Showing papers on "Epileptogenesis published in 1989"

Review: Cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine: A novel experimental model of intractable epilepsy

Abstract: High-dose treatment with pilocarpine hydrochloride, a cholinergic muscarinic agonist, induces seizures in rodents following systemic or intracerebral administration. Pilocarpine seizures are characterized by a sequential development of behavioral patterns and electrographic activity. Hypoactivity, tremor, scratching, head bobbing, and myoclonic movements of the limbs progress to recurrent myoclonic convulsions with rearing, salivation, and falling, and status epilepticus. The sustained convulsions induced by pilocarpine are followed by widespread damage to the forebrain. The amygdala, thalamus, olfactory cortex, hippocampus, neocortex, and substantia nigra are the most sensitive regions to epilepsy-related damage following convulsions produced by pilocarpine. Spontaneous seizures are observed in the long-term period following the administration of convulsant doses of pilocarpine. Developmental studies show age-dependent differences in the response of rats to pilocarpine. Seizures are first noted in 7-12 day-old rats, and the adult pattern of behavioral and electroencephalographic sequelae of pilocarpine is seen in 15-21-day-old rats. During the third week of life the rats show an increased susceptibility to the convulsant action of pilocarpine relative to older and younger animals. The developmental progress of the convulsive response to pilocarpine does not correlate with evolution of the brain damage. The adult pattern of the damage is seen after a delay of 1-2 weeks in comparison with the evolution of seizures and status epilepticus. The susceptibility to seizures induced by pilocarpine increases in rats aged over 4 months. The basal ganglia curtail the generation and spread of seizures induced by pilocarpine. The caudate putamen, the substantia nigra, and the entopeduncular nucleus govern the propagation of pilocarpine-induced seizures. The antiepileptic drugs diazepam, clonazepam, phenobarbital, valproate, and trimethadione protect against pilocarpine-induced convulsions, while diphenylhydantoin and carbamazepine are ineffective. Ethosuximide and acetazolamide increase the susceptibility to convulsant action of pilocarpine. Lithium, morphine, and aminophylline also increase the susceptibility of rats to pilocarpine seizures. The pilocarpine seizure model may be of value in designing new therapeutic approaches to epilepsy.

NMDA antagonists differentiate epileptogenesis from seizure expression in an in vitro model.

Abstract: In an electrographic model of seizures in the hippocampal slice, both of the N-methyl-D-aspartate (NMDA) antagonists 2-amino-5-phosphonovaleric acid and 5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) prevented the progressive development of seizures but did not block previously induced seizures. Thus, a process dependent on the NMDA receptor-ionophore complex establishes a long-lasting, seizure-prone state; thereafter the seizures depend on non-NMDA receptor-ionophore mechanisms. This suggests that there is an important distinction between epileptogenesis and seizure expression and between antiepileptogenic and anticonvulsant pharmacological agents.

Varieties of human secondary epileptogenesis.

Abstract: This article has three goals: (1) to review the evidence that bears upon the occurrence of secondary epileptogenesis in man, (2) to set forth the criteria that distinguish secondary epileptogenesis from multifocal epilepsy--both clinically and by pharmacologic means--and (3) to indicate the importance of an understanding of the pathophysiology of secondary epileptogenesis to clinical decision making in the care of epileptic patients. In Section I, the three different developmental stages of secondary epileptogenesis defined in experimental preparations are outlined, and particular emphasis is placed on the remarkable similarity in the electrographic manifestations reported from animal species ranging from reptile to baboon. The clinical manifestations differ depending, within species, on exactly where in the brain the primary focus is situated and, between species, on the different organizations of the neural substrate within which epileptiform discharge is engendered. Section II is devoted to a review of three separate series of patients whose presenting symptom was epilepsy and in whom the etiology proved to be a histologically verified brain tumor or malformation. The choice of patient material was dictated by the conclusion that the main barrier to acceptance of human secondary epileptogenesis is the difficulty of distinguishing between multiple primary lesions maturing at different rates and those secondarily induced by an already existing single one. In the vast majority of patients where trauma, infection, anoxia, and vascular disease represent the most common etiologies, multiple primary structural injury is an ever-present possibility. Restricting our analysis to tumors of neural, glial, or vascular origin eliminates, as far as practicable, the issue of multiple primary lesions. A significant number of patients with focal epilepsy develop secondary epileptogenic lesions. The evidence presented shows that a primary epileptogenic lesion in man may induce a trans-synaptic and long-lasting alteration in nerve cell behavior characterized by paroxysmal electrographic manifestations and clinical seizures. Furthermore, the more frequent the seizures, the more likely is a secondary focus to become permanent. These observations underscore the importance of rigorous seizure control (electrographic as well as behavioral) and raise the question of earlier surgical intervention where medicinal therapy fails.

GABAergic neocortical neurons are resistant to NMDA receptor‐mediated injury

Abstract: N-methyl-D-aspartate (NMDA) receptors are thought to mediate much of the central neuronal loss produced by certain neurologic insults, including hypoxia-ischemia, hypoglycemia, and trauma. Therefore, the specific vulnerability of GABAergic inhibitory neurons to NMDA receptor-mediated toxicity might be an important determinant of the potential for epileptogenesis following these insults. We have examined the fate of GABAergic cortical neurons in mouse cell cultured neuronal population) were identified either by immunoreactivity with antisera to GABA or by autoradiography following high-affinity uptake of 3H-GABA. Cultures exposed for 5 min to 20 to 750 microM NMDA showed NMDA concentration-dependent, widespread neuronal loss. However, GABAergic neurons were relatively spared, and thus represented an enhanced fraction of neuronal survivors. These observations suggest that GABAergic cortical neurons may possess some intrinsic resistance to NMDA receptor-mediated neurotoxicity, a property which might convey an anticonvulsant "inhibitory safety factor" to neocortex against certain forms of injury.

The effect of MK-801 on kindled seizures: implications for use and limitations as an antiepileptic drug.

Abstract: MK-801 is a new drug that produces a noncompetitive blockade at the subclass of glutamate receptors activated by N-methyl-D-asparate (NMDA). The antiepileptic properties of MK-801 were studied using kindled seizures as a model of complex partial seizures with secondary generalization. A test protocol was employed that allowed: (1) examination of the efficacy of MK-801 against several parameters that gauge different aspects of epileptogenesis; (2) determination of the time-action profile of these effects; and (3) examination of the toxicity of MK-801 in animals experiencing seizures. The drug was found to be potent against the spread of seizures but less effective against parameters linked to partial seizures. At the higher doses of the drug required to truncate hippocampal afterdischarges, considerable neurotoxicity was encountered. In addition, the antiepileptic effects of MK-801 showed a use dependence so that, at a given time after the drug was administered, a greater suppression of seizures was noted if there had been preceding seizures in the presence of the drug than if there had not been. These findings indicate that there may be limitations to the clinical utility of MK-801 as an antiepileptic agent and that the drug may provide greatest benefit when used for the suppression of seizure generalization and when seizures are closely spaced.

The GABAergic Role of the Epileptogenesis in the El Mouse

Abstract: In the epileptogenesis of El mice (El), Ishida, N. ef uZ.l found that the parietal cortex played a major role in the initiation of seizure and that the hippocampus had a high electrical excitability. Ribak, C.E. et u Z . ~ have reported the loss of GABAergic neurons in the focus region in focal epilepsy. Ultramicro-quantitative chemistry which has been established by Lowry, 0.H.,6 Murashima, Y.L. and Kato, T.7 has been applied to the GABAergic system of this mutant mouse brain. We have already reported that the GAD activity of the parietal cortex in the El was almost half of that of the ddY. On the contrary, in the hippocampal CA1, the GAD activity in the El was twice that of the ddY. A similar tendency was observed also in the GABA concentrations. And it has become clear that the key to solve the problem of GABAergic abnormality in the El should be in the parietal cortex and hippocampal CA1. Methods

Spreading of epileptic afterdischarges between entorhinal cortex and hippocampus in acute experiments and the kindling model of epilepsy in the rat--comparing different methods of analysis.

Abstract: Spreading of epileptiform activity in the central nervous system is one of the fundamental problems in epileptology. The patterns of spreading of after-discharges in the hippocampus and entorphinal cortex were studied in acute experiments and using the kindling model of epileptogenesis. Three methods were used to determine the time relations between EEG signals from different brain areas; visual inspections, average amount of mutual information (AAMI) and phase spectrum method. The analysis methods used are adequate for quantification of the degree of coupling between different EEG signals during an afterdischarge, but should be used jointly since different signal features are taken into consideration by different methods. During an afterdischarge only at the beginning the focal area is clearly leading the other brain areas; thereafter the pattern becomes more complex.

Review of Flunarizine in Epilepsy

Abstract: A feature of epileptogenesis is burst firing of individual neurons. The burst comprises a slow paroxysmal depolarizing ion shift (PDS) upon which is superimposed a train of action potentials [6, 36]. Bursting depends largely on influx of Ca2+, although other ionic currents are also involved [37, 56].