dizocilpine-maleate and Epilepsies--Partial

We have used chemiluminescence measurements to examine the relationship between free radical formation and excitotoxicity in a post-traumatic epilepsy model. For this purpose, seven days after injecting iron in rat brain cortices, we measured luminol- and lucigenin-enhanced chemiluminescence in different brain regions (ipsilateral cortex, contralateral cortex, hypothalamus and hippocampus). In all brain regions (except contralateral cortices) both luminol- and lucigenin-enhanced chemiluminescence were increased in iron-injected group compared to saline-injected control group. These increases returned to control values in iron-injected rats pretreated with MK-801. Our results suggest that both free radicals and excitatory amino acids play important roles in the development of post-traumatic epilepsy and that MK-801 has protective effects against iron-induced chemiluminescence formation.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Dizocilpine Maleate; Drug Evaluation, Preclinical; Electroencephalography; Epilepsies, Partial; Excitatory Amino Acid Antagonists; Iron; Luminescent Measurements; Neuroprotective Agents; Rats; Rats, Sprague-Dawley

Epileptogenesis induced by electrical kindling of rats appears to be superior to the acute maximal electroshock seizure (MES) test in normal animals in predicting the efficacy and adverse effect potential of drugs in patients with partial epilepsy. Unfortunately, inclusion of such kindling models in primary screening is hampered by the laborious and expensive procedure of stimulation and recording with implanted brain electrodes. Furthermore the size of the rats excludes their use in initial testing where compound availability is often limited for the 'first batch synthesis'. The present study demonstrates that chronic electrical stimulation with corneal electrodes in mice can rapidly yield large numbers of kindled animals with a seizure phenomenology reflecting partial seizures in man. A pharmacological characterisation showed that corneally kindled mice can be used repeatedly for several drug experiments with reproducible results. The seizure protection and adverse effect potential obtained with proven antiepileptic drugs were similar to the effects observed in amygdala kindled rats and their corresponding clinical profile in partial epilepsy. Protection was obtained with vigabatrin and levetiracetam in this new model despite their lack of anticonvulsant activity in the acute MES test. Furthermore, in agreement with clinical findings with NMDA antagonists, MK-801 revealed more severe adverse effects in corneally kindled mice than in normal animals. These results suggest that corneal kindling of mice represents a sensitive and valid screening model for the identification of new therapies for partial epilepsy in man.

Topics: Amygdala; Animals; Anticonvulsants; Carbamazepine; Cornea; Disease Models, Animal; Dizocilpine Maleate; Drug Evaluation, Preclinical; Electric Stimulation; Electroshock; Epilepsies, Partial; gamma-Aminobutyric Acid; Kindling, Neurologic; Levetiracetam; Male; Mice; Piracetam; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Retina; Seizures; Sensitivity and Specificity; Time Factors; Valproic Acid; Vigabatrin

Excitatory amino acid transmitters are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using N-methyl-D-aspartate (NMDA) receptors, although more recent evidence indicates potential roles for the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors as well. In the present experiments in amygdala-kindled rats, i.e. a model of partial epilepsy, competitive and uncompetitive NMDA antagonists exerted only weak anticonvulsant effects, whereas the AMPA antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline (NBQX) potently increased focal seizure threshold and inhibited seizure spread from the focus. These effects of NBQX were dramatically increased by pretreatment with low doses of NMDA antagonists, whereas adverse effects of NBQX were not potentiated. These data suggest that both non-NMDA and NMDA receptors are critically involved in the kindled state, and that combinations of AMPA and NMDA receptor antagonists provide a new strategy for treatment of epileptic seizures.

Topics: 2-Amino-5-phosphonovalerate; Amygdala; Animals; Anticonvulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Electric Stimulation; Epilepsies, Partial; Female; Kindling, Neurologic; Motor Activity; Quinoxalines; Rats; Rats, Wistar; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Stereotyped Behavior

This study assessed the effects of MK-801 (0.1 and 0.5 mg/kg), a noncompetitive antagonist of N-methyl-D-aspartate receptors, on focal seizure activity elicited by electrical stimulation to the feline hippocampus. Neither afterdischarge duration nor behavioral seizure stage was significantly suppressed following intraperitoneal administration of MK-801 at two dose. Rather, MK-801 at a higher dose induced hippocampal seizure status in some of the cats tested. The present data suggest convulsant properties of MK-801 and limitations of its clinical utility as an antiepileptic agent.

Topics: Animals; Cats; Dizocilpine Maleate; Electric Stimulation; Electroencephalography; Epilepsies, Partial; Evoked Potentials; Female; Hippocampus; Injections, Intraperitoneal; Male; Motor Cortex; Receptors, N-Methyl-D-Aspartate; Visual Cortex