El Mouse as a Model of Focal Epilepsy: A Review

King, Joseph T.; LaMotte, Carole C.

doi:10.1111/j.1528-1157.1989.tb05296.x

Cited by 90 publications

(24 citation statements)

References 52 publications

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“…The EL mouse is an inbred mutant strain that has been used as an animal model of secondarily generalized seizures (1,2). Several lines of evidence indicate that seizure discharges are initiated in the parietal area and then generalized through the hippocampus (3).…”

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confidence: 99%

Role of Nitric Oxide in the Epileptogenesis of EL Mice

2000

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Summary:Purpose: To understand the role of nitric oxide (NO) in the regulation of seizures, we measured the extracellular levels of the NO metabolites nitrite and nitrate as indices of NO generation in the parietal cortex, hippocampus, and temporal cortex of EL mice. Furthermore, alterations of neuronal, endothelial, and inducible nitric oxide synthetase (nNOS, eNOS, and iNOS, respectively) were observed to correlate them with epileptogenesis.Methods: EL mice of 20 weeks and 30 weeks of age (before and after the establishment of epileptogenesis, respectively) were used. Nitrite was quantified using the specific absorbancy of diazo dye. NOS isoenzymes (nNOS, iNOS, and eNOS) were also investigated in the hippocampus during development until mice were 30 weeks old. Samples (total protein, 8.33 to 8.43 Fg) were separated by sodium dodecyl sulfate-polyacrylamide geI electrophoresis and identified by immunoblotting.Results: EL mice that experienced repetitive seizures showed a remarkable increase in nitrite in the hippocampus at 30 weeks of age compared with EL mice that had no experience of seizures. nNOS and iNOS were major and minor components, respectively, and both increased in parallel with the development of epileptogenesis. eNOS was not detectable.Conclusions: Excess iNOS (and subsequent increase in harmful NO) and deficient eNOS (and subsequent decrease in NO identified as an endothelium-derived relaxing factor) may work together to form a focus complex. Key Words: Epileptic mutant-EL mouse-Nitric oxide (NO)-Nitric oxide synthetase (NOS)-Abnormal plasticity-Epileptogenesis.The EL mouse is an inbred mutant strain that has been used as an animal model of secondarily generalized seizures (1,2). Several lines of evidence indicate that seizure discharges are initiated in the parietal area and then generalized through the hippocampus (3). These findings have been substantiated by histochemical and biochemical analyses of glucose utilization (4) and inhibitory neurotransmissions by aminobutyric acid (5). The developmental formation of the focus complex, which consists mainly of the parietal cortex and the hippocampus, has been hypothesized to be key to epileptogenesis in EL mice.In our recent studies, allopurinol, a xanthine oxidase inhibitor, exerted an antiepileptic action on EL mice (6), and the drug ameliorated abnormalities in the activities of the free radical scavenger superoxide dismutase isoenzymes, which are present in the hippocampus (7). Furthermore, DNA fragmentation was found in the hippocampal CA1 region and the parietal cortex in EL mice, presumably as a consequence of the production of free radicals attributable to decreased Cu,Zn-superoxide dismutase (7). Nitric oxide (NO) has been identified as a source of free radical oxidants with special relevance to pathological conditions in the brain, and reactive nitrogen intermediates could damage DNA as an important target (8). In addition, NO, identified as an endothelium-derived relaxing factor (9), is a potent vasodilator that regulates cerebral blo...

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confidence: 99%

Role of Nitric Oxide in the Epileptogenesis of EL Mice

2000

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“…Although no animal model of familial TLE exists, an inbred mouse strain, El (epilepsy-like) exhibits partial seizures with secondary generalization, which resemble human TLE in some ways (107,108). Seizures in this model are spontaneous or elicited by vestibular stimulation or stress.…”

Section: Familial Temporal Lobe Epilepsymentioning

confidence: 99%

Recent Advances in the Genetics of Epilepsy: Insights from Human and Animal Studies

Prasad

Stafstrom

1999

Epilepsia

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Summary: Progress in understanding the genetics of epilepsy is proceeding at a dizzying pace. Due in large part to rapid progress in molecular genetics, gene defects underlying many of the inherited epilepsies have been mapped, and several more are likely to be added each year. In this review, we summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, and correlate these advances with rapidly expanding information about the mechanisms of epilepsy gained from both spontaneous and transgenic animal models. We also provide practical suggestions for clinicians confronted with families in which multiple members are afflicted with epilepsy. Key Words: Epilepsy-GeneticsHuman-Pathophysiology-Animal models.Over the past few years, there has been an explosion of information about the genetic basis of epilepsy and epilepsy syndromes. Some of these advances have been documented in recent reviews (1-6). In parallei with advances in understanding the genetics of human epilepsies, several spontaneous and transgenic animal models of inherited epilepsy have been produced. These approaches will expand our ability to dissect cellular mechanisms of seizure generation and propagation and help us to move from serendipity to rationality in designing targeted therapies for seizure disorders (7,8). In this review we summarize the recent progress in mapping genes for human epilepsy, describe some relevant animal models of genetic epilepsy, and examine the relation between gene defects and the cellular mechanisms of epilepsy. Finally, we provide practical suggestions for clinicians caring for patients and families with inherited epilepsies. Clinical details of the various epilepsy syndromes, available elsewhere, are largely omitted here.Epilepsy, characterized by recurrent seizures, results from excessive synchronous firing of neurons in cortical networks. A number of intricately linked mechanisms at the network, cellular, subcellular, and molecular levels

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“…Epileptic mutant EL mice show secondary generalized seizures (1, 2). Seizure discharges initiate in the parietal cortex and generalize through the hippocampus (3).…”

Section: Introductionmentioning

confidence: 99%

Role of Cytokines during Epileptogenesis and in the Transition from the Interictal to the Ictal State in the Epileptic Mutant EL Mouse

Murashima

Suzuki

Yoshii

2008

Gene�Regul Syst Bio

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Purpose: Epileptic mutant EL mice show secondary generalized seizures. Seizure discharges initiate in the parietal cortex and generalize through the hippocampus. We have previously demonstrated an increase in the activity of inducible nitric oxide synthetase (iNOS) as well as a decrease in the activity of superoxide dismutase (SOD) in the hippocampus of EL mice, suggesting that cell toxic free radicals are increased in the brain of EL mice. In parallel with this, neurotrophic factors were signifi cantly increased in the hippocampus of EL mice in earlier developmental stages before exhibiting frequent seizures. These fi ndings were no longer present after frequent seizures, suggesting that these events may trigger ictogenesis. On the other hand, it is reported that limbic seizures rapidly induce cytokines and related infl ammatory mediators. It remains to be seen, however, whether cytokines contribute to the transition from interictal to ictal state. The present study was designed to address this issue using EL mice.Methods: EL mice at the age from 4 to 23 weeks and their control animal, DDY mice at the age of 10 and 20 weeks were used. Seizures were induced in EL mice once every week since 5 weeks. Cytokines, such as interleukin-1 alpha (IL-1a), interleukin 1-beta (IL-1b), IL-6, IL-1 receptor (IL-1r), IL-1 receptor antagonist (IL-ra) and tumor necrosis factor alpha (TNF-a) were examined by Western blotting in the 'focus complex' of brain (namely, in the parietal cortex and hippocampus) of EL mice in the interictal period at different developmental stages. In 15 week old EL mice, which show seizures once a week, these cytokines were similarly determined 5 min, 2 hr, 4 hr, 11 hr, 24 hr, 3 days and 6 days after the last seizure induced. Results:A signifi cant increase in the level of cytokines was observed in the brain of EL mice at any stages during development, compared with the level of cytokines in the brain of control DDY. Cytokines were increased predominantly before experiencing frequent seizures. In EL mice at the age of 15 weeks, the level of cytokines in the hippocampus was highest 6 days after seizures. In the parietal cortex, cytokines were most highly expressed 2 hr after seizures. The results indicate that cytokines were kept up-regulated until next seizures in the hippocampus, whereas they were transiently up-regulated immediately after seizures in the parietal cortex. Conclusion:It is concluded that in the brain of EL mice, pro-infl ammatory cytokines are increased progressively and periodically in association with the development and the seizure activity, respectively. A periodic increase of cytokines prior to the next seizure episode may play a role in triggering the ictal activity. Namely, alteration of region-specifi c cytokines may induce ictal activities from the interictal state. It is conceivable that infl ammatory cytokines may work together with neuronal factors during epileptogenesis and in the transition from interictal to ictal state.

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El Mouse as a Model of Focal Epilepsy: A Review

Cited by 90 publications

References 52 publications

Role of Nitric Oxide in the Epileptogenesis of EL Mice

Role of Nitric Oxide in the Epileptogenesis of EL Mice

Recent Advances in the Genetics of Epilepsy: Insights from Human and Animal Studies

Role of Cytokines during Epileptogenesis and in the Transition from the Interictal to the Ictal State in the Epileptic Mutant EL Mouse

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