Showing papers on "Epileptogenesis published in 1999"

Emerging insights into the genesis of epilepsy.

Abstract: Epilepsies are a diverse collection of brain disorders that affect 1-2% of the population. Current therapies are unsatisfactory as they provide only symptomatic relief, are effective in only a subset of affected individuals, and are often accompanied by persistent toxic effects. It is hoped that insight into the cellular and molecular mechanisms of epileptogenesis will lead to new therapies, prevention, or even a cure. Emerging insights point to alterations of synaptic function and intrinsic properties of neurons as common mechanisms underlying the hyperexcitability in diverse forms of epilepsy.

Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats.

Abstract: Patients with temporal lobe epilepsy display neuron loss in the hilus of the dentate gyrus. This has been proposed to be epileptogenic by a variety of different mechanisms. The present study examines the specificity and extent of neuron loss in the dentate gyrus of kainate-treated rats, a model of temporal lobe epilepsy. Kainate-treated rats lose an average of 52% of their GAD-negative hilar neurons (putative mossy cells) and 13% of their GAD-positive cells (GABAergic interneurons) in the dentate gyrus. Interneuron loss is remarkably specific; 83% of the missing GAD-positive neurons are somatostatin-immunoreactive. Of the total neuron loss in the hilus, 97% is attributed to two cell types—mossy cells and somatostatinergic interneurons. The retrograde tracer wheat germ agglutinin (WGA)-apoHRP-gold was used to identify neurons with appropriate axon projections for generating lateral inhibition. Previously, it was shown that lateral inhibition between regions separated by 1 mm persists in the dentate gyrus of kainate-treated rats with hilar neuron loss. Retrogradely labeled GABAergic interneurons are found consistently in sections extending 1 mm septotemporally from the tracer injection site in control and kainate-treated rats. Retrogradely labeled putative mossy cells are found up to 4 mm from the injection site, but kainate-treated rats have fewer than controls, and in several kainate-treated rats virtually all of these cells are missing. These findings support hypotheses of temporal lobe epileptogenesis that involve mossy cell and somatostatinergic neuron loss and suggest that lateral inhibition in the dentate gyrus does not require mossy cells but, instead, may be generated directly by GABAergic interneurons.

Immunohistochemical Evidence of Seizure-Induced Activation of trkB Receptors in the Mossy Fiber Pathway of Adult Mouse Hippocampus

Abstract: Recent work suggests that limiting the activation of the trkB subtype of neurotrophin receptor inhibits epileptogenesis, but whether or where neurotrophin receptor activation occurs during epileptogenesis is unclear. Because the activation of trk receptors involves the phosphorylation of specific tyrosine residues, the availability of antibodies that selectively recognize the phosphorylated form of trk receptors permits a histochemical assessment of trk receptor activation. In this study the anatomy and time course of trk receptor activation during epileptogenesis were assessed with immunohistochemistry, using a phospho-specific trk antibody. In contrast to the low level of phosphotrk immunoreactivity constitutively expressed in the hippocampus of adult rats, a striking induction of phosphotrk immunoreactivity was evident in the distribution of the mossy fibers after partial kindling or kainate-induced seizures. The anatomic distribution, time course, and threshold for seizure-induced phosphotrk immunoreactivity correspond to the demonstrated pattern of regulation of BDNF expression by seizure activity. These results provide immunohistochemical evidence that trk receptors undergo activation during epileptogenesis and suggest that the mossy fiber pathway is particularly important in the pro-epileptogenic effects of the neurotrophins.

Selective Inhibition of Kindling Development by Intraventricular Administration of TrkB Receptor Body

Abstract: Recent work has shown that neurotrophin gene expression is increased after seizures evoked in the kindling model of epilepsy, but whether neurotrophins regulate kindling development is as yet unclear. In this study, we attempted to block selectively the activation of distinct neurotrophin receptors throughout kindling development in the rat via chronic intracerebroventricular administration of trk receptor bodies. The efficacy and selectivity of the trk receptor bodies were established by inhibition of neurotrophin-induced trk receptor phosphorylation in pheochromocytoma (PC12) cells and primary cultures of cortical neurons. The intracerebroventricular infusion of trkB receptor body (trkB-Fc) inhibited development of kindling in comparison with that seen with saline or human IgG controls, trkA-Fc, or trkC-Fc. These results imply that activation of trkB receptors contributes to the development of kindling, a form of activity-dependent behavioral plasticity in the adult mammalian brain.

Status epilepticus-induced neuronal injury and network reorganization.

Abstract: It is now evident that prolonged febrile seizures in childhood, or an episode of status epilepticus at any age, can produce the highly characteristic pattern of hippocampal cell loss and shrinkage that is seen later in life, when patients develop temporal lobe epilepsy. Seizure-induced and presumably excitotoxic pathology includes neuronal loss, reactive gliosis, aberrant synaptic reorganization of surviving cells, and hippocampal tissue shrinkage that may alter extracellular space and affect ionic homeostasis. Whether any of these pathological effects of prolonged excitation play a causal role in the epileptogenic process that ultimately leads to spontaneous afebrile seizures remains a subject of intense interest. Two hypotheses have been suggested to explain how seizure-induced neuronal loss might initiate the epileptogenic process. One hypothesis suggests that normal inhibition and excitability is maintained by vulnerable non-principal cells, and that their loss deactivates inhibitory neurons, rendering principal cells disinhibited and hyperexcitable. The other hypothesis regards the initial loss as a stimulus for normally unconnected principal cells to form aberrant recurrent excitatory connections. Additional influences undoubtedly include a kindling process that gradually overcomes polysynaptic inhibition, and changes in extracellular space that may facilitate synaptic and ephaptic depolarization. Identification of the suspected substrates of epileptogenesis will serve as a stimulus for future progress and provide direction for new experimental designs.

Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis.

Abstract: Recent evidence shows that neuropeptide expression in the CNS is markedly affected by seizure activity, particularly in the limbic system. Changes in neuropeptides in specific neuronal populations depend on the type and intensity of seizures and on their chronic sequelae (i.e. neurodegeneration and spontaneous convulsions). This paper reviews the effects of seizures on somatostatin-containing neurons, somatostatin mRNA and immunoreactivity, the release of this peptide and its receptor subtypes in the CNS. Differences between kindling and status epilepticus in rats are emphasized and discussed in the light of an inhibitory role of somatostatin on hippocampal excitability. Pharmacological studies show that somatostatin affects electrophysiological properties of neurons, modulates classical neurotransmission and has anticonvulsant properties in experimental models of seizures. This peptidergic system may be an interesting target for pharmacological attempts to control pathological hyperactivity in neurons, thus providing new directions for the development of novel anticonvulsant treatments.

Stereotactic amygdalohippocampotomy for the treatment of medial temporal lobe epilepsy

Abstract: Summary: Purpose: This study was carried out to assess the safety and efficacy of stereotactic ablation of the amygdala and hippocampus for the treatment of medial temporal lobe epilepsy. Methods: Twenty-two stereotactic amygdalohippocampotomies were performed in 19 patients with unilateral temporal lobe seizures by using magnetic resonance imaging (MRI) localization for target planning and radiofrequency techniques for lesion production. Seizure frequency was assessed at 3-monthly follow-up visits. Two lesion groups were defined. In group I, four to 11 (mean, 6.4) discrete lesions were made, encompassing the amygdala and anterior 13–21 mm (mean, 16.8 mm) of the hippocampus. In group II, a large number of confluent lesions were made (mean, 26.0; range, 12–54) encompassing the amygdala and anterior 15–34 mm (mean, 21.5 mm) of the hippocampus. MRI scanning was carried out 24 h and 6–9 months after surgery. Results: In five group I patients, one (20%) experienced a favorable seizure outcome. Of 15 group II patients, one of whom had previously undergone limited lesioning and was also analyzed as part of group I, nine (60%) experienced a favorable seizure outcome, with two seizure free. MRI scans at 6- to 9-months’follow-up disclosed discrete areas of atrophy in the amygdala and hippocampus, interspersed with preserved brain in the group I patients. More uniform and complete destruction of amygdala and hippocampus was evident in group II patients. All lesions were confined to the amygdala and hippocampus, sparing the parahippocampal gyrus (PHG). Conclusions: The extensive amygdalohippocampal ablation in group II patients improved seizure outcome compared with more limited ablation in group I, but these results were not so good as those from temporal lobectomy in a similar patient group. When considered together with the results of selective amygdalohippocampectomy, and temporal resections that spare hippocampus or amygdala (all producing similar outcomes, and all involving resection of the entorhinal cortex), this study suggests a pivotal role of the entorhinal cortex in temporal epileptogenesis.

AMPA receptors in epilepsy and as targets for antiepileptic drugs

Abstract: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are key mediators of seizure spread in the nervous system and represent promising targets for antiepileptic drugs. There is emerging evidence that AMPA receptors may play a role in epileptogenesis and in seizure-induced brain damage. This evidence suggests that AMPA receptor antagonists could have broad utility in epilepsy therapy. Regional, developmental, and disease-associated variations in AMPA receptors produced by differential expression of AMPA receptor subunits and variations in posttranscriptional processing, including alternative splicing and pre-mRNA editing, provide a diversity of functionally distinct AMPA receptor isoforms that allow opportunities for selective drug targeting. Four types of AMPA receptor antagonist are discussed in this chapter: (a) competitive AMPA recognition site antagonists, including those of the quinoxalinedione and newer nonquinoxalinedione classes, (b) 2,3-benzodiazepine noncompetitive (allosteric) antagonists, (c) desensitization enhancing antagonists, exemplified by SCN-, and (d) antagonists of Ca(2+)-permeable AMPA receptors, including polyamine amide arthropod toxins and their synthetic analogues. Competitive and noncompetitive AMPA receptor antagonists are broad-spectrum anticonvulsants in animal seizure models. Their effectiveness and safety for humans remain to be determined. There is evidence that these antagonists can potentiate the antiseizure activity of N-methyl-D-aspartate (NMDA) receptor antagonists and conventional antiepileptic drugs. This evidence suggests that the preferred use of AMPA receptor antagonists may be in combination therapies. Agents that enhance desensitization may have advantages in comparison with other AMPA receptor antagonists to the extent that they preferentially block high-frequency synaptic signaling and avoid depressing AMPA receptors on interneurons, which would lead to disinhibition and enhanced excitability. Evidence has accumulated that Ca(2+)-permeable AMPA receptors (those lacking the edited GluR2 subunit) may play a role in epileptogenesis and the brain damage occurring with prolonged seizures. Because Ca(2+)-permeable AMPA receptors are predominately expressed in gamma-aminobutyric acid (GABA)ergic interneurons, it is hypothesized that some forms of epilepsy might be caused by reduced GABA inhibition resulting from Ca(2+)-permeable AMPA receptor-mediated excitotoxic death of interneurons. It is further proposed that drugs that selectively target Ca(2+)-permeable AMPA receptors might have antiepileptogenic and neuroprotective properties. Certain polyamine toxins and their analogues are channel-blocking AMPA receptor antagonists that selectively inhibit Ca(2+)-permeable AMPA receptors. These substances might give clues to the development of such antagonists.

Ketogenic diet reduces spontaneous seizures and mossy fiber sprouting in the kainic acid model.

Abstract: The high fat, low carbohydrate, low protein ketogenic diet (KD) has been used to control refractory epilepsy in children since 1920, although its mechanism of action is unknown. Previous animal studies have shown that the KD can increase acute seizure threshold, but the effect of the KD on the process of epileptogenesis has not been studied. We tested the effect of an experimental KD on epileptogenesis in adult rats using the kainic acid (KA) model. P54 rats underwent KA-induced status epilepticus, followed by assignment to a control diet or a KD consisting of (by weight), 14% protein, 70% fat and no carbohydrate. KD-fed animals tolerated the diet and maintained ketosis. KD-fed rats had significantly fewer and briefer spontaneous recurrent seizures and less supragranular mossy fiber sprouting, although the degree of hippocampal pyramidal cell damage was similar in both groups. These results provide the first evidence that the KD retards epileptogenesis in an experimental model.

Episodic corticosterone treatment accelerates kindling epileptogenesis and triggers long-term changes in hippocampal CA1 cells, in the fully kindled state.

Abstract: We tested the effect of episodic (approximately 10 days) corticosterone treatment on: (i) behavioural symptoms during kindling epileptogenesis; and (ii) electrical activity in the CA1 hippocampal area during epileptogenesis, and later on, in the fully kindled state. Male rats received a corticosterone-releasing pellet (100 mg/day) shortly before kindling was started, resulting in elevated hormone levels during the early and middle stages of epileptogenesis. The appearance of moderate behavioural signs of epilepsy and severe tonic-clonic seizures was significantly accelerated in corticosterone-treated animals compared to placebo controls. During epileptogenesis, corticosterone treatment did not affect the amplitude and paired-pulse characteristics of in vivo-recorded CA1 field responses, or the duration of the afterdischarge following tetanic stimulation of the Schaffer collaterals. However, other properties of CA1 cells studied in vitro, in the fully kindled state, were altered by the earlier episodic corticosterone treatment. Thus, in kindled rats, the amplitude of the population spike in the CA1 area was significantly enhanced after prior exposure to high corticosterone levels. Prior episodic steroid treatment resulted furthermore in a significantly increased amplitude of voltage-gated Ca currents, in kindled rats. At that time, corticosterone levels of animals which had received a corticosterone-releasing pellet earlier were no longer elevated compared to the placebo controls; the corticosteroid-treated rats did also not differ from the controls with respect to the mRNA expression levels for the two corticosteroid receptor subtypes in the hippocampus. The data suggest that exposure of animals to a period of stressful experiences during a critical phase in epileptogenesis could impose lasting deleterious effects on the course of epilepsy, even when CORT levels have been normalized again.

Long-Term Depression of Excitatory Synaptic Transmission in the Rat Amygdala

Abstract: In view of the fact that both kindling and fear-potentiated startle are expressed by long-term enhancement of synaptic transmission in the amygdala, synaptic plasticity in this area of the brain is of particular importance. Here, we show for the first time that low-frequency stimulation of the lateral nucleus at 1 Hz for 15 min elicited a long-term depression (LTD) in the basolateral amygdala (BLA) neurons. LTD is expressed specifically at the lateral-BLA synapses but not at ventral endopyriform nucleus-BLA synapses. The induction of LTD requires activation of both NMDA and metabotropic glutamate receptors. Loading cells with a Ca(2+) chelator BAPTA or extracellular superfusion with protein phosphatase inhibitors prevents LTD, suggesting that LTD may result from dephosphorylation of AMPA receptors. The same stimulating protocol could not elicit LTD in neurons from kindled animals, whereas neurons from sham-operated or age-matched control rats were able to exhibit LTD. Together, this study characterizes the properties of LTD in the naive amygdala slices for the first time and demonstrates that epileptogenesis in vivo induces disruption of LTD in the in vitro preparation.

Chronic Epileptogenic Cellular Alterations in the Limbic System After Status Epilepticus

Abstract: Status epilepticus (SE) is associated with both acute and permanent pathological sequellae. One common long term consequence of SE is the subsequent development of a chronic epileptic condition, with seizures frequently originating from and involving the limbic system. Following SE, many studies have demonstrated selective loss of neurons within the hilar region of the dentate gyrus, CA1 and CA3 pyramidal neurons. Selective loss of distinct subpopulations of interneurons throughout the hippocampus is also frequently evident, although interneurons as a whole are selectively spared relative to principal cells. Accompanying this loss of neurons are circuit rearrangements, the most widely studied being the sprouting of dentate granule cell (DGC) axons back onto the inner molecular layer of the dentate gyrus, termed mossy fiber sprouting. Less studied are the receptor properties of the surviving neurons within the epileptic hippocampus following SE. DGCs in epileptic animals exhibit marked alterations in the functional and pharmacological properties of gamma-aminobutyric acid (GABA) receptors. DGCs have a significantly elevated density of GABA(A) receptors in chronically epileptic animals. In addition, the pharmacological properties of GABA(A) receptors in post-SE epileptic animals are quite different compared to controls. In particular, GABA(A) receptors in DGCs from epileptic animals show an enhanced sensitivity to blockade by zinc, and a markedly altered sensitivity to modulation by benzodiazepines. These pharmacological differences may be due to a decreased expression of alpha1 subunits of the GABA(A) receptor relative to other alpha subunits in DGCs of post-SE epileptic animals. These GABA(A) receptor alterations precede the onset of spontaneous seizures in post-SE DGCs, and so are temporally positioned to contribute to the process of epileptogenesis in the limbic system. The presence of zinc sensitive GABA receptors combined with the presence of zinc-containing "sprouted" mossy fiber terminals innervating the proximal dendrites of DGCs in the post-SE epileptic hippocampus prompted the development of the hypothesis that repetitive activation of the DG in the epileptic brain could result in the release of zine. This zinc in turn may diffuse to and block "epileptic" zinc-sensitive GABA(A) receptors in DGCs, leading to a catastrophic failure of inhibition and concomitant enhanced seizure propensity in the post-SE epileptic limbic system.

Animal Models of Epilepsy and Epileptic Seizures

Abstract: In epilepsy research, animal models serve a variety of purposes. First, they are used in the search for new antiepileptic drugs. Second, once the anticonvulsant activity of a novel compound has been detected, animal models are used to evaluate the possible specific efficacies of the compound against different types of seizures or epilepsy. Third, animal models can be used to characterize the preclinical efficacy of novel compounds during chronic administration. Such chronic studies can serve different objectives, for instance, evaluation of whether drug efficacy changes during prolonged treatment, e.g. because of the development of tolerance, or examination of whether a drug exerts antiepilep-togenic effects during prolonged administration, i.e. is a true antiepileptic drug. Fourth, animal models are employed to characterize the mechanism of action of old and new antiepileptic drugs. Fifth, certain models can be used to study mechanisms of drug resistance in epilepsy. Sixth, in view of the possibility that chronic brain dysfunction, such as epilepsy, might lead to altered sensitivity to drug adverse effects, models involving epileptic animals are useful to study whether epileptogenesis alters the adverse effect potential of a given drug. Seventh, animal models are needed for studies on the pathophysiology of epilepsies and epileptic seizures, e.g. the processes involved in epileptogenesis and ictogenesis (Lothman 1996a).

Increased Pyramidal Excitability and NMDA Conductance Can Explain Posttraumatic Epileptogenesis Without Disinhibition: A Model

Abstract: Partially isolated cortical islands prepared in vivo become epileptogenic within weeks of the injury. In this model of chronic epileptogenesis, recordings from cortical slices cut through the injur...

Tetrodotoxin prevents posttraumatic epileptogenesis in rats.

Abstract: Severe cortical trauma frequently causes epilepsy that develops after a long latency. We hypothesized that plastic changes in excitability during this latent period might be initiated or sustained by the level of neuronal activity in the injured cortex. We therefore studied effects of action potential blockade by application of tetrodotoxin (TTX) to areas of cortical injury in a model of chronic epileptogenesis. Partially isolated islands of sensorimotor cortex were made in 28- to 30-day-old male Sprague-Dawley rats and thin sheets of Elvax polymer containing TTX or control vehicle were implanted over lesions. Ten to 15 days later neocortical slices were obtained through isolates for electrophysiological studies. Slices from all animals (n = 12) with lesions contacted by control-Elvax (58% of 36 slices) exhibited evoked epileptiform field potentials, and those from 4 rats had spontaneous epileptiform events. Only 2 of 11 lesioned animals and 6% of slices from cortex exposed to TTX in vivo exhibited evoked epileptiform potentials, and no spontaneous epileptiform events were observed. There was no evidence of residual TTX during recordings. TTX-Elvax was ineffective in reversing epileptogenesis when implanted 11 days after cortical injury. These data suggest that development of antiepileptogenic drugs for humans may be possible.

Role of metabotropic glutamate receptors in epilepsy.

Abstract: Considerable information is available regarding the role of ionotropic glutamate receptors in the generation of interictal spikes. Progress in the study of metabotropic glutamate receptors (mGluRs) makes clear that activation of these receptors can contribute greatly to seizure discharges and epileptogenesis. The effects of activation of the different mGluR subgroups on neuronal hypersynchrony and the initiation and propagation of seizure discharges in hippocampal slices are discussed herein. To help one understand the mechanisms that underlie these effects, information regarding the action of mGluRs on cellular and synaptic properties is summarized. The data bring to the forefront the critical role of mGluRs in epilepsy and emphasize the anticonvulsant effects of group II and III mGluR activation as opposed to the convulsant action of group 1, which elicits seizure discharges and epileptogenesis in experimental models.

Upregulation of NMDA receptors in hippocampus and cortex in the pentylenetetrazol-induced "kindling" model of epilepsy.

Abstract: "Kindling" is a phenomenon of epileptogenesis, which has been widely used as an experimental model of temporal lobe epilepsy. At the present work we investigated the contribution of NMDA receptors in the Pentylenetetrazol-induced "kindling" model in the mouse brain, by using quantitative autoradiography and the radioactive ligands [3H]MK801 and [3H]L-glutamate (NMDA-sensitive component). One week after establishment of kindling, a small but significant increase in [3H]MK801 as well as NMDA-sensitive [3H]glutamate binding was seen, being restricted to the molecular layer (ML) of the dentate gyrus (DG) and the CA3 region of the hippocampus. These binding augmentations persisted one month after establishment of kindling. A significant increase of NMDA receptor binding was also observed in the cortex-somatosensory and temporal one week after acquisition of the kindled state. The upregulation of NMDA receptors seen in DG and CA3 region of the hippocampus could be associated with the kindling process of this model especially with its maintenance phase, since it persists at long term, is area-specific and consistent with electrophysiological data. The increase of NMDA receptors seen in the cortex of the kindled animals could underlie the hyperexcitability detected by electrophysiological studies in this area.

Synaptic plasticity in kindling.

Abstract: Kindling is an experimental model of epilepsy resulting from progressive activity-dependent changes in neuronal structure and function. During kindling, pathologic changes occur at various levels of organization of the nervous system, ranging from altered gene-expression in individual neurons to the loss of specific neuronal populations and the rearrangement of synaptic connections. This chapter summarizes recent findings about the long-lasting (plastic) nature of the alterations at the level of single neurons with emphasis on the role of altered excitatory and inhibitory amino acid receptors. The modified synaptic ligand-gated ion channels (i.e., "epileptic receptors") may ultimately be responsible for the kindling epileptogenesis.

Single-gene models of epilepsy.

Abstract: Single-gene models of epilepsy present valuable opportunities to isolate and experimentally reproduce gene mutations for human seizure disorders, to test molecular mechanisms of epileptogenesis, and to explore strategies to correct early hyperexcitability defects in the developing brain. Although not all inherited epilepsies are monogenic, analysis of epileptic phenotypes in spontaneous and transgenic mouse mutants is beginning to define the kinds of molecular defects favoring inherited aberrant synchronization in central neurons. The range of genes identified shows that rather than arising from a few superfamilies that regulate membrane excitability, the gene products are drawn from many categories involved in widely diverse functions of the cell. Although some primary defects directly alter membrane electrogenesis and neurotransmitter signaling at synapses, others are too far removed from these processes to allow one to visualize the steps by which they promote epileptogenesis. There is now clear evidence that several and probably most epilepsy genes entrain specific patterns of secondary cellular plasticity during brain development. It can be predicted that these downstream rearrangements may partially account for the delayed temporal onset and other progressive features of epilepsy syndromes. Experimental alterations that target the mutant gene product and patterns of secondary network plasticity provide a basis for future strategies to reverse the epileptogenic process.