oxadiazoles and Epilepsy

The modulatory effects of endogenous serotonin on the synaptic transmission and epileptiform activity were studied in the rat hippocampus with the use of extracellular and intracellular recording techniques. Field excitatory postsynaptic potential was reversibly depressed by serotonin in a concentration-dependent manner. Intracellular recordings revealed that serotonin-mediated synaptic depression was unaffected by extracellular Ba2+ or intracellular application of Cs+ while the postsynaptic hyperpolarizing effect was completely blocked. Epileptiform activity induced by picrotoxin (50 microM), a GABA(A) receptor antagonist, was also dose-dependently suppressed by serotonin. The antiepileptic effect was mimicked by 5-hydroxytryptamine1A agonist and was blocked by 5-hydroxytryptamine1A antagonists. 5-Hydroxytryptamine2 antagonist had no effect on the modulation. Similarly, fluoxetine, a selective serotonin re-uptake blocker, potently inhibited the epileptiform activity and this effect was blocked by 5-hydroxytryptamine1A receptor antagonist. Depletion of endogenous serotonin by pretreating the slices with p-chloroamphetamine completely prevented the antiepileptic action of fluoxetine, without modifying the action of serotonin in the same cells. These results suggest that the antiepileptic action of fluoxetine is due to an enhancement of endogenous serotonin which in turn is mediated by 5-hydroxytryptamine1A receptor. Endogenous serotonin transmission in the hippocampus is therefore capable of limiting the development and propagation of seizure activity.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Animals; Barium; Epilepsy; Excitatory Postsynaptic Potentials; Fluoxetine; Hippocampus; In Vitro Techniques; Ketanserin; Male; Membrane Potentials; Metergoline; Neurons; Oxadiazoles; Picrotoxin; Piperazines; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Synaptic Transmission; Tryptamines

The ability of excitatory amino acid receptor agonists, AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and quisqualate to produce seizures was determined in 1-2 day old epileptic and non-epileptic (carrier) chicks. Both compounds produced prolonged clonic seizures in epileptic chicks at doses which were not convulsant in carrier chicks. Seizures produced in epileptics by AMPA were suppressed by the quisqualate antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione), but were not prevented by pretreatment with competitive (2-amino-7-phosphonoheptanoic acid, APH) or non-competitive (MK-801) NMDA (N-methyl-D-aspartate) receptor antagonists. These data do not support the hypothesis that NMDA receptors work in concert with quisqualate receptors. Binding sites for [3H]AMPA were characterized in cerebral hemispheres of both epileptic and carrier chicks. Analysis of the data revealed no significant alterations in the binding affinity (KD) or the number of binding sites (Bmax) of AMPA to tissue preparations from epileptic chickens when compared to carriers. The latter data does not explain the increased susceptibility of epileptic fowl to the convulsant effects of quisqualate and AMPA.

Topics: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Anticonvulsants; Brain; Chickens; Convulsants; Dose-Response Relationship, Drug; Epilepsy; Ibotenic Acid; Kinetics; Oxadiazoles; Oxazoles; Quisqualic Acid; Radioligand Assay; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter

1. Two quinozalinediones, FG9041 and FG9065, which had previously been shown to displace binding to the quisqualate receptor, were tested on rat neocortex and frog spinal cord in vitro against depolarizations induced by quisqualate, kainate and N-methyl-D-aspartate (NMDA). In both preparations effects of quisqualate were reduced the most and those of NMDA the least. 2. The near unitary slopes of the Schild plots were consistent with a competitive type of interaction. pA2 values for FG9041 were estimated to be 6.6, 6.1 and 5.1 in frog cord and 5.9, 5.3 and and about 4 in the rat neocortex for quisqualate, kainate and NMDA antagonism, respectively. FG9065 gave equivalent pA2 values of 6.2, 5.6 and 4.5. 3. At concentrations, which were without effect on depolarizations induced by NMDA, FG9041 and FG9065 reduced or blocked synaptically-evoked field potentials in hippocampal and neocortical slices superfused with normal magnesium-containing medium. Since these synaptic components are also insensitive to NMDA antagonists, these results are consistent with their mediation by postsynaptic receptors of the quisqualate (or kainate) type. 4. By contrast, quinoxalinediones had only limited effects on spontaneous epileptiform activity seen in both neocortical and hippocampal preparations when superfused with magnesium-free medium. These burst discharges were, however, abolished by NMDA antagonists. 5. In the frog spinal cord the early component of the dorsal root to ventral root reflexes was selectively reduced by FG9041 whereas NMDA antagonists reduced the longer latency components. 6. Our results suggest that the quinoxalinediones are likely to be useful pharmacological probes for elucidating the role of non-NMDA receptors in the vertebrate central nervous system.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Anura; Cerebral Cortex; Electric Stimulation; Epilepsy; Evoked Potentials; Hippocampus; In Vitro Techniques; Kainic Acid; Neuromuscular Depolarizing Agents; Oxadiazoles; Quinoxalines; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Kainic Acid; Receptors, Neurotransmitter; Spinal Cord; Synapses

The present studies demonstrated that the microinjection of quisqualic acid (QA) into unilateral amygdala in chronically implanted cats resulted in various types of limbic seizures in accordance with injected doses. The epileptogenic potency of QA in the induction of epileptic seizures was lower then that of kainic acid (KA), which has also been demonstrated in our previous studies. Electroencephalographic changes and clinical manifestations of QA-induced epilepsy were less prominent as compared with those of KA-induced epilepsy. Five micrograms of QA resulted in pure amygdaloid seizures. The moderate dose administration of QA (15 micrograms) was suitable to observe limbic status. Both doses of QA elicited similar characteristic epileptic patterns on EEG, which was quite distinguishable from those of KA. In pathological study, mild degeneration of hippocampal pyramidal cell layer was observed in the cases injected 15 micrograms of QA. These electro-clinical and pathological features are interesting in similarities to those of human complex partial seizures, mesial temporal sclerosis. In conclusion, the strict dose dependency of QA in the production of limbic seizures is a valid advantage for an experimental model of a complex partial epilepsy in man.

Topics: Amygdala; Animals; Brain; Cats; Convulsants; Disease Models, Animal; Electroencephalography; Epilepsy; Microinjections; Oxadiazoles; Quisqualic Acid

Wet dog shake behavior was studied in different models of epilepsy in the rat. Numerous wet dog shakes were associated with limbic seizures in the course of focal epilepsy induced by kindling stimulations or local injections of kainic or quisqualic acid and progressively disappeared during generalization. On the contrary, they were never observed in models of generalized epilepsy. This study suggests that the number of wet dog shakes may be an index of the progression of limbic seizures toward generalization.

Topics: Amygdala; Animals; Disease Models, Animal; Epilepsy; Hippocampus; Kainic Acid; Kindling, Neurologic; Limbic System; Oxadiazoles; Quisqualic Acid; Rats

Topics: Amino Acids, Dicarboxylic; Animals; Anticonvulsants; Aspartic Acid; Epilepsy; Glutamates; Kainic Acid; N-Methylaspartate; Nerve Degeneration; Nervous System Diseases; Oxadiazoles; Quisqualic Acid; Receptors, Amino Acid; Receptors, Cell Surface; Structure-Activity Relationship

Extracellular free sodium (Na+)o and calcium (Ca2+)o concentration changes were measured in the rat motor cortex, using ion-selective microelectrodes. During ionophoretic applications of excitatory amino acids, decreases in (Na2+)o and in (Ca2+)o were observed. Ca2+ signals were not or very little modified by applications of tetrodotoxin while Na+ signals were slightly depressed, up to 20%. Laminar profile analysis revealed that, while the magnitude of Na+ signals was rather constant throughout the cortex, Ca2+ signals were largest in upper cortical layers. Lesioning and pharmacological experiments indicated that the corresponding permeabilities were most probably located on apical dendrites of pyramidal tract neurons. The relative amplitude of Na+ and Ca2+ signals induced by the release of the glutamate agonists N-methyl-D-aspartate, quisqualate and kainate and the shape of the laminar profile of such responses indicated that different ionic permeabilities located on different neurons underlie such responses. Similar experiments performed on chronic epileptogenic motor foci in rats indicated that the amino acid-induced ionic responses were altered. The significance of such alterations for epileptogenesis is discussed.

Topics: Amino Acids; Animals; Aspartic Acid; Calcium; Cobalt; Electric Conductivity; Epilepsy; Glutamates; Kainic Acid; Motor Cortex; N-Methylaspartate; Oxadiazoles; Pyramidal Tracts; Quisqualic Acid; Rats; Sodium

Convulsant and stimulus induced seizures are associated with Ca, Na, K and Cl concentration changes in the extracellular space (ES), which are a resultant of transmembrane ionic fluxes and of changes in the ES size. The ES decreases on average by 30% during a single seizure. An analysis of the causes of ES size changes reveal a large contribution from the spatial glia K buffer mechanism which may account for up to 60% of the ES decreases. NaCl and KCl uptake into cells as well as increases in intracellular osmolarity due to anaerobic glycolysis contribute less to the local cytotoxic edema but account for a net gain of osmotic active particle at the site of the focus. Excitatory amino acids such as glutamate, aspartate, N-methyl-D-aspartate (NMDA), kainate and quisqualate also lead to Na, Cl and eventually Ca uptake into cells and to release of K with dose dependent decreases in [Na]o, [Ca]o and [Cl]o, increases in [K]o and transient decreases in ES size by up to 80% which are possibly associated with a net reduction of osmotically active particles. The predominant cause for this cytotoxic edema is NaCl uptake into cells but spatial K buffering through glial cells also contributes to this type of edema. The possible consequences of the various ion movements and the changes in osmolarity as well as ES size for tissue vulnerability are discussed.

Topics: Animals; Aspartic Acid; Cats; Epilepsy; Extracellular Space; Hippocampus; In Vitro Techniques; Kainic Acid; N-Methylaspartate; Neuroglia; Oxadiazoles; Potassium; Quisqualic Acid; Somatosensory Cortex; Water-Electrolyte Balance

The qualitative and quantitative values of the baseline EEG differed significantly in patients with primarily generalized epilepsy and temporal epilepsy. The administration of anticonvulsants (phenobarbital, finlepsin) leads to a considerable clinical effect and a decrease in the values of the integrated EEG in the functional states studied in conscious subjects. Additional inclusion of sydnocarb into the multimodality treatment results in the intensification of the therapeutic response in patients with petit mal epilepsy which is accompanied by EEG desynchronization, whereas in temporal epilepsy with psychomotor paroxysms, sydnocarb addition produces an opposite effect.

Topics: Anticonvulsants; Carbamazepine; Drug Therapy, Combination; Electroencephalography; Epilepsy; Epilepsy, Absence; Epilepsy, Temporal Lobe; Humans; Oxadiazoles; Phenobarbital; Sydnones