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Epileptogenesis
Selected AbstractsNeuronal plasticity: implications in epilepsy progression and managementDRUG DEVELOPMENT RESEARCH, Issue 8 2007Sherifa A. HamedArticle first published online: 12 FEB 200 Abstract Epilepsy is a common neurological disease. A growing number of research studies provide evidence regarding the progressive neuronal damage induced by prolonged seizures or status epilepticus (SE), as well as recurrent brief seizures. Importantly, seizure is only one aspect of epilepsy. However, cognitive and behavioral deficits induced by progressive seizures or antiepileptic treatment can be detrimental to individual function. The neurobiology of epilepsy is poorly understood involving complex cellular and molecular mechanisms. The brain undergoes changes in its basic structure and function, e.g., neural plasticity with an increased susceptibility in neuronal synchronization and network circuit alterations. Some of these changes are transient, while others are permanent with an involvement of both glutamatergic and ,-aminobutyric acid (GABA)ergic systems. Recent data suggest that impaired neuronal plasticity may underlie the cognitive impairment and behavioral changes associated with epilepsy. Many neurologists recognize that the prevention or suppression of seizures by the use of antiepileptic drugs (AEDs) alone is insufficient without clear predictions of disease outcome. Hence, it is important to understand the molecular mechanisms underlying epileptogenesis because this may allow the development of innovative strategies to prevent or cure this condition. In addition, this realization would have significant impact in reducing the long-term adverse consequences of the disease, including neurocognitive and behavioral adverse effects. Drug Dev Res 68:498,511, 2007. © 2008 Wiley-Liss, Inc. [source] Role of cortical dysplasia in epileptogenesis following prolonged febrile seizureEPILEPSIA, Issue 9 2010Kyung-Il Park Summary Purpose:, Hippocampal sclerosis, characterized by prominent neuronal loss and reactive gliosis, is the most common pathology in human temporal lobe epilepsy (TLE). Although prolonged febrile convulsion (FC) is a risk factor of TLE, it is not clear whether FC provokes hippocampal sclerosis and subsequent TLE. Given that underlying brain lesions, such as cortical dysplasia (CD), in the immature brain predispose patients to FC, CD may link FC and TLE. However, the role of CD in epileptogenesis after FC is also unclear. Here, we investigated whether inborn CD increases the risk of later epilepsy induced by prolonged FC using a rat model. Methods:, Experimental CD was induced by in utero exposure of methylazoxymethanol (MAM). Rat pups from MAM-treated or control rats were then subjected to prolonged FC. We examined morphologic changes in the hippocampi with respect to neuronal loss, reactive gliosis, and synaptogenesis, and evaluated spontaneous recurrent seizures (SRS) by long-term video-EEG (electroencephalography). Results:, The MAM+FC group had a significantly lower hippocampal neuronal density in the CA1 and dentate hilus than other control groups. A robust increase in glial cells and synaptic reorganization was also detected in the MAM+FC groups. Furthermore, later SRS occurred in all rats in the MAM+FC group and in 50% and 25% of the rats in the FC-only and MAM-only group, respectively. The frequency and total duration of SRS was highest in the MAM+FC group. Discussion:, Our results suggest that preexisting CD in the immature brain augments the proepileptogenic effects of prolonged FC, leading to TLE. [source] Therapeutic approaches to epileptogenesis,Hope on the horizonEPILEPSIA, Issue 2010Asla Pitkänen Summary Prevention of epileptogenesis is an unmet need in medicine. During the last 3 years, however, several preclinical studies have demonstrated remarkable favorable effects of novel treatments on genetic and acquired epileptogenesis. These include the use of immunosuppressants and treatments that modify cellular adhesion, proliferation, and/or plasticity. In addition, the use of antiepileptic drugs in rats with genetic epilepsy or proconvulsants in acquired epilepsy models has provided somewhat unexpected favorable effects. This review summarizes these studies, and introduces some caveats when interpreting the data. In particular, the effect of genetic background, the severity of epileptogenic insult, the method and duration of seizure monitoring, and size of animal population are discussed. Furthermore, a novel scheme for defining epileptogenesis-related terms is presented. [source] Remodeling of extracellular matrix and epileptogenesisEPILEPSIA, Issue 2010Alexander Dityatev Summary Extracellular matrix (ECM) in the brain is composed of molecules synthesized and secreted by neurons and glial cells, which form stable aggregates of diverse composition in the extracellular space. In the mature brain, ECM undergoes a slow turnover and restrains structural plasticity while supporting multiple physiologic processes, including perisomatic ,-aminobutyric acid (GABA)ergic inhibition, synaptic plasticity, and homeostatic regulations. Seizures lead to striking remodeling of ECM, which may be essentially engaged in different aspects of epileptogenesis. This view is supported by human genetic studies linking ECM molecules and epilepsy, by data showing altered epileptogenesis in mice deficient in ECM molecules, and by evidence that ECM may shape seizure-induced sprouting of mossy fibers, granule cell dispersion, and astrogliosis. Therefore, restraining seizure-induced remodeling of ECM or suppressing the signaling triggered by the remodeled ECM might provide effective therapeutic strategies to antagonize the progression of epileptogenesis. [source] Preemptive effect of nucleus of the solitary tract stimulation on amygdaloid kindling in freely moving catsEPILEPSIA, Issue 3 2010Victor M. Magdaleno-Madrigal Summary Purpose:, The nucleus of the solitary tract (NTS) is a primary site where vagal afferents terminate. The aim of this study was to analyze the preemptive effect of NTS electrical stimulation on daily amygdaloid kindling (AK) in freely moving cats. Methods:, Seven adult male cats were used. Bipolar electrodes were stereotaxically implanted into both amygdalae, lateral geniculate bodies, hippocampi, and prefrontal cortices. In addition, a bipolar stainless steel electrode was implanted in the left NTS. Cats were recorded under the following experimental conditions: The NTS was stimulated for 6 days before the initiation of AK (1 min on/5 min off, 1 h total). AK was performed by stimulating the amygdala every 24 h (1 s, 60 Hz, 1 ms) until behavioral stage VI was reached. Results:, The number of stimulations to reach stage VI in control animals was 23.4 ± 3.7, in lateral tegmental field (LTF) animals was 17.0 ± 2.1 days. Animals subjected to preemptive NTS stimulation showed a significant increase (53.8 ± 5.9). In addition, behavioral development was retarded, with an increase in the number of stimulations required to reach stage III. In this group, overall kindling development was delayed, and amygdaloid afterdischarge duration did not show a progressive increase as was observed in the control group. Discussion:, Our results indicate that preemptive NTS electrical stimulation interferes with epileptogenesis. This anticonvulsive effect could be related to the activation of certain structures that inhibit seizure development. Therefore, results suggest that NTS mediates the anticonvulsive effect of vagus nerve stimulation. [source] Pursuing paradoxical proconvulsant prophylaxis for epileptogenesisEPILEPSIA, Issue 7 2009Caren Armstrong Summary There are essentially two potential treatment options for any acquired disorder: symptomatic or prophylactic. For acquired epilepsies that follow a variety of different brain insults, there remains a complete lack of prophylactic treatment options, whereas at the same time these epilepsies are notoriously resistant, once they have emerged, to symptomatic treatments with antiepileptic drugs. The development of prophylactic strategies is logistically challenging, both for basic researchers and clinicians. Nevertheless, cannabinoid-targeting drugs provide a very interesting example of a system within the central nervous system (CNS) that can have very different acute and long-term effects on hyperexcitability and seizures. In this review, we outline research on cannabinoids suggesting that although cannabinoid antagonists are acutely proconvulsant, they may have beneficial effects on long-term hyperexcitability following brain insults of multiple etiologies, making them promising candidates for further investigation as prophylactics against acquired epilepsy. We then discuss some of the implications of this finding on future attempts at prophylactic treatments, specifically, the very short window within which prevention may be possible, the possibility that traditional anticonvulsants may interfere with prophylactic strategies, and the importance of moving beyond anticonvulsants,even to proconvulsants,to find the ideal preventative strategy for acquired epilepsy. [source] Stress, the hippocampus, and epilepsyEPILEPSIA, Issue 4 2009Marian Joëls Summary Stress is among the most frequently self-reported precipitants of seizures in patients with epilepsy. This review considers how important stress mediators like corticotropin-releasing hormone, corticosteroids, and neurosteroids could contribute to this phenomenon. Cellular effects of stress mediators in the rodent hippocampus are highlighted. Overall, corticosterone,with other stress hormones,rapidly enhances CA1/CA3 hippocampal activity shortly after stress. At the same time, corticosterone starts gene-mediated events, which enhance calcium influx several hours later. This later effect serves to normalize activity but also imposes a risk for neuronal injury if and when neurons are concurrently strongly depolarized, for example, during epileptic activity. In the dentate gyrus, stress-induced elevations in corticosteroid level are less effective in changing membrane properties such as calcium influx; here, enhanced inhibitory tone mediated through neurosteroid effects on ,-aminobutyric acid (GABA) receptors might dominate. Under conditions of repetitive stress (e.g., caused from experiencing repetitive and unpredictable seizures) and/or early life stress, hormonal influences on the inhibitory tone, however, are diminished; instead, enhanced calcium influx and increased excitation become more important. In agreement, perinatal stress and elevated steroid levels accelerate epileptogenesis and lower seizure threshold in various animal models for epilepsy. It will be interesting to examine how curtailing the effects of stress in adults, for example, by brief treatment with antiglucocorticoids, may be beneficial to the treatment of epilepsy. [source] Retarded kindling progression in mice deficient in the extracellular matrix glycoprotein tenascin-REPILEPSIA, Issue 4 2009Katrin Hoffmann Summary Purpose:, We investigated the role of the extracellular matrix glycoprotein tenascin-R (TNR) in formation of a hyperexcitable network in the kindling model of epilepsy. The idea that TNR may be important for this process was suggested by previous studies showing that deficiency in TNR leads to abnormalities in synaptic plasticity, perisomatic GABAergic inhibition and more astrocytes in the hippocampus of adult mice. Methods:, Constitutively TNR deficient (TNR,/,) mice and their wild-type littermates received repeated electrical stimulation in the amygdala over several days until they developed fully kindled generalized seizures at which time their brains were studied immunohistochemically. Results:, In TNR,/, mice, kindling progression was retarded compared with wild-type littermate controls. Morphological analysis of the mice used for the kindling studies revealed that, independently of genotype, numbers of parvalbumin-positive interneurons in the dentate gyrus correlated positively with afterdischarge threshold alterations in kindled mice. The kindling-induced increase in the number of S100 expressing astrocytes in the dentate gyrus was enhanced by TNR deficiency and correlated negatively with the kindling rate. Discussion:, Our data support the view that TNR promotes formation of a hyperexcitable network during kindling and suggest that an increase in S100-expressing astrocytes may contribute to retarded epileptogenesis in TNR,/, mice. [source] Experimental epileptology before 1900EPILEPSIA, Issue 3 2009Mervyn J. Eadie Summary The available English and other major Western European language literature was reviewed to assess the stage of development of experimental epileptology prior to the end of the 19th Century. The relevant investigations had been carried out in animals of various species employing a number of methods of evoking convulsive seizures, mainly mechanical, electrical or chemical stimulation or surgical removal of parts of the cerebral cortex. The studies had produced some conflicting data but (i) allowed the development of a number of reasonably satisfactory experimental models of convulsive epileptic seizures (ii) confirmed that such epileptic seizures arose from the cerebral cortex, and (iii) suggested that for local onset epileptic seizures to become generalised tonic-clonic ones, the opposite motor cortex and probably a brain stem, possibly pontine, centre needed to be involved. No generally acceptable animal model of chronic epilepsy had been developed, and the non-motor manifestations of epileptic seizures were still largely unexplored experimentally. Nevertheless, the pre-1900 investigations not only laid the foundations for the 20th Century expansion of experimental studies on epileptogenesis but also advanced the understanding of epileptic seizure production. [source] Gene therapy in epilepsyEPILEPSIA, Issue 1 2009Véronique Riban Summary Results from animal models suggest gene therapy is a promising new approach for the treatment of epilepsy. Several candidate genes such as neuropeptide Y and galanin have been demonstrated in preclinical studies to have a positive effect on seizure activity. For a successful gene therapy-based treatment, efficient delivery of a transgene to target neurons is also essential. To this end, advances have been made in the areas of cell transplantation and in the development of recombinant viral vectors for gene delivery. Recombinant adeno-associated viral (rAAV) vectors in particular show promise for gene therapy of neurological disorders due to their neuronal tropism, lack of toxicity, and stable persistence in neurons, which results in robust, long-term expression of the transgene. rAAV vectors have been recently used in phase I clinical trials of Parkinson's disease with an excellent safety profile. Prior to commencement of phase I trials for gene therapy of epilepsy, further preclinical studies are ongoing including evaluation of the therapeutic benefit in chronic models of epileptogenesis, as well as assessment of safety in toxicological studies. [source] Audiogenic kindling in Wistar and WAG/Rij rats: Kindling-prone and kindling-resistant subpopulationsEPILEPSIA, Issue 10 2008Lyudmila V. Vinogradova Summary Purpose:, Audiogenic kindling (AK) is a model of naturally occurring epileptogenesis triggered by repeated sound stimulation of rats genetically prone to audiogenic seizures. It is accepted that limbic seizure networks underlie progressive changes in behavioral seizure pattern during AK. The present study investigated AK progression in rats susceptible and unsusceptible to absence seizures. Methods:, Progression of AK as indicated by an appearance and intensification of limbic clonus was examined in Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats with genetic absence epilepsy and in Wistar rats. Results:, Subpopulations of kindling-prone and kindling-resistant rats were found in both Wistar and WAG/Rij strains. Despite identical seizure responses to the first sound stimulation, AK progression dramatically differed between the two subpopulations. AK-prone rats exhibited rapid kindling development up to maximal stage-5 severity. In AK-resistant rats, limbic clonus did not appear after 30 stimulations or if it appeared, it did not progress beyond stage 2. The proportions of AK-prone and AK-resistant animals within Wistar and WAG/Rij strains were similar. Comparison of Wistar and WAG/Rij rats within the kindling-prone and kindling-resistant groups did not reveal a significant strain effect on AK progression. However, within the WAG/Rij strain, a significantly higher incidence of absence seizures was found in AK-resistant rats compared to AK-prone rats. Conclusions:, The present study demonstrates that sensitivity to sound-induced epileptogenesis differs dramatically within Wistar and WAG/Rij strains, whereas genetic susceptibility to absence seizures does not change AK progression significantly. It is supposed that an increased incidence of nonconvulsive seizures and resistance to kindling result from a common seizure modulating mechanism. [source] Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: An ontogenic studyEPILEPSIA, Issue 10 2008Andréy Mazarati Summary Purpose:, To examine antiepileptogenic and antiictogenic potential of retigabine (RTG) under conditions of rapid kindling epileptogenesis during different stages of development. Methods:, The experiments were performed in postnatal day 14 (P14), P21, and P35 male Wistar rats. After stereotaxic implantation of hippocampal stimulating and recording electrodes, the effects of RTG on baseline afterdischarge (AD) properties were studied. Next, the animals underwent rapid kindling (sixty 10 s trains, bipolar 20 Hz square wave pulses delivered every 5 min). The progression of seizures (kindling acquisition), and responses to test stimulations after kindling (retention) were compared between RTG and vehicle-treated rats. Additionally, the effects of RTG on the severity of seizures in previously kindled animals were examined. Results:, When administered intraperitoneally in doses that induced only mild, or no motor deficits, RTG significantly dampened brain excitability, evident as the increase of AD threshold and shortening of AD duration. During kindling, RTG delayed the development of focal seizures in P14 rats, and prevented the occurrence of full limbic seizures at all three ages. At P14 and P21, but not at P35, pretreatment with RTG prevented the establishment of kindling-induced enhanced seizure susceptibility. Administration of RTG to kindled animals decreased the severity of seizures induced by test stimulation. The effect was most prominent at P14. Discussion:, RTG exerted both antiepileptogenic and antiictogenic effects under conditions of rapid kindling model. These effects were apparent during postneonatal, early childhood, and adolescent stages of development. [source] Molecular and diffusion tensor imaging of epileptic networksEPILEPSIA, Issue 2008Aimee F. Luat Summary Several studies have shown that seizure-induced cellular and molecular changes associated with chronic epilepsy can lead to functional and structural alterations in the brain. Chronic epilepsy, when medically refractory, may be associated with an expansion of the epileptic circuitry to involve complex interactions between cortical and subcortical neuroanatomical substrates. Progress in neuroimaging has led not only to successful identification of epileptic foci for surgical resection, but also to an improved understanding of the functional and microstructural changes in long-standing epilepsy. Positron emission tomography (PET), functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) are all promising tools that can assist in elucidating the underlying pathophysiology in chronic epilepsy. Studies using PET scanning have demonstrated dynamic changes associated with the evolution from acute to chronic intractable epilepsy. Among these changes are data to support the existence of secondary epileptogenesis in humans. MRI with DTI is a powerful tool which has the ability to characterize microstructural abnormalities in epileptic foci, and to demonstrate the white matter fibers and tracts participating in the epileptic network. In this review, we illustrate how PET and DTI can be applied to depict the functional and microstructural alterations associated with chronic epilepsy. [source] Mechanisms of Epileptogenesis in Tuberous Sclerosis Complex and Related Malformations of Cortical Development with Abnormal Glioneuronal ProliferationEPILEPSIA, Issue 1 2008Michael Wong Summary Malformations of cortical development (MCDs) are increasingly recognized as causes of medically intractable epilepsy. In order to develop more effective, rational therapies for refractory epilepsy related to MCDs, it is important to achieve a better understanding of the underlying mechanisms of epileptogenesis, but this is complicated by the wide variety of different radiographic, histopathological, and molecular features of these disorders. A subset of MCDs share a number of characteristic cellular and molecular abnormalities due to early defects in neuronal and glial proliferation and differentiation and have a particularly high incidence of epilepsy, suggesting that this category of MCDs with abnormal glioneuronal proliferation may also share a common set of primary mechanisms of epileptogenesis. This review critically analyzes both clinical and basic science evidence for overlapping mechanisms of epileptogenesis in this group of disorders, focusing on tuberous sclerosis complex, focal cortical dysplasia with balloon cells, and gangliogliomas. Specifically, the role of lesional versus perilesional regions, circuit versus cellular/molecular defects, and nonneuronal factors, such as astrocytes, in contributing to epileptogenesis in these MCDs is examined. An improved understanding of these various factors involved in epileptogenesis has direct clinical implications for optimizing current treatments or developing novel therapeutic approaches for epilepsy in these disorders. [source] Cortical Epileptogenesis,Hughlings Jackson and His PredecessorsEPILEPSIA, Issue 11 2007Mervyn J. Eadie Summary:,Aim: To trace the concept that the cerebral cortex is the site of epileptogenesis before Hughlings Jackson published the idea in 1870 in the paper "A study of convulsions" which marks the beginning of modern epileptology. Method: Perusal of 19th century English language medical literature. Result: The existence of cortical epileptogenesis was postulated by Richard Bright in 1831 and 1836, touched on by Robert Bentley Todd in 1849, and rediscovered independently by Samuel Wilks in 1866. Wilks's idea probably became known to both John Thompson Dickson and John Hughlings Jackson and was then developed further, particularly by Jackson. Conclusion: The thought of Samuel Wilks probably played a more important role in the origins of modern epileptology than has sometimes been appreciated. [source] Molecular Neuropathology of Temporal Lobe Epilepsy: Complementary Approaches in Animal Models and Human Disease TissueEPILEPSIA, Issue 2007Michael Majores Summary:, Patients with temporal lobe epilepsies (TLE) frequently develop pharmacoresistance to antiepileptic treatment. In individuals with drug-refractory TLE, neurosurgical removal of the epileptogenic focus provides a therapy option with high potential for seizure control. Biopsy specimens from TLE patients constitute unique tissue resources to gain insights in neuropathological and molecular alterations involved in human TLE. Compared to human tissue specimens in most neurological diseases, where only autopsy material is available, the bioptic tissue samples from pharmacoresistant TLE patients open rather exceptional preconditions for molecular biological, electrophysiological as well as biochemical experimental approaches in human brain tissue, which cannot be carried out in postmortem material. Pathological changes in human TLE tissue are multiple and relate to structural and cellular reorganization of the hippocampal formation, selective neurodegeneration, and acquired changes of expression and distribution of neurotransmitter receptors and ion channels, underlying modified neuronal excitability. Nevertheless, human TLE tissue specimens have some limitations. For obvious reasons, human TLE tissue samples are only available from advanced, drug-resistant stages of the disease. However, in many patients, a transient episode of status epilepticus (SE) or febrile seizures in childhood can induce multiple structural and functional alterations that after a latency period result in a chronic epileptic condition. This latency period, also referred to as epileptogenesis, cannot be studied in human TLE specimens. TLE animal models may be particularly helpful in order to shed characterize new molecular pathomechanisms related to epileptogenesis and open novel therapeutic strategies for TLE. Here, we will discuss experimental approaches to unravel molecular,neuropathological aspects of TLE and highlight characteristics and potential of molecular studies in human and/or experimental TLE. [source] Neuroprotective Strategies to Avert Seizure-Induced Neurodegeneration in EpilepsyEPILEPSIA, Issue 2007Janice R. Naegele Summary:, Neurodegeneration in limbic circuits is a hallmark feature of chronic temporal lobe epilepsy (TLE). Studies in experimental animal models and human patients indicate that seizure-induced neuronal injury involves some active, as well as passive cell death processes. Experimental approaches that inhibit active steps in cell death programs have been shown to reduce neuronal cell death and sclerosis, but not to prevent epileptogenesis in animal models of TLE. These findings suggest that we need additional research using both animal models and brain slices from human patients to understand the pathological mechanisms underlying seizure generation. Such comparative studies will also aid in evaluating the potential therapeutic value of inhibiting cell death in seizure disorders. [source] The Blood,Brain Barrier and EpilepsyEPILEPSIA, Issue 11 2006Emily Oby Summary:, During the past several years, there has been increasing interest in the role of the blood,brain barrier (BBB) in epilepsy. Advances in neuroradiology have enhanced our ability to image and study the human cerebrovasculature, and further developments in the research of metabolic deficiencies linked to seizure disorders (e.g., GLUT1 deficiency), neuroinflammation, and multiple drug resistance to antiepileptic drugs (AEDs) have amplified the significance of the BBB's relationship to epilepsy. Prior to 1986, BBB research in epilepsy focused on three main areas: ultrastructural studies, brain glucose availability and transport, and clinical uses of AEDs. However, contrast-based imaging techniques and medical procedures such as BBB disruption provided a framework that demonstrated that the BBB could be reversibly disrupted by pathologic or iatrogenic manipulations, with important implications in terms of CNS drug delivery to "multiple drug resistant" brain. This concept of BBB breakdown for therapeutic purposes has also unveiled a previously unrecognized role for BBB failure as a possible etiologic mechanism in epileptogenesis. Finally, a growing body of evidence has shown that inflammatory mechanisms may participate in the pathological changes observed in epileptic brain, with increasing awareness that blood-borne cells or signals may participate in epileptogenesis by virtue of a leaky BBB. In this article we will review the relationships between BBB function and epilepsy. In particular, we will illustrate consensus and divergence between clinical reality and animal studies. [source] Neocortical Microenvironment in Patients with Intractable Epilepsy: Potassium and Chloride ConcentrationsEPILEPSIA, Issue 2 2006Ali Gorji Summary:,Purpose: The regulation of extracellular ion concentrations plays an important role in neuronal function and epileptogenesis. Despite the many studies into the mechanisms of epileptogenesis in human experimental models, no data are available regarding the fluctuations of extracellular potassium ([K+]o) and chloride ([Cl,]o) concentrations, which could underlie seizure susceptibility in human chronically epileptic tissues in vivo. Methods: By using cerebral microdialysis during surgical resection of epileptic foci, the basic [K+]o and [Cl,]o as well as their changes after epicortical electric stimulation were studied in samples of dialysates obtained from 11 patients by ion-selective microelectrodes. Results: The mean basal values of [K+]o and [Cl,]o in all patients were 3.83 ± 0.08 mM and 122.9 ± 2.6 mM, respectively. However, significant differences were observed in the basal levels of both [K+]o and [Cl,]o between different patients. Statistically, no correlation was found between basal [K+]o or [Cl,]o and electrocorticogram (ECoG) spike activity, but in one patient, dramatically lowered baseline [Cl,]o was accompanied by enhanced ECoG spike activity. Application of epicortical electrical stimulation increased [K+]o but not [Cl,]o in all cases. According to the velocity as well as spatial distribution of [K+]o reduction to the prestimulation levels, three different types of responses were observed: slow decline, fast decline, and slow and fast declines at adjacent sites. Conclusions: These data may represent abnormalities in ion homeostasis of the epileptic brain. [source] Epileptiform Activity Induced by Pharmacologic Reduction of M-Current in the Developing Hippocampus in VitroEPILEPSIA, Issue 1 2006Fernando Peña Summary:,Purpose: Benign familial neonatal convulsions (BFNCs), an inheritable epilepsy that occurs in neonates but not in adults, is caused by hypofunctional mutations in genes codifying for the M-type K+ current. In an attempt to develop an in vitro model of this disease, we tested whether blocking M-current with linopirdine induces epileptiform activity in brain slices from animals of different ages. Methods: Horizontal hippocampus,entorhinal cortex slices were obtained from neonatal (1,2 weeks after birth) and adult (8,9 weeks after birth) rats. Extracellular field recordings of the CA1 region were performed. After recording control conditions, linopirdine was added to the bath, and field activity was recorded continuously for 3 h. 4-Aminopyridine, a drug commonly used to induce epileptiform activity in vitro, was used as a control for our experimental conditions. Results: Bath perfusion of linopirdine induced epileptiform activity only in slices from neonatal rats. Epileptiform activity consisted of interictal-like and ictal-like activity. In slices from adult rats, linopirdine induced erratic interictal-like activity. In contrast, 4-aminopyridine was able to induce epileptiform activity in slices from both neonatal and adult rats. Conclusions: We demonstrated that blockade of M-current in vitro produces epileptiform activity with a developmental pattern similar to that observed in BNFCs. This could be an in vitro model that can be used to study the cellular mechanisms of epileptogenesis and the developmental features of BFNCs, as well as to develop some therapeutic strategies. [source] Proteomic Identification of the Involvement of the Mitochondrial Rieske Protein in EpilepsyEPILEPSIA, Issue 3 2005Heike Junker Summary:,Purpose: Kindled seizures are widely used to model epileptogenesis, but the molecular mechanisms underlying the attainment of kindling status are largely unknown. Recently we showed that achievement of kindling status in the Sprague,Dawley rat is associated with a critical developmental interval of 25 ± 1 days; the identification of this long, well-defined developmental interval for inducing kindling status makes possible a dissection of the cellular and genetic events underlying this phenomenon and its relation to normal and pathologic brain function. Methods: By using proteomics on cerebral tissue from our new rat kindling model, we undertook a global analysis of protein expression in kindled animals. Some of the identified proteins were further investigated by using immunohistochemistry. Results: We report the identification of a modified variant of the Rieske iron-sulfur protein, a component of the mitochondrial cytochrome bc1 complex, whose isoelectric point is shifted toward more alkaline values in the hippocampus of kindled rats. By immunohistochemistry, the Rieske protein is well expressed in the hippocampus, except in the CA1 subfield, an area of selective vulnerability to seizures in humans and animal models. We also noted an asymmetric, selective expression of the Rieske protein in the subgranular neurons of the dorsal dentate gyrus, a region implicated in neurogenesis. Conclusions: These results indicate that the Rieske protein may play a role in the response of neurons to seizure activity and could give important new insights into the molecular pathogenesis of epilepsy. [source] Long-term Changes in Postnatal Susceptibility to Pilocarpine-induced Seizures in Rats Exposed to Gamma Radiation at Different Stages of Prenatal DevelopmentEPILEPSIA, Issue 10 2003Zuzanna Setkowicz Summary:,Purpose: To determine whether brains irradiated at different stages of prenatal development also have different postnatal susceptibility to seizures evoked by pilocarpine. Methods: Pregnant Wistar rats were exposed to a single 1.0-Gy dose of gamma rays on gestation days 13, 15, 17, or 19 (E13, E15, E17, and E19, respectively). On postnatal day 60, their offspring received i.p. pilocarpine injections to evoke status epilepticus. Behavior of the animals was observed continuously for 6 h after the injection, and motor manifestations of seizure activity were rated, and survival times recorded. After 7-day survival, the animals were killed, and their brains were weighed. Results: The average brain weight of animals exposed to irradiation at earlier prenatal stages (E13 or E15) was significantly lower than that after irradiation on E17 or E19. However, effects of the irradiation on the susceptibility to pilocarpine-induced seizures were quite opposite. The intensity of status epilepticus evoked in rats irradiated on E13 or E15 was significantly lower than that in nonirradiated controls or in those irradiated on E17 or E19. Moreover, after irradiation on E13 or E15, survival of the animals was significantly higher in relation not only to other irradiated groups but also to the controls. Conclusions: The results suggest than the extent of neuronal deficit, even if relatively greater, cannot always lead to higher susceptibility of the dysplastic brain to seizures. Functional consequences of the deficit, even if its magnitude is relatively smaller but involving specific brain areas, appear to be critical for the epileptogenesis. [source] Ibotenate Injections into the Pre- and Parasubiculum Provide Partial Protection against Kainate-Induced Epileptic Damage in Layer III of Rat Entorhinal CortexEPILEPSIA, Issue 7 2001Tore Eid Summary: ,Purpose: A loss of neurons in layer III of the entorhinal cortex (EC) is often observed in patients with temporal lobe epilepsy and in animal models of the disorder. We hypothesized that the susceptibility of layer III of the EC to prolonged seizure activity might be mediated by excitatory afferents originating in the presubiculum. Methods: Experiments were designed to ablate the presubiculum unilaterally by focal ibotenate injections and to evaluate the effect of this deafferentation on the vulnerability of EC layer III neurons to the chemoconvulsant kainate (injected systemically 5 days later). Results: After treatment with kainate, 11 of the 15 rats preinjected with ibotenate showed clear-cut, partial neuroprotection in layer III of the EC ipsilateral to the ibotenate lesion. Serial reconstruction of the ibotenate-induced primary lesion revealed that entorhinal neurons were protected only in animals that had lesions in the pre- and parasubiculum, especially in the deep layers (IV,VI). Conclusions: The deep layers of the pre- and parasubiculum appear to control the seizure-induced damage of EC layer III. This phenomenon may be of relevance for epileptogenesis and for the pathogenesis of temporal lobe epilepsy. [source] Zonisamide Reduces the Increase in 8-Hydroxy-2,-Deoxyguanosine Levels Formed During Iron-Induced Epileptogenesis in the Brains of RatsEPILEPSIA, Issue 9 2000M. Komatsu Summary: Purpose: To examine the change of 8,-hydroxy-2,-deoxyguanosine (8-OHdG) levels, which are used as a marker for oxidative DNA damage, in iron-induced epileptogenic foci of the rat cerebrum. Method: Male Wistar rats were given a cortical injection of ferric chloride, and their 8-OHdG levels were determined over time. Additional animals were pretreated with the antiepileptic drug zonisamide (ZNS) before the ferric chloride injection, and their 8-OHdG levels were compared with the nonpretreated rats. Results: Fifteen minutes after ferric chloride solution injection, the level of 8-OHdG increased, reaching a maximum 30 minutes after injection. Sixty minutes after injection, the levels coincided with those of controls. ZNS, in concentrations of 50 and 100 mg/kg body weight, prevented the increase of 8-OHdG levels within the cerebrum 30 minutes after iron solution injection. Conclusions: These results indicate that the formation of iron-induced epileptogenic foci in rats is related to DNA-damage-induced reactive oxygen species and that the inhibition of 8-OHdG formation by ZNS after iron injection may be due to the drug's antioxidant activity. The data suggest that free radical species known to be formed during iron salts,induced focal epileptogenesis cause damage to isocortical DNA. Furthermore, ZNS appears to inhibit the focal injuring response to DNA that occurs following iron salts,induced acute epileptogenesis. [source] Cortical Dysplasias and Epilepsy: Multi-Institutional Survey in JapanEPILEPSIA, Issue 2000Morimi Shimada Purpose: Cortical dysplasia (CD) is a major brain malformation causing intractable epilcpsy. Neurosurgery now succcssfully controls some intractable epilepsies associated with CD. In this study, thc incidence 11 epilepsy and thc frequency of seizurcs were analyzed in different types 01 CD. Methods: This study, supported by a rcse;lrch grant from the Ministry of Health and Wellare of Japan, is part of a research project on the clinical presentation and pathogcnesis of brain dysgenesis. Questionnaires regarding the type of CD, family and pact historics, clinical signs and symptoms and their severity were distributed to I200 institutions comprising child neurologists or pediatricians. CDs werc classified into following 6 types; lissencephaly (agyria-pachygyria spcctrum), cobblestone lissencephaly, polymicrogyria including schizencephaly and hilateral perisylvian syndrome, diffuse heterotopia, focal heterotopia, and hemiinegalencephaly. All patients who had been diagnoscd as CD either by MRI, CT, autopsy or histological cxamination at or after surgical treatment wcre included. Diagnosis of CD by CT or MRI was mainly made by a radiologist, child neurologist, or pediatrician. Double classification was corrected. Epilepsy was classified according to criteria of the ILEA. Seizure frcquencies wcre recorded. Results: A total or 676 cases from 328 institutions was availablc, and distributed as follows: 277 of lissencephaly, I48 of cobblestone lissencephaly (10 cases of Walkcr-Warburg syndrome and 138 Fukuyaina type congcnital muscular dystrophy), I30 of polymicrogyria, 40 of diffuse heterotopia (24 subcortical band hetcrotopia and I6 perivcntricular nodular hcterotopia), 37 of focal heterotopia, and 44 of hemimegalencephaly. In 130 cases of polymicrogyria, 13 cases of bilatcral perisylvian syndrome, and 38 cases of schizencephaly were includcd. Of 667 cases available for study, 500 (75.0%) had epilepsy in which generalized epilepsy including West and Lcnnox syndromes comprised 54.1 % and localization-related epilepsies comprised 46.7%. Thc frequency of seizures could be ascertained in 455 cases, of which 36.0% had daily seizures, and I I .4%) had more than onc seizure per week. The incidencc of epilepsy in cach type of CD was as follows: 86% inlissencephaly, 50% in cobblestone lissencephaly (patients with WalkcrWarburg syndrome had epilepsy in 90%, whercas those with Fukuyama type congenital muscular dystrophy had epilepsy in 46.7%), 71.3% in polymicrogyria, 77.5% in diffusc hetcrotopia (9 1.7% in subcortical band heterotopia and 56.2% in periventricular nodular heterotopia), 74.3% in focal heterotopia, and 93.2% in hemimegalcncephaly. Conclusion: As recent investigations have reported, this study confirmed the high incidence of intractable cpilepsy in CDs. Epilepsy was more prevalcnt in cases with subcortical heterotopia than i n cascs with periventricular nodular helcrotopia. Thc incidcnce or epilepsy was also higher in the focal hcterotopias located subcortically than those dccper in white matter or in the periventricular region. Thcse differences in incidence of epilepsy depending on the location of hcterotopia may give somc clues to the nature of epileptogenesis in CD. [source] VIQ-PIQ Discrepancies in Partial Epilepsy: On the Relation to Lat- eralities of Focal MRI Lesions, P3 Peaks, and Focal Spikes.EPILEPSIA, Issue 2000Osamu Kanazawa Purpose: A number of previous ncurophysiological studies have indicated that the glutamatergic system is important in the induction of epileptiform activity and the dcvelopment of epileptogenesis. Clutamate transport is the primary mechanism of inactivation of syiiaptically released glutamate. GLAST is classified BS an astrocytic transporter and occurs in high concentrations in the ccrebcllum. The pathophysiologic rolc of GLAST in epilepsy is not known in detail. To investigate the role of thc astroglial glutamatc transporter GLAST in epileptogenesis, we compared amygdalu-kindling and pentylenctetrazolc (PTZ) induced seizures in GLAST-deficient mice (GLAST(-/-)) wild-type mice (GLAST(+/+)), and maternal C57Black6/J mice (C57). Purpose: Subtest IQ such as verbal IQ (VIQ) and performance IQ (PIQ) in WAIS or WISC are thought to represent neuropsychological functions of the left and right hemispheres, respectively. The P300 (P3) event-related potential reflects cognitive processes. We do not ye1 know the brain site of P3 origin or how epileptogenic foci (EF) influ- ence P3 potentials. To examine neuropsychological influence by partial epilepsy (PE), we studied VIQ-PIQ discrepancies in PE in relation to lateralities of focal MRI lesions, P3 peaks, and EF. Methods: Thirteen patients showed VIQ-PIQ discrepancies significant at the p7lt;O.O5 level, represented by a>l2-point spread for the WAIS in adults, and a 15-point spread in the WISC in children. We evoked P3 potentials in the individuals with discrepant IQ differences by asking them to keep a mental count of rare tones, including introduction of oddbail tones. EEGs were recorded by the international 10,20 system and P3 peaks were shown in a topographical view by offline analysis. Patients were divided into normal and abnormal groups according to MRI findings, and were examined for the laterali- ties of the dominant side in subtest IQ (conventionally, we regarded higher VIQ as left hemisphere dominant and higher PIQ as right hemisphere dominant), P3 peaks, and EF. We did not correlate results with lert or right handedness. Results: Five patients (38.5%) were in the normal group and 8 patients (61.5%) were in the abnormal group. Concordance of the lateralities in P3 peaks and dominant side in subtest IQ was shown in 1 patient (20%) in the normal group and 5 patients (62.5%) in the abnormal group. In the normal group, all patients showed contralateral P3 peak shift to EF, and all except I patient showed contralateral P3 peak shift to the dominant side in subtest IQ. The other 3 patients in the abnormal group showed unilateral focal cortical dysplasias (FCD), ipsilateral P3 shift, and contralateral dominant side in subtest IQ to the focal MRI lesions. Conclusion: In our partial epilepsy series with VIQ-PIQ discrepancies, concordance of the lateralities in P3 peaks and dominant side in subtest IQ was shown in < half of the patients. Epileptogenic foci seem to have 3 different grades of influence on P3 peak shift and dominant side in subtest IQ according to the severities of accompanying focal MRI lesions: 1. Without MRI lesions, EF can make P3 peak shift contralaterally, but the dominant side in the subtest IQ shift ipsilaterally; 2. With less severe focal MRI lesions such as hippocampal atrophy etc., EF can make not only P3 peaks but also the dominant side in the subtest IQ shift contralaterally; 3. With severe focal MRI lesions such as FCD, EF can make the dominant side in the subtest IQ shift contralaterally, but the P3 peak may shift ipsilaterally. Epileptogenic foci without MRI lesions seem to control ipsilateral P3 potentials. MRI lesions render a hemisphere unlikely to become dominant, but epileptogenic foci can coexist with apparently normal neuropsychological function. [source] N -methyl- d -aspartate, hyperpolarization-activated cation current (Ih) and ,-aminobutyric acid conductances govern the risk of epileptogenesis following febrile seizures in rat hippocampusEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2010Mohamed Ouardouz Abstract Febrile seizures are the most common types of seizure in children, and are generally considered to be benign. However, febrile seizures in children with dysgenesis have been associated with the development of temporal lobe epilepsy. We have previously shown in a rat model of dysgenesis (cortical freeze lesion) and hyperthermia-induced seizures that 86% of these animals developed recurrent seizures in adulthood. The cellular changes underlying the increased risk of epileptogenesis in this model are not known. Using whole cell patch-clamp recordings from CA1 hippocampal pyramidal cells, we found a more pronounced increase in excitability in rats with both hyperthermic seizures and dysgenesis than in rats with hyperthermic seizures alone or dysgenesis alone. The change was found to be secondary to an increase in N -methyl- d -aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs). Inversely, hyperpolarization-activated cation current was more pronounced in naïve rats with hyperthermic seizures than in rats with dysgenesis and hyperthermic seizures or with dysgenesis alone. The increase in GABAA -mediated inhibition observed was comparable in rats with or without dysgenesis after hyperthermic seizures, whereas no changes were observed in rats with dysgenesis alone. Our work indicates that in this two-hit model, changes in NMDA receptor-mediated EPSCs may facilitate epileptogenesis following febrile seizures. Changes in the hyperpolarization-activated cation currents may represent a protective reaction and act by damping the NMDA receptor-mediated hyperexcitability, rather than converting inhibition into excitation. These findings provide a new hypothesis of cellular changes following hyperthermic seizures in predisposed individuals, and may help in the design of therapeutic strategies to prevent epileptogenesis following prolonged febrile seizures. [source] The antiepileptic drug levetiracetam selectively modifies kindling-induced alterations in gene expression in the temporal lobe of ratsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2004Jessie Gu Abstract Gene expression profiling by microarrays is a powerful tool for identification of genes that may encode key proteins involved in molecular mechanisms underlying epileptogenesis. Using the Affymetrix oligonucleotide microarray, we have surveyed the expression levels of more than 26,000 genes and expressed sequence tags (ESTs) in the amygdala-kindling model of temporal lobe epilepsy. Furthermore, the effect of the antiepileptic drug levetiracetam (LEV) on kindling-induced alterations of gene expression was studied. Treatment of rats with LEV during kindling acquisition significantly suppressed kindling development. For gene expression profiling, six groups of rats were included in the present study: (i) and (ii) sham-operated rats treated with saline or LEV; (iii) and (iv) electrode-implanted but non-kindled rats treated with saline or LEV; (v) and (vi) kindled rats treated with saline or LEV. Treatment was terminated after 11 or 12 daily amygdala stimulations, when all vehicle-treated rats had reached kindling criterion, i.e. a stage 5 seizure. Twenty-four hours later, the ipsilateral temporal lobe was dissected for mRNA preparation. Six temporal lobe preparations from each group were analysed for differential gene expression. In control (non-kindled) rats, LEV treatment was devoid of any significant effect on gene expression. In saline-treated kindled rats, a large number of genes were observed to display mRNA expression alterations compared with non-kindled rats. LEV treatment induced marked effects on gene expression from kindled rats. Previously described epilepsy-related genes, such as neuropeptide Y (NPY), thyrotropin-releasing hormone (TRH) and glial fibrillary acidic protein (GFAP) were confirmed to be up-regulated by kindling and partially normalized by LEV treatment. Real-time quantitative polymerase chain reaction confirmed NPY, TRH and GFAP expression data from chip experiments. Furthermore, a number of novel genes were identified from the gene chip experiments. A subgroup of these genes demonstrated correlation between expression changes and kindled phenotype measurements. In summary, this study identified many genes with potentially important roles in epileptogenesis and highlighted several important issues in using the gene chip technology for the study of animal models of CNS disorders. [source] Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsyGLIA, Issue 4 2006Tae-Cheon Kang Abstract Recent studies have demonstrated that blockade of neuronal death in the hippocampus cannot prevent epileptogenesis in various epileptic models. These reports indicate that neurodegeneration alone is insufficient to cause epilepsy, and that the role of astrocytes in epileptogenesis should be reconsidered. Therefore, the present study was designed to elucidate whether altered morphological organization or the functionalities of astrocytes induced by status epilepticus (SE) is responsible for epileptogenesis. Glial responses (reactive microgliosis followed by astroglial death) in the dentate gyrus induced by pilocarpine-induced SE were found to precede neuronal damage and these alterations were closely related to abnormal neurotransmission related to altered vesicular glutamate and GABA transporter expressions, and mossy fiber sprouting in the dentate gyrus. In addition, newly generated astrocytes showed down-regulated expressions of glutamine synthase, glutamate dehydrogenase, and glial GABA transporter. Taken together, our findings suggest that glial responses after SE may contribute to epileptogenesis and the acquisition of the properties of the epileptic hippocampus. Thus, we believe that it is worth considering new therapeutic approaches to epileptogenesis involving targeting the inactivation of microglia and protecting against astroglial loss. © 2006 Wiley-Liss, Inc. [source] Increased expression of GluR2-flip in the hippocampus of the Wistar audiogenic rat strain after acute and kindled seizuresHIPPOCAMPUS, Issue 1 2010Daniel Leite Góes Gitaí Abstract The Wistar Audiogenic Rat (WAR) is an epileptic-prone strain developed by genetic selection from a Wistar progenitor based on the pattern of behavioral response to sound stimulation. Chronic acoustic stimulation protocols of WARs (audiogenic kindling) generate limbic epileptogenesis, confirmed by ictal semiology, amygdale, and hippocampal EEG, accompanied by hippocampal and amygdala cell loss, as well as neurogenesis in the dentate gyrus (DG). In an effort to identify genes involved in molecular mechanisms underlying epileptic process, we used suppression-subtractive hybridization to construct normalized cDNA library enriched for transcripts expressed in the hippocampus of WARs. The most represented gene among the 133 clones sequenced was the ionotropic glutamate receptor subunit II (GluR2), a member of the ,-amino-3-hydroxy-5-methyl-4-isoxazoleopropionic acid (AMPA) receptor. Although semiquantitative RT-PCR analysis shows that the hippocampal levels of the GluR2 subunits do not differ between naïve WARs and their Wistar counterparts, we observed that the expression of the transcript encoding the splice-variant GluR2-flip is increased in the hippocampus of WARs submitted to both acute and kindled audiogenic seizures. Moreover, using in situ hybridization, we verified upregulation of GluR2-flip mainly in the CA1 region, among the hippocampal subfields of audiogenic kindled WARs. Our findings on differential upregulation of GluR2-flip isoform in the hippocampus of WARs displaying audiogenic seizures is original and agree with and extend previous immunohistochemical for GluR2 data obtained in the Chinese P77PMC audiogenic rat strain, reinforcing the association of limbic AMPA alterations with epileptic seizures. © 2009 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||