cgp-37849 and Seizures

Mechanism of ictogenesis of D- and L-stereroisomers of homocysteic acid was studied in 12-day-old rats by means of antagonists of N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. There was no qualitative difference between the two stereoisomers in generation of emprosthotonic (flexion) as well as generalized tonic-clonic seizures. Moderate differences were observed in the first, nonconvulsive effects of the two isomers. As generation of the two types of seizures is concerned, NMDA and AMPA participate in generalized tonic-clonic seizures whereas NMDA receptors play a dominant role in generation of flexion seizures.

Topics: 2-Amino-5-phosphonovalerate; Animals; Benzodiazepines; Dizocilpine Maleate; Homocysteine; Male; Quinoxalines; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Seizures; Stereoisomerism

The epileptogenic and neurodegenerative effects of gamma-dendrotoxin, from Dendroaspis angusticeps, a specific blocker of a non-inactivating, voltage-sensitive K+ channel, were studied after focal injection into one dorsal hippocampus in rats pretreated with CGP040116, a N-methyl-D-aspartate (NMDA) receptor antagonist, and in rats bearing a monolateral surgical lesion of the Schaffer collaterals whose terminals originate from CA3 pyramids and release glutamate in the CA1 hippocampal area. Administration of 35 pmol gamma-dendrotoxin elicited in all of the treated animals (n=8) bilateral EEG discharges and damage to the hippocampal formation. Quantitation of the damage revealed significant bilateral neuronal cell loss in the CA1, CA3 and CA4 pyramidal cell layers. The lowest dose (0.35 pmol; n=4) of the toxin used did not affect EEG activity and failed to cause significant hippocampal cell loss whereas the 3.5 pmol (n=6) dose caused EEG seizures and hippocampal cell loss limited to the CA1 area. Systematic intraperitoneal administration of CGP040116 (5mg/kg given 30 min. previously) delayed the onset of EEG seizures and reduced the number of epileptogenic discharges typically observed in rats receiving an injection of gamma-dendrotoxin (35 pmol) alone. Similarly, this treatment prevented the damage inflicted to the hippocampus by the toxin and in no instance was significant neuronal loss observed. Protection against seizures and hippocampal damage was also observed by a monolateral surgical lesion to the Schaffer collaterals. In conclusion, the present data suggest that an excitotoxic, glutamate-mediated, type of mechanism underlies seizures and hippocampal damage induced by gamma-dendrotoxin in rats.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dose-Response Relationship, Drug; Elapid Venoms; Electroencephalography; Excitatory Amino Acid Antagonists; Glutamic Acid; Hippocampus; Injections, Intraperitoneal; Male; Neurons; Peptides; Potassium Channel Blockers; Rats; Rats, Wistar; Seizures

Renal failure has been viewed as a state of cellular calcium toxicity due to the retention of small fast-acting molecules. We have tested this hypothesis and identified potentially neuroexcitatory compounds among a number of putative uremic neurotoxins by examining the acute in vitro effects of these compounds on cultured central neurons. The in vitro neuroexcitatory and synergistic effects of guanidinosuccinate and spermine were also examined in vivo.. The acute effects of 17 candidate uremic neurotoxins on murine spinal cord neurons in primary dissociated cell culture were investigated using the tight-seal whole-cell recording technique. The compounds studied comprised low-molecular-weight solutes like urea, indoles, guanidino compounds, polyamines, purines and phenoles, homocysteine, orotate, and myoinositol. Currents evoked by these compounds were further examined using various ligand- and voltage-gated ion channel blockers. The acute in vivo effects of guanidinosuccinate and spermine were behaviorally assessed following their injection in mice.. It was shown that 3-indoxyl sulfate, guanidinosuccinate, spermine, and phenol evoked significant whole-cell currents. Inward whole-cell current evoked by 3-indoxyl sulfate was not blocked by any of the applied ligand- or voltage-gated ion channel blockers, and the compound appeared to influence miscellaneous membrane ionic conductances, probably involving voltage-gated Ca2+ channels as well. Phenol-evoked outward whole-cell currents were at least partly due to the activation of voltage-gated K+ channels, but may also involve a variety of other ionic conductances. On the other hand, inward whole-cell currents evoked by guanidinosuccinate and spermine were shown to be due to specific interaction with voltage- and ligand-gated Ca2+ channels. Guanidinosuccinate-evoked current was caused by activation of N-methyl-d-aspartate (NMDA) receptor-associated ion channels. Low (micromol/L) concentrations of spermine potentiated guanidinosuccinate-evoked current through the action of spermine on the polyamine binding site of the NMDA receptor complex, whereas current evoked by high (mmol/L) concentrations of spermine alone involved direct activation of voltage-gated Ca2+ channels. Finally, intracerebroventricular administration of 0.25 micromol/L spermine potentiated clonic convulsions induced by guanidinosuccinate. These neuroexcitatory and synergistic effects of guanidinosuccinate and spermine could take place at pathophysiologic concentrations.. The observed in vitro and in vivo effects of uremic retention solutes suggest that the identified compounds could play a significant role in uremic pathophysiology. Some of the compounds tested displayed in vitro and in vivo neuroexcitatory effects that were mediated by ligand- and voltage-gated Ca2+ channels. The findings suggest a mechanism for the involvement of calcium toxicity in the central nervous system complications in renal failure with particular reference to guanidinosuccinate and spermine.

Topics: 2-Amino-5-phosphonovalerate; 6-Cyano-7-nitroquinoxaline-2,3-dione; Animals; Bicuculline; Calcium Channels; Cells, Cultured; Drug Synergism; Excitatory Amino Acid Antagonists; GABA Antagonists; Guanidines; Membrane Potentials; Mice; Neurons; Nickel; Piperidines; Potassium Channel Blockers; Seizures; Spermine; Spinal Cord; Succinates; Synapses; Tetraethylammonium; Tetrodotoxin; Uremia

In this paper we examined the effect of flumazenil (Ro 15-1788, 10 mg/kg), a benzodiazepine receptor antagonist, on the anticonflict activity of DL-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 37849), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, and 1-aminocyclopropanecarboxylic acid (ACPC), a partial agonist at glycine(B) receptors, in the Vogel conflict drinking test in rats. The effect of flumazenil on the anxiolytic-like (in the plus-maze test) and the anticonvulsant (in the maximal electroshock-induced seizures) activities of CGP 37849 in rats was also studied. Diazepam was used as a reference drug. CGP 37849 (2. 5-5 mg/kg), ACPC (50-200 mg/kg) and diazepam (2.5-5 mg/kg) significantly and dose-dependently increased the number of shocks accepted during experimental sessions in the conflict drinking test. Flumazenil partly but significantly reduced the anticonflict effect of CGP 37849, and it fully blocked the anticonflict effect of ACPC and diazepam. CGP 37849 (2.5-5 mg/kg) and diazepam (2.5-5 mg/kg) were also active in the plus-maze test, as they significantly increased the percentage of the time spent in and entries into the open arms of the plus-maze, both those effects having been antagonized by flumazenil. Flumazenil alone was inactive in both the conflict drinking and the plus-maze tests. In the maximal electroshock-induced seizures, both CGP 37849 (2.5-5 mg/kg) and diazepam (5-10 mg/kg) produced anticonvulsant effects, of which only that of diazepam was antagonized by flumazenil. The results of the present study showing antagonism of flumazenil towards the anxiolytic-like effects of CGP 37849 and ACPC suggest involvement of benzodiazepine receptors in such an activity of the NMDA and glycine(B) receptor ligands, respectively, which may be due to a possible interaction between NMDA and GABA/benzodiazepine systems. The lack of effect of the benzodiazepine antagonist on the anticonvulsant activity of CGP 37849 indicates that involvement of benzodiazepine receptors in the pharmacological action of the NMDA antagonist is not a general phenomenon.

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amino Acids, Cyclic; Animals; Anti-Anxiety Agents; Conflict, Psychological; Diazepam; Dose-Response Relationship, Drug; Drinking Behavior; Electroshock; Excitatory Amino Acid Antagonists; Flumazenil; GABA-A Receptor Antagonists; Male; Maze Learning; Rats; Rats, Wistar; Seizures

The objective of the study was to examine the role of N-methyl-D-aspartate (NMDA) receptors in the modulation of a brain tolerance after a transient cerebral ischemia. Adult mice were exposed for 30 min to bilateral clamping of common carotid arteries (BCCA) under anaesthesia. The competitive NMDA antagonist CGP-40116 was administered intraperitoneally (i.p.) in two experimental paradigms, (a) acute treatment: twice, 4.0 mg/kg; 1.5 h before the clamping of vessels and 6 h after re-circulation and (b) chronic treatment in a dose of 1.0 mg/kg; started 24 h after re-circulation and continued once daily for 13 days with the last injection 24 h before the induction of convulsions. Seizures were evoked with pilocarpine (400 mg/kg, i.p.) 14 days after BCCA. The preliminary study showed that BCCA induced protection against pilocarpine toxicity. The acute treatment with CGP-40116 partially diminished the anticonvulsant phenomenon. In contrast, the chronic treatment with the drug led to a marked potentiation of the effect. The whole brain gamma-aminobutyric acid (GABA) analysis performed 14 days after BCCA showed a moderate increase in vehicle-treated mice and a significant elevation after chronic treatment with CGP-40116. It can be concluded that NMDA antagonists may exert the opposite effects on the brain tolerance against pilocarpine toxicity after BCCA. The acute treatment with CGP-40116 diminished its induction while the chronic low-dose treatment enhanced a brain tolerance, possibly through the mechanism of chemical preconditioning.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Behavior, Animal; Brain; Brain Chemistry; Carotid Artery, Common; gamma-Aminobutyric Acid; Ischemic Attack, Transient; Ischemic Preconditioning; Male; Mice; Muscarinic Agonists; Pilocarpine; Seizures

To assess the role of NMDA receptors in the modulation of a brain tolerance after a transient cerebral mild ischemia, adult mice were exposed for 30 min to bilateral clamping of the common carotid arteries (BCCA) under pentobarbital anaesthesia. The competitive NMDA antagonist CGP-40116 was administered intraperitoneally (i.p.) in two experimental paradigms: a) acute treatment: twice, 4.0 mg/kg; 1.5 hour before the clamping of vessels and 6 hours after re-circulation and b) chronic treatment in a dose of 1.0 mg/kg; started 24 hours after re-circulation and continued once daily for 13 days with the last injection 24 hours before the induction of convulsions. Seizures were evoked with bicuculline (3.5 mg/kg, i.p.) 14 days after BCCA. Transient brain oligemia induced protection against bicuculline toxicity. The acute treatment with CGP-40116 only partially diminished the anticonvulsant phenomenon. In contrast, the chronic treatment with the drug markedly potentiated the effect. It can be concluded that NMDA receptors only partially participate in the induction of a protective effect against bicuculline toxicity after BCCA. The chronic treatment with low doses of the NMDA antagonist may enhance the brain tolerance, possibly due to the chemical preconditioning.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Behavior, Animal; Bicuculline; Convulsants; Disease Susceptibility; Excitatory Amino Acid Antagonists; Ischemic Attack, Transient; Ischemic Preconditioning; Mice; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Seizures; Time Factors

The aim of this study was to evaluate the effect of N-methyl-D-aspartate (NMDA) and kainate used at nonconvulsive doses upon protective efficacy of chlormethiazole against maximal electroshock-induced seizures. NMDA (50 mg/kg, i.p.) reduced the anticonvulsant potency of chlormethiazole increasing its ED50 value from 126.9 to 155.0 mg/kg. The effect of NMDA was completely reversed by the competitive NMDA receptor antagonist D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116) (0.06 mg/kg i.p.). Kainic acid (9 mg/kg i.p.) did not affect the anticonvulsive properties of chlormethiazole. Our results suggest that NMDA but not kainate receptor-mediated events participate in the anticonvulsant action of chlormethiazole.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Chlormethiazole; Electroshock; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Kainic Acid; Male; Mice; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures

Anticonvulsant action of CGP 40116, a competitive antagonist of N-methyl-D-aspartate type of excitatory amino acid receptors, was studied in rats during development (7, 12, 18, 25 and 90 days old). Two types of motor seizures were elicited by a subcutaneous injection of pentylenetetrazol. Pretreatment with CGP 40116 did not influence minimal, predominantly clonic seizures in any age group. Generalized tonic-clonic seizures were at first modified--their tonic phase was restricted to forelimbs, then selectively suppressed--and with increasing dosage the clonic phase was blocked too. This effect exhibited only minor quantitative changes during development.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Dose-Response Relationship, Drug; Rats; Receptors, N-Methyl-D-Aspartate; Seizures

The competitive N-methyl-D-aspartate (NMDA) antagonist DL-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CAS 127910-31-0, 4-methyl-APPA, CGP 37849) and its ethyl ester (CAS 127910-32-1, CGP 39551) potently block NMDA-evoked whole-cell current on mouse spinal neurones in primary dissociated cell cultures with IC50 (+/- SE) values of 189 +/- 9 nmol/l (CGP 37849) and 2100 +/- 220 nmol/l (CGP 39551), respectively. The compounds dose-dependently blocked vestibular stimulation-induced convulsions in EL mice, 2 h after oral administration, with ED50 (95% CI) values of 135 (78-236) mumol/kg (CGP 37849) and 65 (45-94) mumol/kg (CGP 39551). In male Swiss albino mice, performance in the step-through passive avoidance procedure was dose-dependently impaired with ED50 (95% CI) values of 85 (56-157) mumol/kg (CGP 37849) and 27 (18-42) mumol/kg (CGP 39551). In addition performance of these animals in the rotarod test of motor coordination was impaired, 2 h after oral administration of CGP 39551, with an ED50 (95% CI) of 142 (100-201) mumol/kg. These findings demonstrate anticonvulsant activity in these potent NMDA antagonists after oral administration with CGP 39551 possessing greater relative potency. However, the unfavourable ratio of therapeutic dose versus dose inducing memory or motor impairment supports the prevailing notion that such adverse effects of the presently available compounds preclude the use of NMDA antagonists as long-term therapies.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Avoidance Learning; Cells, Cultured; Electric Stimulation; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred Strains; N-Methylaspartate; Neurons; Patch-Clamp Techniques; Postural Balance; Receptors, N-Methyl-D-Aspartate; Seizures; Spinal Cord; Vestibule, Labyrinth

Seizures were induced in immature 18-day-old rats by i.p. administration of homocysteine (11 mmol/kg) and the effects of selected antagonists of NMDA receptors [MK-801 (0.5 mg/kg), AP7 (0.33 mmol/kg), CGP 40116 (10 mg/kg)] and non-NMDA receptors [GDEE (4 mmol/kg), NBQX (two doses, 30 mg/kg each)] were studied. The effect of MgSO4 (two doses, 2 mmol/kg each) was also tested. The anticonvulsant effect was evaluated not only from the behavioral manifestations of seizures, but also in terms of some indicators of brain energy metabolism. Rat pups were sacrificed during generalized clonic-tonic seizures, corresponding to 16-45 min after homocysteine administration. Comparable time intervals were used for sacrificing the pups which had received the protective drugs. In contrast to neonatal rats, in which only NMDA antagonists could prevent homocysteine-induced seizures, both NMDA and non-NMDA receptor antagonists exerted an anticonvulsant effect in 18-day-old rats. In addition, the pronounced anticonvulsant effect could be achieved by the combined treatment with low subthreshold doses of NMDA (MK-801) and non-NMDA (NBQX) receptor antagonists. The protection was evident not only in suppressing behavioral symptoms of seizures, but also in preventing most of the metabolic changes accompanying seizures, mainly glycogen degradation. More than a sevenfold accumulation of lactate occurring during seizures was markedly reduced by all the tested drugs, but was not completely eliminated. All antagonists, when given alone in the same doses as those used for seizure protection, remained without any effect on lactate levels. Comparison of the present data with previous findings concerning neonatal rats suggests that there may be a developmental change in anticonvulsant efficacy of non-NMDA receptor antagonists against homocysteine-induced seizures in rats.

Topics: 2-Amino-5-phosphonovalerate; Age Factors; Animals; Anticonvulsants; Behavior, Animal; Brain Chemistry; Dizocilpine Maleate; Dose-Response Relationship, Drug; Energy Metabolism; Excitatory Amino Acid Antagonists; Glutamates; Homocysteine; Male; Neuroprotective Agents; Quinoxalines; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

Topics: 2-Amino-5-phosphonovalerate; Amino Acids; Amygdala; Animals; Anticonvulsants; Electroencephalography; Kindling, Neurologic; Male; Microinjections; Motor Activity; N-Methylaspartate; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Seizures; Time Factors

Tolerance occurred to the sedative actions of the competitive NMDA antagonists, CGP39551 and CGP37849, as measured by a decrease in spontaneous locomotor activity after 1 week or 2 weeks of administration, respectively, in studies using the TO strain of mice. Crosstolerance was seen between these compounds. When CGP37849 was given after 2 weeks treatment with CGP39551, an increase in locomotor activity was seen. Chronic barbiturate treatment, producing tolerance to the actions of pentobarbitone, did not affect the sedative properties of CGP39551 or CGP37849. Chronic treatment with CGP39551 did not alter the ataxic actions of pentobarbitone. Seven days of treatment with HA966 caused complete tolerance to its sedative actions, but no crosstolerance was seen to pentobarbitone, CGP39551, or CGP37849. A small but significant decrease was seen in the convulsion thresholds to NMDA after 15 days of treatment with CGP39551, and a small significant increase in ratings of convulsive behavior after 16 days injections of CGP37849. No significant changes were found in either Bmax or Kd for [3H]-MK-801 binding in cerebrocortical tissue 24 h after the last chronic treatment with either of the NMDA antagonists.

Topics: 2-Amino-5-phosphonovalerate; Animals; Ataxia; Behavior, Animal; Dizocilpine Maleate; Drug Tolerance; Hypnotics and Sedatives; Male; Mice; Motor Activity; N-Methylaspartate; Pyrrolidinones; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

The biologically active enantiomer (CGP 40116) of the new competitive N-methyl-D-aspartate (NMDA) receptor antagonist CGP 37849 was investigated for its effects on pilocarpine-induced limbic motor seizures and unconditioned motor behaviour in the mouse. CGP 40116 (1-8 mg/kg IP) reduced the incidence and severity of pilocarpine-induced motor seizures, although the overall effect was weak. In contrast to the noncompetitive NMDA antagonist MK 801, there were no signs of CGP 40116 producing a proconvulsant response in this model. In the nonhabituated mouse, MK 801 promoted hyperlocomotion at low doses and hypolocomotion and ataxia at high doses, while CGP 40116 dose-dependently suppressed motor behaviour. Because CGP 40116 and MK 801 exert opposite effects on the seizure threshold to pilocarpine and differentially alter species-typical behaviours in the mouse, it is suggested that different populations of NMDA receptors may mediate their effects. The indivisibility of seizure suppression and motor impairment noted previously with noncompetitive NMDA antagonists such as MK 801 appears also to apply to the new generation competitive NMDA antagonist CGP 40116.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Grooming; Limbic System; Locomotion; Male; Mice; Mice, Inbred Strains; Motor Activity; Pilocarpine; Receptors, N-Methyl-D-Aspartate; Seizures

1. The competitive antagonists at the N-methyl-D-aspartate (NMDA) receptor, CGP39551 and CGP37849, protected against the barbiturate withdrawal syndrome in mice, as measured by ratings of convulsive behaviour on handling. 2. The effective doses of these compounds were lower than those required to prevent seizures due to NMDA in naive animals; these were in turn lower than those needed to prevent the convulsive effects of the alpha-aminobutyric acid (GABA) antagonist, bicuculline. 3. The NMDA-receptor antagonists did not alter the increase in the incidence of convulsions due to the GABAA antagonist, bicuculline, that is seen during barbiturate withdrawal, although the latencies to these convulsions during barbital withdrawal were significantly increased after CGP39551. 4. Barbiturate withdrawal did not affect the convulsive actions of NMDA, whether measured by the incidence of convulsions or by intravenous infusion. 5. The Bmax for [3H]-dizocilpine ([3H]-MK801) binding was significantly increased by chronic barbital treatment in cerebrocortical but not in hippocampal tissues, while the Kd remained unaltered in either case. 6. At 1 h and 24 h after administration of a single dose of barbitone, the Bmax for [3H]-dizocilpine binding was unaltered in cerebrocortical tissue. Acute addition of barbitone in vitro did not alter [3H]-dizocilpine binding or the displacement of binding of thienylcyclohexylpyridine.

Topics: 2-Amino-5-phosphonovalerate; Animals; Barbital; Bicuculline; Cerebral Cortex; Dizocilpine Maleate; Hippocampus; Male; Mice; Motor Activity; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Seizures; Substance Withdrawal Syndrome

Increased levels of the endogenous convulsant guanidinosuccinate (GSA) might contribute to the epileptic symptomatology presenting in patients with renal failure. Little is known, however, about the underlying epileptogenic mechanism of guanidinosuccinate-induced convulsions. In this paper, we present pharmacological evidence for a direct excitatory action of this compound. In particular, the close involvement of N-methyl-D-aspartate (NMDA) receptors in the pathogenesis of GSA-induced generalized convulsions is suggested. GSA potentiated NMDA-induced convulsions significantly, but not L-glutamate- or kainate-induced convulsions. Conversely, and in addition, NMDA receptor antagonists, like D(-)-2-amino-5-phosphonovalerate, CGP 37849 [DL)-(E)-2-amino-4-methyl-5-phosphono-3-pentenoate] or ketamine (but not kynurenate), blocked the convulsions induced by i.c.v. injection of GSA dose dependently whereas anti-epileptic drugs, like carbamazepine, diazepam, phenobarbital or valproate, only abolished the tonic extension phase of these convulsions. Thus, NMDA receptors appear to be involved, at least partly, in GSA-induced convulsions.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Drug Interactions; Female; Glutamates; Glutamic Acid; Guanidines; Kainic Acid; Ketamine; Kynurenic Acid; Male; Mice; Receptors, N-Methyl-D-Aspartate; Seizures; Succinates

An assortment of glutamate antagonists with differing selectivities for NMDA and AMPA-type glutamate receptors, were tested for their effects in the mouse pilocarpine model of complex partial seizures. MK 801 (0.1-0.8 mg/kg) and high doses of HA 966 (50 mg/kg) were proconvulsant, whilst CGP 40116 (1-8 mg/kg) and low doses of HA 966 (0.4-10 mg/kg) inhibited pilocarpine-induced convulsions. CPP (5-20 mg/kg) and NBQX (1-50 mg/kg) were without effect. The dopamine D1 agonist SKF 38393 (10 mg/kg) facilitated the convulsant effects of low-dose pilocarpine (100 mg/kg). MK 801 (0.1-0.2 mg/kg) and HA 966 (50 mg/kg) interacted synergistically with SKF 38393 to promote the proconvulsant effects of D1 stimulation, whilst CPP (10-20 mg/kg) and HA 966 (10 mg/kg) had the opposite effect. CGP 40116 and NBQX were without effect. These results show that the convulsant qualities of MK 801 and SKF 38393, that have been detected in animal models of Parkinson's disease, can be reproduced in the pilocarpine model of epilepsy. Whilst the glutamate antagonists all interact synergistically with SKF 38393 to improve its antiparkinson activity, only MK 801 and high doses of HA 966 similarly potentiate the convulsions associated with D1 stimulation. An appropriate mixture of a glutamate antagonist and a D1 agonist could theoretically be used beneficially in the treatment of Parkinson's disease, without causing epilepsy as a side effect.

Topics: 2-Amino-5-phosphonovalerate; 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; Animals; Dizocilpine Maleate; Dopamine Agents; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Mice; Mice, Inbred Strains; Pilocarpine; Piperazines; Pyrrolidinones; Quinoxalines; Receptors, AMPA; Receptors, Dopamine D1; Receptors, N-Methyl-D-Aspartate; Seizures

CGP 37849 (1 mg/kg i.p.) enhanced the protective action of carbamazepine, diphenylhydantoin and phenobarbital against maximal electroshock-induced convulsions in mice. At 0.25 mg/kg CGP 37849 was inactive and at 0.5 mg/kg it potentiated the anticonvulsive activity of phenobarbital. CGP 39551 (5 mg/kg i.p.) reduced the ED50 values of diphenylhydantoin and phenobarbital, being without influence on carbamazepine. In the dose of 1.25 mg/kg, CGP 39551 potentiated the antielectroshock action of diphenylhydantoin and at 2.5 mg/kg that of phenobarbital. Neither NMDA receptor antagonist elevated the total plasma levels of antiepileptic drugs. Consequently, a pharmacokinetic interaction (in terms of total plasma levels at least) seems unlikely to be responsible for the observed potentiation of the antiepileptic drugs' activity. Combinations of CGP 37849 with either carbamazepine or phenobarbital resulted in a motor and memory impairment quantified by the chimney test and passive avoidance task, respectively. Moreover, combined treatment with phenobarbital and CGP 39551 caused a memory deficit. In contrast, diphenylhydantoin combined with either CGP 37849 or 39551 was devoid of adverse effects. It may be concluded that NMDA receptor blockade results in enhanced anticonvulsive action of common antiepileptics against maximal electroshock-induced seizures.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Avoidance Learning; Behavior, Animal; Carbamazepine; Drug Synergism; Electroshock; Male; Memory; Mice; Motor Activity; Phenobarbital; Phenytoin; Receptors, N-Methyl-D-Aspartate; Seizures

Two novel N-methyl-D-aspartic acid (NMDA) competitive antagonists, CGP 37849 (1.25 and 2.5 mg/kg) and CGP 39551 (10 mg/kg), significantly raised the threshold for electroconvulsions in mice. CGP 37849 in doses of 0.125-1.0 mg/kg and CGP 39551 in doses of 0.625-5 mg/kg i.p. considerably potentiated the protective activity of magnesium valproate against maximal electroshock-induced convulsions. The anticonvulsant activity of sodium valproate was potentiated by CGP 37849 (1 mg/kg) to a similar degree, which suggests that magnesium is not involved in the observed interaction. Neither CGP agent influenced the plasma level of valproate, so a pharmacokinetic interaction, in terms of total plasma levels, is not probable. Furthermore, the performance of mice injected with magnesium valproate (91 mg/kg) and CGP 37849 (0.25 mg/kg), which provided 50% protection against maximal electroshock-induced convulsions, in the long-term memory test and chimney test did not differ significantly from that of the control animals. The combination of magnesium valproate and CGP 39551 had a neurotoxic potential comparable to that of valproate alone. The results suggest that a combined treatment of valproate and some competitive NMDA antagonists may be important from a clinical point of view.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Behavior, Animal; Dose-Response Relationship, Drug; Drug Synergism; Electroshock; Male; Mice; Receptors, N-Methyl-D-Aspartate; Seizures; Valproic Acid

The effects of combined treatment with low doses (1-5 mg/kg i.p.) of the competitive NMDA receptor antagonist, CGP 37849 (DL-[E]-2-amino-4-methyl-5-phosphono-3-pentenoic acid), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. CGP 37849, 5 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 80 mg/kg i.p. However, the increase in anticonvulsant activity was parallelled by a marked increase in motor impairment, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, at doses of 2.5-5 mg/kg, CGP 37849 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. In non-kindled rats, combined treatment with CGP 37849 and valproate induced significantly less marked adverse effects than in kindled rats. The data on combined treatment with CGP 37849 and valproate substantiate that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events. Since kindling is thought to be a predictive model of complex partial seizures, these results suggest that competitive NMDA receptor antagonists such as CGP 37849 may be of limited usefulness against this seizure type in humans.

Topics: 2-Amino-5-phosphonovalerate; Amygdala; Animals; Anticonvulsants; Ataxia; Female; Kindling, Neurologic; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Valproic Acid

The anticonvulsant and behavioural actions of CGP 37849 and CGP 39551, two novel competitive NMDA receptor antagonists, were examined in fully amygdala kindled rats following systemic administration. Only weak anticonvulsant effects were observed following either i.p. or i.v. injection of the antagonists. Moreover, behavioural abnormalities (ataxia, hyperactivity, muscular hypotonia) were apparent at all anticonvulsant doses. These results suggest that CGP 37849 and CGP 39551 may be of limited therapeutic usefulness against complex partial seizures in man, the seizure type showing greatest refractoriness to presently available medication.

Topics: 2-Amino-5-phosphonovalerate; Animals; Anticonvulsants; Injections, Intraperitoneal; Injections, Intravenous; Kindling, Neurologic; Male; Motor Activity; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures

A sensitive method of estimation of generalized seizure thresholds (GSTs) was used to estimate the relative anticonvulsant potencies of four competitive NMDA antagonists against fully amygdala-kindled seizures. All of the antagonists tested showed potent, dose-dependent anticonvulsant activity following focal administration at doses causing no, or only minimal, overt behavioural abnormalities. These doses were similar to those which have previously been shown to inhibit the development of the kindling process i.e. which show antiepileptogenic activity. Two novel, competitive NMDA antagonists, CGP 37849 and CGP 39551, both unsaturated analogues of the NMDA antagonist AP5, showed by far the greatest anticonvulsant potencies (211-fold and 33-fold greater activity than the parent molecule, respectively). Recent reports of oral anticonvulsant activity of these two compounds in both rodent and primate models of epilepsy (12, 13) make them leading candidates for clinical testing as novel antiepileptic agents in man. Previous reports of weak or non-existent anticonvulsant activity of competitive NMDA antagonists in the kindling model of epilepsy most likely result from the use of experimental protocols which are inherently insensitive in detecting drug-induced changes in seizure thresholds.

Topics: 2-Amino-5-phosphonovalerate; Amygdala; Animals; Anticonvulsants; Binding, Competitive; Electric Stimulation; Kindling, Neurologic; Male; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Seizures

alpha-Dendrotoxin (Dtx), a snake polypeptide, increases neuronal excitability by blocking certain fast-activating, voltage-dependent K+ channels. Thus, the behavioural, electrocortical (ECoG) and neuropathological effects of Dtx, injected into rat brain areas, were studied. A unilateral injection of 35 pmol of Dtx into the CA1 hippocampal area or the dendate gyrus (DG; upper blade) immediately produced motor and ECoG seizures, followed at 24 h by multi-focal brain damage and significant neuronal loss. Whilst brain damage was seen bilaterally, significant neuronal loss occurred only in regions (CA1, CA3, CA4 and DG) ipsilateral to the site of injection. A lower dose (3.5 pmol) of toxin elicited motor and ECoG seizures but failed to produce brain damage. Seizures were observed 50 min after injecting Dtx (35 pmol) into the amygdala, though significant neuronal loss was not evident. 4-Aminopyridine (100 nmol), given into the CA1 area elicited a similar motor and ECoG pattern to that of Dtx except no brain damage could be seen at 24 h. Systemic pretreatment with antagonists of N-methyl-D-aspartate receptors (MK-801 or CGP 37849) did not protect against the effects typically evoked by injecting Dtx into the CA1 area.

Topics: 2-Amino-5-phosphonovalerate; Animals; Brain Diseases; Dizocilpine Maleate; Elapid Venoms; Electroencephalography; Hippocampus; Injections; Male; Nerve Degeneration; Neurotoxins; Potassium Channels; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures

The effects of combined treatment with low doses (0.025-0.05 mg/kg i.p.) of the non-competitive NMDA receptor antagonist, MK-801 (dizocilpine), and the antiepileptic drug, valproate, were studied in amygdala-kindled and non-kindled rats. MK-801, 0.05 mg/kg, did not exert anticonvulsant effects in fully kindled rats but increased the anticonvulsant potency of valproate, 100 mg/kg i.p. However, the increase in anticonvulsant activity was paralleled by a marked increase in adverse effects such as motor impairment and hyperactivity, resulting in a considerable reduction of the therapeutic index of the combined treatment compared to valproate alone. Furthermore, MK-801 potentiated the adverse effects but not the anticonvulsant activity of 50 mg/kg valproate. Combined treatment with MK-801 and valproate induced much less marked adverse effects in non-kindled rats than in kindled rats. The competitive NMDA receptor antagonist, CGP 37849 1 mg/kg i.p., did not alter the effects of valproate in kindled rats. The data on combined treatment with MK-801 and valproate substantiate the conclusion that kindling alters the susceptibility to manipulations of NMDA receptor-mediated events.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Drug Synergism; Female; Kindling, Neurologic; Motor Activity; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Seizures; Valproic Acid

Intracerebroventricular (ICV) injection of N-methyl-D-aspartate (NMDA) was shown to induce generalized seizures in mice. The competitive NMDA antagonists DL-2-amino-5-phosphonovaleroate (DL-AP7) and 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonate (CPP), the NMDA "channel blocker" antagonist (+)-5-methyl-10,11-dihydro 5H-dibenzo-[a,d] cycloheptan-5,10-imine maleate (MK-801) and the strychnine-insensitive glycine antagonists kynurenic acid (KYNA) and 7-chloro-kynurenic acid (7-Cl-KYNA), when co-administered (ICV) with NMDA, antagonized NMDA-induced generalized seizures. Administration (ICV) of DL-AP7, CPP and MK-801 resulted in impared learning performance in a passive avoidance task in mice, with ED50 close to the anticonvulsant dose. The glycine antagonists KYNA and 7-Cl-KYNA at high doses significantly failed to affect performance in the same model of learning. The results indicate that compounds acting at the strychnine-insensitive glycine site may have a larger "therapeutic window" as anticonvulsants than antagonists of the NMDA receptor and channel.

Topics: 2-Amino-5-phosphonovalerate; Animals; Dizocilpine Maleate; Injections, Intraventricular; Kynurenic Acid; Learning; Male; Mice; N-Methylaspartate; Piperazines; Receptors, Glycine; Receptors, Neurotransmitter; Seizures; Strychnine