dizocilpine-maleate and Epilepsy--Absence

The effects of a single and multiple doses of ginkgolide A, B, C, and bilobalide, active components of Ginkgo biloba extract (EGb 761), on absence seizures were investigated in male WAG/Rij rats, a genetic animal model of absence epilepsy. Furthermore, the interactions of ginkgolide A together with NMDA receptor antagonist MK-801, AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), or L-type calcium channel blocker nicardipine were studied to figure out how ginkgolide A affects spike-wave discharges (SWDs) in the brain. The experiments were done using 6-8-month-old male WAG/Rij rats with infusion cannula and EEG electrode implanted. Ginkgolide A, B, C, and bilobalide were administered intraperitoneally for 7 days at a dose of 6 mg/kg. In interaction groups, 6 μg ginkgolide A was injected intracerebroventricularly in combination with MK-801 (10 μg), CNQX (1 μg), and nicardipine (50 μg) for 7 days. EEG was recorded from animals at the baseline, first dose, and seventh dose periods for 4 h. Ginkgolide A (p = .028), C (p = .046), and bilobalide (p = .043) significantly increased the frequency of SWDs in WAG/Rij rats. Ginkgolide A injected into the lateral ventricle with MK-801 (p = .046), CNQX (p = .043), and nicardipine (p = .046) significantly increased the number of SWDs after seventh dose. Finally, the EGb 761-related increase in absence epilepsy was determined to be caused by ginkgolide A, C, and bilobalide. All three receptor antagonists/channel blockers do not inhibit the pro-absence effect of ginkgolide A. The findings revealed that ginkgolide A's pro-absence effect is mediated by brain circuits other than ionotropic glutamate receptors or L-type calcium channels.

Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bilobalides; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Epilepsy, Absence; Excitatory Amino Acid Antagonists; Ginkgolides; Male; Nicardipine; Rats; Seizures

The WAG/RIJ rats exhibit spontaneously occurring spike-wave discharges (SWD) accompanied by behavioural phenomena, with characteristics similar to the human absence type epilepsy. To study the mechanisms involved in this type of epileptiform activity we investigated the effects of the serotonin-1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and the N-methyl-D-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801). Intracerebroventricular (i.c.v.) injection of 8-OH-DPAT caused marked, dose dependent increase, MK-801 a decrease in the cumulative duration and number of spike-wave discharges. Pretreatment with MK-801 (10 microg/rat i.c.v.) abolished the increase caused by 8-OH-DPAT (20 microg/rat i.c.v.), but the decrease in SWD to MK-801 was counterbalanced by 8-OH-DPAT. These data provide evidence for an interaction of glutamatergic and serotonergic mechanisms in the triggering and maintenance of epileptic activity in this genetic model of absence epilepsy.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Action Potentials; Animals; Brain Chemistry; Disease Models, Animal; Dizocilpine Maleate; Epilepsy, Absence; Excitatory Amino Acid Antagonists; Injections, Intraventricular; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Receptor Agonists

The reticular part of the substantia nigra is known to be a critical site in the control of epileptic seizures. Potentiation of the direct striatonigral GABAergic projection has been shown to suppress seizures in different animal models of epilepsy. Besides this GABAergic input, the substantia nigra receives glutamatergic inputs, especially from the indirect striatonigral pathway, via the subthalamic nucleus. To investigate the involvement of the nigral excitatory amino acid transmission in the remote control of non-convulsive generalized seizures, several drugs interacting with glutamatergic receptors were first injected into the substantia nigra pars reticulata in rats with spontaneous absence seizures. Blockade of N-methyl-D-aspartate receptors suppressed spontaneous generalized non-convulsive seizures in the rat, whereas blockade of non-N-methyl-D-aspartate receptors was without effect. Second, inhibition of the subthalamic projection by bilateral injections of a GABAergic agonist in this structure similarly suppressed absence seizures. These results suggest that excitatory amino acid inputs are critical in the triggering of the nigral control of generalized epilepsies. Furthermore, they support the hypothesis of a possible involvement of the subthalamonigral pathway in the control of generalized non-convulsive seizures.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Epilepsy, Absence; Glutamic Acid; Male; Microinjections; N-Methylaspartate; Rats; Rats, Wistar; Substantia Nigra

In the selected strain of GAERS Wistar rats (Genétic Absence Epilepsy Rats from Strasbourg), all animals present spontaneously recurrent absence seizures characterized by bilateral and synchronous generalized spike-and-wave discharges (SWD) accompanied by behavioural arrest. SWD depend on a thalamo-cortical network connecting the reticular and relay nuclei of the thalamus and their cortical projection areas. This loop involves both GABAergic and glutamatergic synapses. In the present study, we investigated the implication of NMDA transmission in the genesis of absence seizures in GAERS. Intra-peritoneal or intra-cerebroventricular injections of NMDA, the competitive NMDA antagonist CGP 40116, the non-competitive NMDA antagonist (+)-MK 801 and the antagonist of the glycine modulatory site 5,7-dichlorokynurenic acid dose-dependently suppressed SWD. Bilateral infusions of the same drugs in the lateral relay nuclei of the thalamus had similar suppressive effects. Intra-cerebroventricular or intrathalamic administration of D-serine, an agonist of the glycine modulatory site, had no effect on SWD. These data show that NMDA neurotransmission, especially within the thalamus, plays a major role in the control of absence seizures in GAERs. Disregulation of NMDA-mediated transmission by NMDA or antagonists, interacting with various sites of the receptor complex, may suppress the thalamo-cortical oscillatory activity which underlies SWD.

Topics: Animals; Disease Models, Animal; Dizocilpine Maleate; Epilepsy, Absence; Male; Models, Genetic; N-Methylaspartate; Rats; Thalamus

The possible role of thalamic NMDA receptors in the generation of experimental absence-like seizures was studied in rats. Bilaterally synchronous spike wave discharges were induced by gamma-hydroxybutyric acid (GHB) and were recorded simultaneously from different thalamic nuclei and the layers I-IV of frontoparietal cortex. Bilateral infusions of NMDA into thalamic mediodorsal nucleus, the intralaminar central lateral/paracentral nucleus, ventroposterolateral, or reticular nucleus of the thalamus in conscious rats, prior to GHB administration suppressed GHB-induced SWD in a dose dependent manner. However, no such suppression of GHB-induced SWD was observed when NMDA infusions were made into the above thalamic sites after the onset or development of GHB-induced SWD. Pretreatment with high doses of competitive (CGP 43487) or non-competitive NMDA receptor antagonists (MK-801 and ketamine) also dose dependently suppressed GHB-induced SWD. Both MK-801 and CGP 43487 dose dependently antagonized NMDA-mediated inhibition of GHB-induced SWD activity but at lower doses did not produce significant inhibition of GHB-induced SWD. The anti-SWD effects of NMDA, MK-801 and ketamine but not CGP 43487 were more pronounced in the mediodorsal and intralaminar thalamic nuclei than in the ventroposterolateral or reticular nucleus of thalamus. Because low doses of NMDA antagonists failed to disrupt the generation of seizures in the GHB model, these findings do not support a role for thalamic NMDA receptors in the pathogenesis of absence-like seizures induced by gamma-hydroxybutyric acid.

Topics: Animals; Brain Mapping; Disease Models, Animal; Dizocilpine Maleate; Electroencephalography; Epilepsy, Absence; Hydroxybutyrates; Injections, Spinal; Male; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Thalamus; Time Factors

gamma-Hydroxybutyric acid (GHB), a naturally occurring compound which is synthesized from gamma-aminobutyric acid (GABA), induces bilaterally synchronous spike wave discharges, associated with behavioral changes, reminiscent of petit mal or generalized absence seizures in rats. In the present study, possible involvement of excitatory amino acids (EAAs) in GHB-induced spike wave discharges was investigated. The noncompetitive antagonist of NMDA receptors, MK-801, attenuated GHB-induced spike wave discharges at all doses tested (0.025-1.0 mg/kg) but dose-dependently induced suppression of EEG bursts in GHB-treated animals. The suppression of bursts was never observed with GHB in control experiments. N-Methyl-D-aspartate (NMDA) had a similar effect on GHB-induced spike wave discharges, when it was administered prior to GHB. This effect of NMDA was partially reversed by MK-801. The competitive antagonists of NMDA receptors, (+/-)CPP and CGP 43487 and the antagonist at the strychnine-insensitive glycine site, HA-966, also suppressed GHB-induced spike wave discharges with the EEG progressing to suppression of bursts but were weaker in this regard than MK-801 or NMDA. These data raise the possibility of involvement of excitatory amino acids in the GHB model of absence seizures.

Topics: Amino Acids; Animals; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electroencephalography; Epilepsy, Absence; Injections, Intraventricular; Male; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sodium Oxybate; Strychnine