Showing papers on "Epileptogenesis published in 1994"

The role of glutamate in epilepsy and other CNS disorders.

Abstract: Glutamate is the principal excitatory neurotransmitter in the brain and, as such, it inevitably plays a role in the initiation and spread of seizure activity. It also plays a critical role in epileptogenesis. The process of "kindling" limbic seizures in rodents by repeated electrical stimulation is dependent on activation of N-methyl-D-aspartate (NMDA) receptors. The function of these receptors is enhanced in the hippocampus of kindled rats and in the cerebral cortex of patients with focal epilepsy. Microdialysis studies show an increase in the extracellular concentration of glutamate and aspartate before or during seizure onset, suggesting that either enhanced amino acid release or impaired uptake contributes to seizure initiation. Glutamate antagonists selective for NMDA or non-NMDA receptors are potent anticonvulsants when given systemically in a wide variety of animal models of epilepsy. They are of limited efficacy against kindled seizures in rats and (on the basis of preliminary evidence) in patients with drug-refractory complex partial seizures. Cognitive side effects appear to be a significant problem with competitive, as well as noncompetitive, NMDA antagonists. Glutamate receptor antagonists provide significant protection against brain damage following global or focal cerebral ischemia or acute traumatic injury in rodent models. Anticonvulsant compounds of the lamotrigine type, which act on sodium channels and reduce ischemia-induced glutamate release, are cerebroprotective in rodent ischemia models and are free from the cognitive side effects of NMDA-receptor antagonists.

The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy.

Abstract: Temporal lobe seizures are frequently associated with a characteristic pattern of hippocampal pathology (hippocampal sclerosis), as well as pathology in other temporal lobe structures. Despite more than a century of study, the relationship between pathology and epileptogenesis remains unclear. Endfolium sclerosis, which is characterized by the loss of dentate hilar neurons that are presumed to govern dentate granule cell excitability, is evident whenever hippocampal sclerosis exists and is the only temporal lobe pathology in some patients. Because prolonged seizures or head trauma produce endfolium sclerosis and granule cell hyperexcitability in experimental animals, hilar neuron loss may be the common pathological denominator and primary network defect underlying development of a hippocampal seizure "focus." Physiological studies suggest that vulnerable hilar mossy cells normally excite neurons that mediate granule cell inhibition. Recent anatomical studies indicate that the axons of mossy cells project longitudinally, out of the lamellar plane in which their cell bodies lie. If mossy cells in one lamella excite inhibitory neurons in surrounding lamellae, neocortical excitation of one segment of the granule cell layer may produce lateral inhibition and limit neocortical excitation to the targeted lamella. In patients who have had status epilepticus, prolonged febrile seizures, head trauma, or encephalitis, loss of dentate mossy cells may deafferent inhibitory neurons, render them "dormant," and thereby disinhibit an enlarged expanse of the granule cell layer. The selective loss of neurons that normally govern lateral inhibition in the dentate gyrus may cause functional delamination of the granule cell layer and result in synchronous, multilamellar discharges in response to cortical stimuli. Repetitive seizures may ultimately produce the full pattern of hippocampal and mesial temporal sclerosis by destroying cells within the seizure circuit that were not injured irreversibly by the initial insult. Thus, hippocampal pathology may be both the cause and effect of seizures that originate in the temporal lobe.

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Abstract: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.

Chronic neocortical epileptogenesis in vitro

Abstract: 1. We used an in vitro model to explore critical aspects of chronic epileptogenesis. Partial neocortical isolations having intact blood supply were made in rat and guinea pig from postnatal day 7 t...

Seizures, brain damage and brain development

Abstract: Recent evidence suggests that hippocampal damage can be both the result of seizure activity and the cause of further chronic epilepsy. A review of current models of status epilepticus-induced brain damage reveals that excitotoxic mechanisms probably mediate the lesions in most brain regions. NMDA receptors appear to play a dominant role, although non-NMDA glutamate receptors are important in several specific neuronal populations. In the immature brain, a number of unique metabolic features determine a different set of vulnerabilities, resulting in a brain which is more resistant than the adult's to certain mechanisms of brain damage, but quite vulnerable to others. The inhibition of growth by severe seizure activity has implications for the developing brain that have not yet been fully explored. The mechanisms by which seizure-induced hippocampal lesions cause chronic epilepsy have been explored in several recent animal models. A rearrangement of hippocampal circuits may result from death of selected populations of inhibitory neurons, or from misdirected regeneration by excitatory neurons. It could lead to chronic epilepsy through loss of normal inhibition, through sprouting of new excitatory connections, through conservation of excitatory connections which in a healthy brain would be pruned during development, or through facilitation of kindling by one of these mechanisms. These recent results are beginning to reconcile the pathology seen in human hippocampi ablated for intractable epilepsy with that observed in experimental animals, and offer the promise of even greater advances in the future. They suggest a mechanism for Gower's dictum that "seizures beget seizures" and highlight the importance of the interneurons of the dentate gyrus in epileptogenesis.

Rat hippocampal kindling induces changes in the glutamate receptor mRNA expression patterns in dentate granule neurons.

Abstract: The expression level of the mRNAs encoding the Flip and Flop versions of the AMPA-selective glutamate receptor subunits A, B, C and D was studied using in situ hybridization in the hippocampus of rats kindled by Schaffer collateral/commissural fibre stimulation. The expression levels of the Flip variant of GluR-A, B and C mRNAs were bilaterally enhanced in the dentate granule neurons of fully kindled animals 24 h after the last seizure. These changes were already observed after the sixth kindling stimulation (preconvulsive-stage), but not after a single afterdischarge. Four weeks after the last seizure, when the animals were still hypersensitive to kindling stimulations, only GluR-A Flip expression was enhanced. These results suggest that kindling epileptogenesis is accompanied by an increased number and enhanced sensitivity of the expressed AMPA type glutamate receptors in the fascia dentata, leading to an enhanced excitatory synaptic transmission which may contribute to the process of kindling epileptogenesis.

Are there unifying principles underlying the generation of epileptic afterdischarges in vitro

Abstract: To find general principles in the cellular mechanisms of epileptogenesis, one must analyze experimental epilepsy models and determine what exists in common between them. We consider here afterdischarges in hippocampal slices induced using either (1) GABAA blockade (e.g. with bicuculline), (2) a bathing solution lacking Mg2+ ions (low Mg-induced epilepsy), or (3) 4-aminopyridine (4AP). By 'afterdischarge' we mean an event that lasts hundreds of milliseconds or more, involving the synchronous firing of all the neurons in a population, shaped into a long initial burst and a series of one or more secondary bursts, and terminating in a prolonged afterhyperpolarization (AHP). We propose that the following features exists in common between these three experimental epilepsies: (1) recurrent excitatory synaptic connections; (2) sustained dendritic synaptic excitation, mediated by either AMPA or NMDA receptors, or both; (3) an intrinsic cellular response to sustained excitation, consisting of rhythmical dendritic bursts, primarily mediated by Ca spikes. In conclusion, if the picture outlined here proves correct, then the stereotypic appearance of epileptic afterdischarges--consisting of synchronized population bursts in series, whatever the network alteration leading to seizures--does indeed reflect a common set of mechanisms. The mechanisms cannot, apparently, be formulated in simple terms of this receptor or that receptor. Rather, we suggest, the recurrent excitatory synapses are able, under diverse circumstances, collectively to produce sustained dendritic conductances in neuronal populations. Pyramidal neurons, by virtue of their normal intrinsic membrane properties, respond to such sustained conductances with rhythmical bursts. The recurrent synapses, in a dual role, serve to maintain the synchrony of these bursts, and so shape the activity into a synchronized oscillation.

Experimental neurobiology of epilepsies.

Abstract: Epileptic discharges are a pathological extreme of neuronal synchrony. Experimental models of both focal and primary generalized epilepsies reveal the importance of the interaction of intrinsic (membrane current) properties of neurons and the synaptic networks which connect them. Focal epilepsies depend on excitatory networks within individual cortical structures, but full seizures may require widely dispersed neuronal networks. Absence seizures are generated by the thalamocortical system, and depend on inhibitory postsynaptic potentials, Ca2(+)-activated K+ currents and low threshold "T" currents. Other forms of synchronization can occur under particular circumstances, including field effects and gap junctions, but at the moment appear to be less generally involved in epileptogenesis. The cellular and network mechanisms of chronic experimental epilepsies are more complex and involve synaptic reorganization, and functional disconnection of inhibitory neurons.

Prognosis of childhood seizure disorders: present and future.

Abstract: The prognoses for seizure disorders have been examined since the beginnings of epileptology, and only recently has the realization emerged that, ultimately, prognosis depends on causation, which, in turn, determines whether a condition is self-limited or progressive. This factor is more important than either mode or alacrity of therapeutic intervention. The epilepsies are a series of conditions that have the final common path of either increasing cerebral irritability or synchronizing normally occurring electrical activity in such a manner that seizures result. In turn, some seizure disorders are characterized by secondary changes in neuronal synaptogenesis, leading to the development of circuits of predilection, which then render the process autonomous. Epileptogenesis has then become epilepsy, which is the norm in acquired rather than genetic epileptogenesis. An understanding of the basic differences between the primary (idiopathic) epilepsies and the secondary (acquired or symptomatic) epilepsies is basic to a discussion concerning prognosis and to the development of a definitive individualized treatment plan. An elucidation of the genetic factors in idiopathic epilepsy and their neurochemical consequences represents a major frontier in epileptology.

New antiepileptic drug development

Abstract: Summary: The development of new antiepileptic drugs is poised on the cusp between empiricism and the rational scientific development of medicaments designed to perform specific neurophysiologic functions in keeping with modern ideas of epilepsy generation and spread. It takes into account the difference between seizures and their underlying disorder known as epilepsies and the fact that, although seizures can be effectively treated with pharmacologic agents, the development of epilepsy requires both a predisposition (which may be innate or preventable) and precipitating factors that determine the timing of the individual seizures. The local membrane phenomena or cellular substrates of epilepsy can be described, as can the process of epileptogenesis. New antiepileptic development can be viewed in the light of these concepts.

MRI Stereotactic Placement of Intracranial Electrodes

Abstract: Intracranial electrode evaluations in patients with medically intractable epilepsy are meant to define regions of epileptogenesis when this is not possible by non-invasive methods.

Modulation of endogenous ADP-ribosylation in the kindling model of epilepsy.

Abstract: ADP-ribosylation occurs through the transfer of an ADP-ribose moiety from NAD to specific substrate proteins. This biochemical process catalyzed by ADP-ribosyltransferase is concerned in the regulatory mechanisms of numerous cellular functions.'* ADPribosylation reactions are classified into two major groups: mono ADP-ribosylation and poly ADP-ribosylation. Exogenous toxins, especially pertussis toxin and cholera toxin, induce the ADP-ribosylation. l7 '' Occurrence of the endogenous ADP-ribosylation in the brain has been revealed in recent studies and it is suggested that the endogenous ADP-ribosylation regulates some neural f~nc t ions .~ l9 The kindling is a quite suitable model in the search for the basic mechanisms of epilepsies. We have already reported the alteration in the ability of Gs to bind GTP and alteration of pertussis toxin-catalyzed ADP-ribosylation in the amygdaloid kindled brain.5-7 G proteins

Experimental seizure models and new antiepileptic drugs

Abstract: The objective of this programme of work was to study experimental seizure models and new antiepileptic drugs. Initial investigations addressed the contribution of basic animal models of epilepsy to its experimental study. Next, an attempt was made to emphasise the crucial role of neuronal inhibition and excitation in epileptogenesis and to relate these phenomena to the study of novel antiepileptic agents. Finally, the future of epilepsy research, in terms of appropriate strategies for AED development and innovative experimental paradigms was examined. Investigation of basic animal seizure models Of all the experimental seizure models in current laboratory employment, the pentylenetetrazol (PTZ) test, and the maximal (MES) and minimal (Min-ES) electroshock tests are among the most popular by virtue of their simplicity and economy. The primary aim of these studies was to afford a familiarity with these three basic animal seizure models and to validate them as techniques for subsequent use. These studies also incorporated an investigation of concentration-effect relationships with PTZ which attempted to delineate previously observed efficacy problems with this compound in our laboratory. Validation of all three experimental models was satisfactory, with results reflecting those reported in the literature. Although the concentration-effect studies with PTZ afforded a degree of insight into its pharmacokinetics, attempts to provide a suitable explanation for its lack of convulsant action in some animals proved unsuccessful. Antiepileptic drug enhancement of neuronal inhibition Impairment of gamma-aminobutyric acid (GABA)-mediated neuronal inhibition is believed to be one of the fundamental aetiological mechanisms of epileptogenesis. These investigations compared and contrasted the experimental anticonvulsant profiles and mechanisms of action of vigabatrin (VGB) and tiagabine (TGB), two novel AEDs which have been proposed to enhance GABA-mediated inhibition. VGB raised the threshold for induction of tonic seizures, determined by the Min-ES test, but was without effect in the PTZ and MES tests. TGB, in contrast, exhibited anticonvulsant effects against both PTZ- and MES-induced seizures. Drug mechanisms were investigated in isolated brain tissue and in primary cultures of cerebral cortical astrocytes and neurones. Previously reported mechanisms of action of the two drugs were confirmed, with VGB inhibiting GAB A metabolism by an action on GABA-aminotransferase (GABA-T), and TGB blocking GAB A uptake in a non-cell-specific manner. An inhibitory effect of VGB on glutamic acid decarboxylase (GAD) was also verified, and an additional, previously unreported action of the drug on GABA uptake was proposed. Antiepileptic drug attenuation of neuronal excitation Glutamate-induced neuronal excitability and voltage-sensitive calcium influx are believed to be inexorably entwined at all stages of epileptogenesis. These studies compared and contrasted the experimental anticonvulsant profiles and mechanisms of action of nimodipine (NMD) and amlodipine (AML), members of the dihydropyridine (DHP) class of calcium channel blockers which have been proposed as putative AEDs. In single dose, NMD was effective against MES-induced seizures and also raised the tonic seizure threshold, determined by the Min-ES test. Its effects in the MES test appeared to extend Novel strategies for antiepileptic drug development It has been proposed that to satisfactorily address the problem of refractory epilepsy the development of novel antiepileptic agents with similarly novel mechanisms of action is required. Nicotinylalanine (NA) is a newly-synthesised neuroactive compound which is believed to exert its effects by inhibition of the kynurenine pathway, resulting in increased brain concentrations of kynurenic acid, an endogenous antagonist at the glycine recognition site on the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor. This study explored the anticonvulsant profile of NA in three standard animal models of seizure. NA protected against PTZ induced seizures in mice in a dose and time dependent manner and was also active in the maximal and minimal electroshock tests. These preliminary results would suggest that NA warrants further investigation as a putative AED. Development of a novel animal model of epilepsy It is now recognised that few, if any, of the existing "animal models of the epilepsies" mirror the condition of chronically recurrent spontaneous seizures which is characteristic of human epilepsy. This study followed the preliminary development of an innovative model of partial epilepsy, proposed to more closely mimic the human condition. This model was characterised by a laser-induced lesion in the rat somatosensory cortex. Production of cortical laser lesions in the rat proved to be a feasible procedure. Histological investigation proposed the lesions to be highly reproducible and to possess cellular characteristics similar to those of disruptive brain insults in man. The lesion did not appear to be intrinsically epileptogenic, nor did the procedure influence the latency to generalised PTZ-induced seizures. Preliminary autoradiographical studies suggested that brain damage associated with the procedure was confined to the lesion tract itself, and that cerebral glucose metabolism was additionally altered in adjacent, otherwise healthy, tissue. Despite possessing several attractive features, the full potential of this model for use in epilepsy research remains to be evaluated.

Pathogenesis of epileptic focus

Abstract: An epileptogenesis as well as relation between epileptogenesis and memory consolidation have been analysed with kindling model. A role of kindling in pathogenesis of seizures in man, including formation of the secondary epileptic foci, has been discussed. An emphasis is on a controversial significance of gliomatous scar for the formation of epileptic focus and spreading of discharges on the adjacent brain structures.