitro develops recurrent spontaneous prolonged field bursts that resemble an in vivo phenomenon called maximal dentate activation. To understand how pH changes in vivo might affect this phenomenon, the slices were exposed to different extracellular pH environments in vitro. The field bursts were highly sensitive to extracellular pH over the range 7.0-7.6 and were suppressed at low pH and enhanced at high pH. Granule cell resting membrane potential, action potentials, and postsynaptic potentials were not significantly altered by pH changes within the range that suppressed the bursts. The pH sensitivity of the bursts was not altered by pharmacologic blockade of N-methyl-D-aspartate (NMDA), non-NMDA, and GABA(A) receptors at concentrations of these agents sufficient to eliminate both spontaneous and evoked synaptic potentials. Gap junction patency is known to be sensitive to pH, and agents that block gap junctions, including octanol, oleamide, and carbenoxolone, blocked the prolonged field bursts in a manner similar to low pH. Perfusion with gap junction blockers or acidic pH suppressed field bursts but did not block spontaneous firing of single and multiple units, including burst firing. These data suggest that the pH sensitivity of seizures and epileptiform phenomena in vivo may be mediated in large part through mechanisms other than suppression of NMDA-mediated or other excitatory synaptic transmission. Alterations in electrotonic coupling via gap junctions, affecting field synchronization, may be one such process.

Topics: Animals; Calcium; Dentate Gyrus; Electrophysiology; Epilepsy; Excitatory Amino Acid Antagonists; Gap Junctions; Hydrogen-Ion Concentration; Hypnotics and Sedatives; In Vitro Techniques; Male; Octanols; Oleic Acids; Periodicity; Potassium; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, GABA-A; Receptors, N-Methyl-D-Aspartate; Seizures; Synapses; Synaptic Transmission

The effect of intrastriatal administration of glutaric acid (GTR), a metabolite that accumulates in glutaric acidemia type I (GA-I), on the behavior of adult male rats was investigated. After cannula placing, rats received unilateral intrastriatal injections of GTR buffered to pH 7.4 with NaOH or NaCl. GTR induced rotational behavior toward the contralateral side of injection and clonic convulsions in a dose-dependent manner. Rotational behavior was prevented by intrastriatal preadministration of DNQX and muscimol, but not by the preadministration of MK-801. Convulsions were prevented by intrastriatal preinjection of muscimol. This study provides evidence for a participation of glutamatergic non-NMDA and GABAergic mechanisms in the GTR-induced behavioral alterations. These findings may be of value in understanding the physiopathology of the neurological dysfunction in glutaric acidemia.

Topics: Animals; Behavior, Animal; Convulsants; Corpus Striatum; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; GABA Agonists; gamma-Aminobutyric Acid; Glutamates; Glutarates; Injections; Male; Muscimol; Quinoxalines; Rats; Rats, Wistar; Seizures; Stereotyped Behavior

The present study investigated the effect of dextromethorphan and 6,7-dinitroquinoxaline-2,3-dione (DNQX) pre-treatment on the development of cocaine- and lidocaine-induced seizures. The dopaminergic action of cocaine was also studied. The NMDA antagonist dextromethorphan and the non-NMDA (AMPA/kainate) antagonist DNQX both significantly decreased the intensity of the seizure response to intravenous convulsant doses of cocaine and lidocaine individually (20 mg/kg) and in combination (5 mg/kg each). The incidence of seizures in rats receiving cocaine or lidocaine individually was significantly reduced by pre-treatment with dextromethorphan but not DNQX. Haloperidol did not have an effect on the incidence or intensity of seizures induced by cocaine or lidocaine, alone or in combination. The results suggest that local anesthetic-induced convulsive seizures are mediated by excitatory glutamate transmission through both NMDA and non-NMDA receptor systems.

Topics: Anesthetics, Local; Animals; Cocaine; Dextromethorphan; Excitatory Amino Acid Antagonists; Incidence; Injections, Intravenous; Lidocaine; Male; Narcotics; Quinoxalines; Rats; Rats, Sprague-Dawley; Seizures

Alpha-dendrotoxin (alpha-DTx), a snake venom toxin which blocks several types of fast-activating voltage-dependent potassium channels, induces limbic seizures and neuronal damage when injected into the brain. The mechanisms underlying these convulsant and neuropathological actions are not fully understood. We have studied the effects of alpha-DTx on neurotransmitter release and electrical activity in rat hippocampal brain slices and the role of excitatory amino acid receptors in mediating these actions of the toxin. alpha-DTx increased the basal release of acetylcholine, glutamate, aspartate, and GABA in a concentration-dependent manner and induced epileptiform bursting in the CA1 and CA3 regions of the slice. The increase in neurotransmitter release was evident during the first 4 min after toxin addition, whereas the bursting appeared after a concentration-dependent delay (20-40 min with 250 nM toxin). The N-methyl-D-aspartate (NMDA) receptor antagonists AP5 and MK-801 had no effect on the frequency or amplitude of dendrotoxin-induced epileptiform bursts, but the non-NMDA antagonists CNQX and DNQX abolished bursting in both CA1 and CA3 within 4-6 min. In contrast, the toxin-induced increases in neurotransmitter release were not blocked by DNQX. This study has demonstrated that, following exposure to alpha-DTx, there is a rapid increase in the release of neurotransmitters which precedes the onset of epileptiform bursting in the hippocampus. Since DNQX abolished the bursting but had no effect on the increase in neurotransmitter release, these results suggest that DNQX blocks alpha-DTx-induced epileptiform activity by antagonism of postsynaptic non-NMDA receptors.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Acetylcholine; Action Potentials; Animals; Aspartic Acid; Dizocilpine Maleate; Elapid Venoms; Excitatory Amino Acid Antagonists; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Male; Neurotoxins; Neurotransmitter Agents; Potassium Channels; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Non-NMDA receptor antagonists CNQX, DNQX, and NBQX (10-40 mg/kg IP) were tested against pentylenetetrazol-induced (100 mg/kg SC) seizures in 7 to 90-day-old rats. All three drugs significantly decreased the incidence of tonic hindlimb component of tonic-clonic pentylenetetrazol seizures, often in favor of increased incidence of forelimb tonus throughout development. In addition, in 7 to 25-day-old rats, DNQX and NBQX decreased the severity of seizures due to a decrease in total incidence of the tonic component of tonic-clonic seizures compared to age-matched controls. However, neither drug was able to consistently suppress the incidence or increase latency to onset of clonic and tonic-clonic pentylenetetrazol seizures. The data suggest that, during development, non-NMDA receptor transmission may play a role in the generation of the tonic component, but not in the generation of other components of pentylenetetrazol-induced seizures.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Aging; Animals; Anticonvulsants; Behavior, Animal; Epilepsy, Tonic-Clonic; Hindlimb; Male; Muscle Tonus; Pentylenetetrazole; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, Kainic Acid; Seizures; Synaptic Transmission

A novel series of quinoxalinediones possessing imidazolyl and related heteroaromatic substituents was synthesized and evaluated for their activity to inhibit [3H]AMPA binding from rat whole brain. From the structure-activity relationships, it was found that the 1H-imidazol-1-yl moiety could function as a bioisostere for the cyano and nitro groups, and that 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (11) showed the most potent activity for the AMPA receptor. Compound 11 was evaluated for selectivity versus other excitatory amino acid receptors, and its action against AMPA at its receptor in the rat striatum was characterized. These data showed that compound 11 was a selective antagonist for the AMPA receptor with a Ki value of 0.084 microM, being approximately equipotent with 2,3-dihydro-6-nitro-7-sulfamoylbenzo(f)quinoxaline (3) (NBQX; Ki = 0.060 microM). Compound 11 was also found to give protection against sound-induced seizure on DBA/2 mice at the minimum effective dose of 3 mg/kg ip (3; 10 mg/kg ip).

Topics: Acoustic Stimulation; Animals; Anticonvulsants; Binding Sites; Brain; Imidazoles; Male; Mice; Mice, Inbred DBA; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Structure-Activity Relationship

Antagonists of the N-methyl-D-aspartate (NMDA) type of excitatory amino acid (EAA) receptors blocked cocaine-induced stereotypy, locomotor stimulation and convulsions. These effects in general appear to involve selectively NMDA type of receptors. The results suggest that NMDA-activated systems are an integral component in the reaction sequences involved in the expression of several behavioral effects of cocaine.

Topics: Animals; Caffeine; Cocaine; Dextromethorphan; Dizocilpine Maleate; Haloperidol; Male; Mice; Mice, Inbred Strains; Motor Activity; N-Methylaspartate; Pipecolic Acids; Quinoxalines; Rats; Rats, Inbred Strains; Seizures; Stereoisomerism; Stereotyped Behavior

The role of the N-methyl-D-aspartate (NMDA) and non-NMDA excitatory amino acid (EAA) receptors in the mechanism of behavioral sensitization to amphetamine-induced sterotypy was investigated in mice. The results confirm previous observations that NMDA antagonists can block the induction of the phenomenon but not the expression; in contrast, DNQX, a non-NMDA receptor antagonist, can block both the induction and the expression of the sensitization. The differential effects of the two classes of antagonists suggest that the induction and the expression are the result of different mechanisms, both of which involve the EAA system. The DNQX results differ from those of haloperidol, which can also block both the induction and expression, because haloperidol can completely block the amphetamine-induced responses in naive and in sensitized animals; whereas DNQX is without effect on the amphetamine activity in naive animals and, in the sensitized animal, can block only that portion of the response that is derived from the sensitization phenomenon. The effects of the EAA antagonists support the hypothesis that the enhanced responsiveness in the sensitized animals is derived from the activation of EAA receptors, which, in turn, increases the release of dopamine in the striatum. Finally, the involvement of the non-NMDA receptors in the expression of the behavioral sensitization further substantiates the postulate that the amphetamine-induced sensitization is a behavioral manifestation of long-term potentiation (LTP).

Topics: Amphetamine; Analysis of Variance; Animals; Dose-Response Relationship, Drug; Haloperidol; Kainic Acid; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Quinoxalines; Seizures; Stereotyped Behavior

CNQX and DNQX are compounds that have recently been reported to show potent non-NMDA excitatory amino acid receptor antagonist activity. Effects of these compounds on seizures induced by homocysteine thiolactone and quisqualic acid were studied in order to examine the pharmacological properties of these compounds. In a dosage of 1.16 micrograms intracerebroventricularly (ICV), CNQX prolonged the latency to the onset of quisqualate-, but not homocysteine-induced seizures. DNQX was not effective when given either ICV or systemically, although a 3.78 micrograms dose of DNQX given ICV markedly increased the variability in latency to seizure onset, suggesting a combination of pro- and anticonvulsant effects. Higher dosages of both CNQX and DNQX induced seizure-like activity after ICV injection. These data confirm that CNQX has pharmacological effects corresponding to its effects on cellular responses to quisqualate and kainate agonists, but these effects are weak and may limit its usefulness as a pharmacological tool.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anticonvulsants; Female; Homocysteine; Mice; Oxadiazoles; Quinoxalines; Quisqualic Acid; Seizures