Showing papers on "Epileptogenesis published in 1993"

Circuit Mechanisms of Seizures in the Pilocarpine Model of Chronic Epilepsy: Cell Loss and Mossy Fiber Sprouting

Abstract: We used the pilocarpine model of chronic spontaneous recurrent seizures to evaluate the time course of supragranular dentate sprouting and to assess the relation between several changes that occur in epileptic tissue with different behavioral manifestations of this experimental model of temporal lobe epilepsy. Pilocarpine-induced status epilepticus (SE) invariably led to cell loss in the hilus of the dentate gyrus (DG) and to spontaneous recurrent seizures. Cell loss was often also noted in the DG and in hippocampal subfields CA1 and CA3. The seizures began to appear at a mean of 15 days after SE induction (silent period), recurred at variable frequencies for each animal, and lasted for as long as the animals were allowed to survive (325 days). The granule cell layer of the DG was dispersed in epileptic animals, and neo-Timm stains showed supra- and intragranular mossy fiber sprouting. Supragranular mossy fiber sprouting and dentate granule cell dispersion began to appear early after SE (as early as 4 and 9 days, respectively) and reached a plateau by 100 days. Animals with a greater degree of cell loss in hippocampal field CA3 showed later onset of chronic epilepsy (r = 0.83, p < 0.0005), suggesting that CA3 represents one of the routes for seizure spread. These results demonstrate that the pilocarpine model of chronic seizures replicates several of the features of human temporal lobe epilepsy (hippocampal cell loss, supra- and intragranular mossy fiber sprouting, dentate granule cell dispersion, spontaneous recurrent seizures) and that it may be a useful model for studying this human condition. The results also suggest that even though a certain amount of cell loss in specific areas may be essential for chronic seizures to occur, excessive cell loss may hinder epileptogenesis.

Epileptogenic effects of status epilepticus

Abstract: Determining whether and under what conditions status epilepticus (SE) leads to undesirable long-term sequelae has major clinical ramifications. In addition to structural brain damage and enduring neurological deficits following SE, it has been suggested that SE can establish a chronic condition of active epilepsy. These three residua (epileptic brain damage, neurological deficits, and epilepsy) have been especially linked to protracted SE. The older clinical literature indicates that these sequelae are especially likely if SE occurs in an immature brain, but this point has been challenged in recent studies. Clinical and animal model work that examines the issue of chronic nervous system deficits arising as a consequence of SE is reviewed, with particular attention to the question of the epileptogenic effect of SE. Because of the inherent problem of not being able to exclude occult neurological disease antecedent to SE in brain, animal model work promises to be especially relevant to the issues at hand. Work done on adult rats has shown that a previously normal brain can be "converted" after a bout of SE to an epileptic brain, as manifest both by epileptic brain damage resembling that found in the hippocampus of patients with intractable temporal lobe epilepsy and by spontaneous recurrent seizures registered in the hippocampus. A two-step model is proposed: morphological brain injury takes place first and this change, in turn, promotes seizures. This model is offered as one way in which chronic active epilepsy can be established by a transient episode of SE. Although some findings from work with animal models have been interpreted as not supporting the idea that the immature brain is sensitive to a chronic epileptogenic influence initiated by SE, the majority of such work is consistent with this idea. On the other hand, a considerable amount of animal work indicates that the brains of immature animals are quite resistant to SE-induced brain damage, in contrast to those of adults. Thus, under these circumstances, a different process of epileptogenesis than the two-step model may be operational. It is concluded that, under appropriate conditions, SE does exert an epileptogenic effect that persists.

Immediate early gene expression in experimental epilepsy.

Abstract: Neuronal excitation by experimentally induced seizures elicits the rapid induction of a set of genes called immediate early genes (IEGs). The gene products of fos, jun and Krox, multimember gene families that belong to the class of IEGs, participate in a fundamental biological control mechanism, the regulation of gene transcription. IEG encoded proteins act as third messengers in an intracellular signal transduction cascade between neural cell surface receptors, cytoplasmic second messenger systems and specific target genes in the nucleus, a process for which the term 'stimulus transcription coupling' has been given. Almost all types of seizures cause dynamic alterations of IEG expression in neurons of the limbic system, but also in non-limbic areas, such as the cortex, striatum and thalamus. IEG encoded transcription factors are thought to up- or down-regulate effector genes with preferential expression in the central nervous system, including genes for neurotransmitters, growth factors, receptors, synaptic and axonal proteins. If the concept holds true that IEGs act as molecular switches converting epileptic short-term excitation of neurons into alterations of the molecular phenotype, future research may help to explain hitherto unexplained phenomena in epileptogenesis including changes of synaptic efficacy, kindling and sprouting.

Axon terminal hyperexcitability associated with epileptogenesis in vitro. I. Origin of ectopic spikes

Abstract: 1. Intracellular and extracellular recording techniques were used to study the increase in ectopic (i.e., nonsomatic) action-potential generation occurring among CA3 pyramidal cells during the kind...

Axon terminal hyperexcitability associated with epileptogenesis in vitro. II. Pharmacological regulation by NMDA and GABAA receptors

Abstract: 1. The preceding report presented evidence that the kindling-like induction of electrographic seizures (EGSs) in the hippocampal slice is accompanied by a lasting increase in the excitability of CA3 axon terminals, which is manifested by an increase in action-potential initiation at this site. In this report we explore the role of the N-methyl-D-aspartate (NMDA) receptor in the induction and maintenance of this antidromic firing, as well as the role of the gamma-aminobutyric acid type A (GABAA) receptor in regulating this activity once it has been induced. 2. Kindling-like stimulus trains (60 Hz, 2 s) were delivered to s. radiatum of CA3 at 10-min intervals. As EGSs developed in control artificial cerebrospinal fluid (ACSF), the frequency of axon terminal firing increased markedly (by 10.33 +/- 3.29 spikes/min, mean +/- SE P > 0.1). Thus the NMDA receptor is required for the induction but not maintenance of increased axon terminal firing, as we previously have shown to be the case for EGSs.(ABSTRACT TRUNCATED AT 250 WORDS)

Basic aspects of epilepsy.

Abstract: This review on epilepsy research progress summarizes developments in both animal and human studies of the basic neurophysiologic and neurochemical mechanisms of the epilepsies. Furthermore, anatomic and genetic aspects of epileptic seizures and new models of epilepsy will be discussed. Finally, new data on pharmacologic strategies for treatment of epilepsy are presented, including a critical survey of recent antiepileptic drug developments. One of the most disappointing recent findings in this aspect is that competitive antagonists at the N-methyl-D-aspartate subtype of glutamate receptors seem to be unsuited for antiepileptic therapy because epileptogenesis reduces the therapeutic index of such drugs in experimental as well as epileptic patients.

Increased expression of GAP-43, somatostatin and neuropeptide Y mRNA in the hippocampus during development of hippocampal kindling in rats.

Abstract: The expression and distribution of the mRNA coding for the growth-associated protein-43 (GAP-43), a putative marker for neuritic growth, for preprosomatostatin and the preproneuropeptide Y (ppNPY) were analysed in the rat hippocampus during the development of hippocampal kindling by an in situ hybridization technique and computer-assisted grain counting in the cell. The levels of GAP-43 mRNA increased significantly in the CA3 pyramidal neurons and hilar polymorphic neurons of the dentate gyrus 2 days after stage 2 of kindling (preconvulsive stage) but not stage 5 (full seizure expression) in the stimulated hippocampus. The distribution of GAP-43 mRNA was the same in the hippocampus of kindled rats as in sham-stimulated animals. Preprosomatostatin mRNA and ppNPY mRNA contents rose significantly in the hilar polymorphic neurons of the dentate gyrus of the stimulated and contralateral hippocampus at both stages of kindling, with the greatest effect at stage 5. In addition, the number of ppNPY mRNA neurons in the fascia dentata was significantly higher in kindled rats than in controls, but there were no differences in the number of preprosomatostatin mRNA-positive cells. Preprosomatostatin and ppNPY mRNAs were also increased in the neurons of the stratum oriens of the CA1 - CA3 subfield of fully kindled animals, whereas at stage 2 only neurons of the CA1 stratum oriens showed a significant increase of preprosomatostatin mRNA. No changes in preprosomatostatin and ppNPY mRNA expression were observed in the various regions of the hippocampus after a single afterdischarge or 1 month after stage 5. These data show that synthesis of somatostatin and neuropeptide Y increases in certain neurons of the hippocampus during the development of hippocampal kindling, and support the suggestion that these peptides are involved in epileptogenesis. Moreover, the increased synthesis of GAP-43 may contribute to the synaptic remodelling of certain hippocampal neurons during kindling.

The molecular basis of kindling.

Abstract: Kindling is an experimental model of epilepsy that involves activity-dependent changes in neuronal structure and function. During kindling, pathological changes may occur at several organizational levels of the nervous system, from alterations in gene-expression in individual neurons to the loss of specific neuronal populations and rearrangement of synaptic connectivity resulting from sustained stimulation of major excitatory pathways. This review summarizes recent developments in alterations at single neuronal and molecular levels that may be responsible for kindling epileptogenesis.

Epilepsy: Generation of epileptiform discharge by local circuits of neocortex

Abstract: Introduction So many books have been written on epilepsy that it may seem rash to add another … (Jackson, 1874)1 The neuronal essence of seizures is exceptionally synchronous activity. Cortical neurons performing normal tasks tend to fire with relatively low synchrony (Abeles, 1982), but during a seizure the activity of affected neurons is abruptly usurped. The kernel of this idea was suggested by John Hughlings Jackson in the nineteenth century; however, the pathological changes that allow hypersynchrony, and the mechanisms that mediate it, are still elusive (Dichter & Ayala, 1987). Synchrony necessarily requires interactions between neurons, and the most obvious substrate for interaction is synaptic circuitry. Here, we focus on the neurons and circuitry involved in epileptiform activity within the neocortex. The justification for another discourse on the subject is recent research that suggests specific circuit-oriented mechanisms for epileptogenesis. We begin with a brief description of our experimental model, essentially just an isolated fragment of neocortex in a controlled environment. Our concern is the minimum amount of tissue necessary for epileptiform activity, and in the cerebral cortex that turns out to be a surprisingly small volume.

Evidence of Secondary Epileptogenesis in Amygdaloid Overkindled Cats: Electroclinical Documentation of Spontaneous Seizures

Abstract: Twenty-four spontaneously occurring convulsive seizures were documented by closed-circuit TV (CCTV)-EEG monitoring in 3 cats subjected to unilateral amygdaloid overkindling for < or = 2 years. Electroclinical manifestations suggested that the seizures originated in the kindled amygdala (AM) (10 seizures in 3 cats), contralateral AM (7 seizures in 3 cats), or ipsilateral frontal cortex (7 seizures in 1 cat). All seizures of AM origin except one occurred during sleep 23 h to 20 days after the last stimulation-induced kindled seizure and culminated in secondarily generalized seizures. The seizures of frontal cortical origin occurred during waking within 1 h of a kindled seizure and remained partial in nature. In seizures of AM origin, ictal patterns at the primary and secondary sites were mirror images of each other, but latency of onset of each seizure stage in seizures of secondary site AM origin was longer than that in seizures of primary site AM origin in 2 of the 3 animals. We conclude that the secondary epileptogenic functional alterations capable of producing clinical seizures do occur in AM-overkindled cats, but the seizures are not entirely independent of the primary kindled site.

Comparison of the effects of increased potassium and of adenosine on hippocampal neurons from normal and genetically epileptic tg/tg mice.

Abstract: Summary: Tottering mice are an experimental model of genetically determined generalized epilepsy of the absence type. We investigated possible mechanisms underlying epileptogenic hyperexcitability in these mice by studying input/output (I/O) curves of the extracellular response of CA1 neurons to stratum radiatum stimulation in hippocampal slices maintained in vitro. Increases in extracellular potassium are considered to contribute to epileptogenesis, whereas adenosine has been proposed to be an endogenous antiepileptic agent. Moderate elevations (+ 2 mM) of extracellular K+ concentrations induced a significantly smaller increase of this response (leftward shift of the input/output curves) in slices from epileptic mice as compared with controls. Perfusion of slices with adenosine 10 |μM decreased excitability in both groups of slices, especially with regard to response threshold. Adenosine more effectively decreased the responses elicited by low-intensity stimulation than those elicited by high intensity. No significant difference between the groups of slices was observed. On the basis of the present data, it is unlikely that the previously observed hyperexcitability of hippocampal neurons of tottering mice results from a genetically altered sensitivity to moderate increases in [K+]0 or to adenosine.

Epilepsy: Sensitivity of the immature central nervous system to epileptogenic stimuli

Abstract: Introduction During the last ten years, there has been an increased interest in investigating the basic mechanisms of epilepsy in the immature brain. It was already known that the behavioral manifestations of seizures were age dependent but it was widely believed that in the immature central nervous system (CNS) inhibitory events predominated (Purpura & Housepian, 1961; Purpura, 1969, 1972). Therefore, it was assumed that the immature brain was not prone to seizures. However, the preponderance of recently acquired data indicates that the developing CNS is more susceptible to seizures than is the adult CNS. This concept is based on both epidemiological (Gibbs & Gibbs, 1963; Vernadakis & Woodbury, 1969; Hauser & Kurland, 1975; Woodbury, 1977) and experimental (Moshe et al ., 1983; Albala et al ., 1984; Schwartzkroin, 1984; Swann & Brady, 1984; Cavalheiro et al ., 1987; Sperber & Moshe, 1988; Moshe, 1989) studies. Additional data have revealed that epileptogenesis during development may not be a linear event. There appear to be periods of increased seizure susceptibility, followed by relatively more resistant ‘developmental windows’ (Schwartzkroin, 1984; Moshe 1989; Moshe et al ., 1992). Furthermore, since brain areas do not mature at the same time, epileptogenesis may differ from site to site.

Mechanisms of post-traumatic seizures: a quantum pharmacological analysis of the molecular properties of an epileptogenic focus following iron-induced membrane peroxidation

Abstract: Late post-traumatic epilepsy following severe head trauma has been well documented. While there is increasing evidence suggesting that iron-induced lipid peroxidation of neural membranes may accompany cerebral haemorrhage, the pathogenic processes of post-traumatic epileptogenesis remain unknown. Furthermore, the effective prophylactic use of standard anticonvulsant drugs is unsubstantiated. The rational design of therapeutic agents specific for the prevention and treatment of post-traumatic epilepsy hinges on understanding the molecular membrane events at the epileptogenic focus. This study employs the techniques of theoretical quantum pharmacology to provide a structural analysis of neural phospholipid membranes, investigating changes in membrane integrity at the epileptogenic focus as the molecular basis for seizure activity. Molecular mechanics calculations and molecular dynamics simulations were used to model the biochemical events of the epileptogenic focus. We predict that applications of quantum pharmacological techniques to model biochemical events may provide an understanding of proconvulsive pathogenic mechanisms in post-traumatic epilepsy.

Epilepsy: Rapidly recurring seizures and status epilepticus: ictal density as a factor in epileptogenesis

Abstract: Introduction The frequency with which seizures occur has received little attention as a factor in epileptogenesis. As a result, there is sparse information relating to the question of whether widely spaced seizures and status epilepticus activate the same pathophysiological processes or whether each is associated with its own particular set of events; it is also not known whether seizures and status epilepticus lead to the same acute and chronic sequelae. In addition, events involved in the progression from isolated seizures to status epilepticus have not been identified. Over the past several years our laboratory has examined these questions. In order to have precise control over the site of origin and timing of seizures we have used electrical stimulation through electrodes stereotactically positioned in the hippocampal formation of rats. Our work has revealed that small differences in the timing of seizure recurrence can give rise to different sorts of epileptic response. As a consequence various models of epilepsy have emerged. Each is suited to investigate the questions germane to its own particular kind of epileptic condition. However, by comparing results among the models, a number of other broader issues can be explored. Much of our work has utilized awake animals, but we have also extended the models to rats anesthetized with urethane. This extension allows certain studies that are difficult or impossible to perform in the awake rat.

Seizure stage, persistence of kindled epileptogenesis, and mossy fiber sprouting.

Abstract: In clinically, some patients with epilepsy, particularly with TLE, become intractable. Reynolds reports in his review5 that the number of seizures before treatment contributes to a less favourable outcome. This clinical evidence shows that the intractability of epilepsy may be, at least partially, due to increased seizure susceptibility caused by seizure repetition. The present study, using the kindling model, aims to confirm that early treatment may prevent such acquired increase in seizure susceptibility as well as to know whether the intractability is related to mossy fiber sprouting, that is postulated to have a causal role in epileptogenesis.6

Epileptogenesis in perirhinal cortex in vitro.

Abstract: The limbic system comprising pyriform cortex, perirhinal cortex and endopyriform nucleus has recently been considered to play an important role for kindling. Perirhinal cortex might be of special interest to elucidate the mechanism underlying the propagation of kindling-induced seizures The present study examined the excitatory nature of perirhinal cortex using in vitro slice techniques. Nineteen naive male Sprague Dawley rats were sacrificed and the brain was quickly removed. We cut the brain into slices (400 pm thick, N = 5 1) that cover perirhinal cortex, endopyriform nucleus and pyriform cortex as shown in Fig. 1A. Conventional slice technique was applied to obtain extracellular and intracellular recordings as was previously reported.6 A single electrical stimulation in the layer I11 of pyriform cortex elicited field potentials with an extremely long duration ( > 200 msec). These potentials normally consisted of slow potentials and repetitive spiky potentials. Pyriform cortex, however, showed small potentials with a short duration (Fig. 1A). Interestingly, potentials recorded in perirhinal cortex and endopyriform nucleus were of an all-or-none nature, in that stimulation at the subthreshold levels failed to evoke a response whereas suprathreshold stimulation elicited full-blown potentials (Fig. 1B). Intracellular recordings revealed that these potentials are EPSPs since these potentials were depolarizing at the membrane potential of -50 mV, which is more positive to the reverse potential of IPSPs (data not shown). Superfusion of low Mg2+ ACSF produced spontaneous epileptic activity with tonic and clonic phases in perirhinal cortex and endopyriform nucleus (Fig. 2A). The epileptic activity was observed specifically in perirhinal cortex and endopyriform nucleus. Pyriform cortex, in contrast, showed only weak spontaneous activities. As for the latency to the onset of spontaneous epileptic activity, endopyriform nucleus appeared to lead perirhinal cortex. In the minislice from which endopyriform nucleus was removed, however, perirhinal cortex was still capable of producing spontaneous discharges that were

[The anticonvulsive activity of the 1,4-dihydropyridine derivative riodipine and other anticonvulsants when used in combination].

Abstract: The anticonvulsant efficacy of combinations of novel calcium antagonist ryodipine with known antiepileptic drugs of different classes was studied in the experiments in mice using the maximal electroshock seizure test, and isobolographic analysis method for the development of complex pathogenetic therapy (CPT) of epilepsy. The synergetic potentiation effect was obtained in all drug combinations. In combinations of ryodipine with sodium valproate, diazepam, carbamazepine, phenytoin, ethosuximide and phenobarbital by 30-, 15-, 10-, 8-, 7-, and 5-fold respectively decreased. The experimental data suggest that the suppression of Ca2+ entry mechanism (ryodipine effect) in complex with the influence on other epileptogenesis mechanisms results in a marked potentiation of the antiepileptic effect. CPT of epilepsy which can provide potentiation of effects of each drug and a significant reduction of their doses is regarded to be expedient.

Experimental Seizure‐Induced Brain Damage: Electrophysiological, Metabolic and Pathological Correlation

Abstract: Limbic seizures elicited by an intra-amygdaloid KA injection is the only and unique model which can produce unilateral hippocampal degenerative lesions and atrophy. This model is important not only to investigate neurophysiological epileptogenesis but also to study the causative process of human mesial temporal sclerosis observed in patients with intractable complex partial seizure.