Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The twitcher mouse is well known as a naturally occurring authentic mouse model of human globoid cell leukodystrophy (GLD; Krabbe disease) due to genetic deficiency of lysosomal galactosylceramidase. The twitcher mice used most commonly are on the C57BL/6J background. We generated twitcher mice that were on the mixed background of C57BL/6J and 129SvEv, the standard strain for production of targeted mutations. Twitcher mice on the mixed background were smaller and had a shorter lifespan than were those on the C57BL/6J background. Many twitcher mice on the mixed background developed generalized seizures around 30 days that were never seen in twitcher mice on the C57BL/6J background. Neuropathologically, although the degree of the typical demyelination with infiltration of macrophages was similar in the central and peripheral nervous systems, in both strains, marked neuronal cell death was observed only in twitcher mice on the mixed background. In the hippocampus, the neuronal cell death occurred prominently in the CA3 region in contrast to the relatively well-preserved CA1 and CA2 areas. This neuropathology has never been seen in twitcher mice on the C57BL/6J background. Biochemically, the brain of twitcher mice on the mixed background showed much greater accumulation of lactosylceramide. Genetic background must be carefully taken into consideration when phenotype of mutant mice is evaluated, particularly because most targeted mutants are initially on a mixed genetic background and gradually moved to a pure background. These findings also suggest an intriguing possibility of important function of some sphingolipids in the hippocampal neuronal organization and maintenance.
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PMID:Genetic background markedly influences vulnerability of the hippocampal neuronal organization in the "twitcher" mouse model of globoid cell leukodystrophy. 1526 20

[(123)I]Iomazenil (IMZ) is a specific ligand for central-type benzodiazepine receptors (BZRs) and is available for single photon emission computed tomography (SPECT) to detect epileptogenic foci. We have recently demonstrated time-dependent alterations of [(125)I]IMZ binding in the rat kainate model of temporal lobe epilepsy. Quantitative evaluation of central-type benzodiazepine receptors with [(125)I]Iomazenil in experimental epileptogenesis. I. The rat kainate model of temporal lobe epilepsy. In the present study, we investigated regional changes in central-type BZRs in the cortical dysplasia (CD) model of epilepsy in rats. Pregnant rats were irradiated at day 17 of gestation with 1.2 Gy to produce CD in their pups, and in vitro autoradiography with [(125)I]IMZ was performed at 8 weeks after birth. Intact rats at the same age were used as controls. [(125)I]IMZ binding was significantly decreased in various cortical regions of the in utero irradiated rats, including the bilateral frontal cortex (down to 92-93% of control), cingulate cortex (91-92%), hippocampal areas CA1 (95%), CA2 (94-95%) and CA4 (95-96%), and caudate/putamen (90-94%). In addition, amygdala-kindling was significantly facilitated in the CD model, especially during the late phase of kindling, suggesting seizure susceptibility of this model. These results may replicate the clinical usefulness of central-type BZRs neuroimaging for detection of human epileptogenic CD and indicate dysfunction of GABA-A/BZR-mediated inhibition responsible for the seizure susceptibility.
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PMID:Quantitative evaluation of central-type benzodiazepine receptors with [(125)I]Iomazenil in experimental epileptogenesis: II. The rat cortical dysplasia model. 1545 Oct 13

This study aimed at quantitatively evaluating hippocampal central-type benzodiazepine receptors (BZRs) in the kainate model of temporal lobe epilepsy (TLE) by in vitro autoradiography (ARG) using [(125)I] Iomazenil (IMZ) specific ligand for central-type BZRs. Kainate (1 microg/0.5 microl) was injected into the left amygdala to induce limbic status epilepticus. One, three, or six months after injection, in vitro ARG with [(125)I] IMZ and cell counts were performed in the hippocampal CA1-4 regions and dentate gyrus ipsilateral to the kainate injection site, and were compared with the vehicle-injected control group. In all kainate-treated rats, clear pyramidal neuron loss was observed in left hippocampal areas CA1-4. Compared with the control group, progressive reduction of [(125)I] IMZ binding was also observed. This resulted in a marked binding decrease paralleling pyramidal neuron loss in hippocampal areas CA1 (down to 83% of control), CA2 (76%), CA3 (75%), and CA4 (90%) at 6 months after kainate administration. Conversely, [(125)I] IMZ binding significantly increased in the dentate gyrus (up to 106% of control) at 1 month, but returned to nearly normal at 3-6 months. These results suggest that central-type BZR neuroimaging is useful in detecting hippocampal sclerosis in the mesial TLE, though central BZR alterations differ depending on hippocampal subfields and post-seizure time-courses.
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PMID:Quantitative evaluation of central-type benzodiazepine receptors with [(125)I] Iomazenil in experimental epileptogenesis. I. The rat kainate model of temporal lobe epilepsy. 1545 Oct 12

The neuronal ceroid-lipofuscinoses (NCLs) are recessively inherited lysosomal storage diseases, currently classified into 8 forms (CLN1-CLN8). Collectively, the NCLs constitute the most common group of progressive encephalopathies of childhood, and present with visual impairment, psychomotor deterioration and severe seizures. Despite recent identification of the underlying disease genes, the mechanisms leading to neurodegeneration and epilepsy in the NCLs remain poorly understood. To investigate these events, we examined the patterns of storage deposition, neurodegeneration, and glial activation in the hippocampus of patients with CLN1, CLN2, CLN3, CLN5 and CLN8 using histochemistry and immunohistochemistry. These different forms of NCL shared distinct patterns of neuronal degeneration in the hippocampus, with heavy involvement of sectors CA2-CA4 but relative sparing of CA1. This selective pattern of degeneration was also observed in immunohistochemically identified interneurons, which exhibited a graded severity of loss according to phenotype, with calretinin-positive interneurons relatively spared. Furthermore, glial activation was also regionally specific, with microglial activation most pronounced in areas of greatest neuronal loss, and astrocyte activation prominent in areas where neuronal loss was less evident. In conclusion, the NCLs share a common pattern of selective hippocampal pathology, distinct from that seen in the majority of temporal lobe epilepsies.
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PMID:Hippocampal pathology in the human neuronal ceroid-lipofuscinoses: distinct patterns of storage deposition, neurodegeneration and glial activation. 1560 81

Susceptibility to kainate-induced seizures is enhanced by zinc deficiency. To evaluate kainate-induced excitotoxicity in zinc deficiency, the relationship between kainate-induced seizures and hippocampal cell death was examined in control and zinc-deficient mice. Mice were fed a control and zinc-deficient diet for 4 weeks, and then intraperitoneally injected with 12 mg/kg kainate every 60 min three times. The rate of dead mice to the total mice was higher in zinc-deficient group than in control group 3 days after the last injection of kainate. In the survivals, which exhibited tonic convulsions in both control and zinc-deficient groups, kainate-induced hippocampal cell death was also analyzed by cresyl violet staining. Neuronal loss was more observed in the CA1, CA2 and CA3 pyramidal cell layers of zinc-deficient group than those of the control group. TUNEL-positive cells were significantly more detected in the CA1 and CA3 pyramidal cell layers of zinc-deficient group. These results demonstrate that kainate-induced hippocampal cell death occurs more easily in zinc deficiency. Extracellular zinc concentration detected with ZnAF-2 was significantly decreased in the hippocampal CA3 of zinc-deficient mice, in agreement with the previous data measured by in vivo microdialsysis. Synaptically released zinc may be less involved in kainate-induced hippocampal cell death in zinc deficiency.
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PMID:Increase in hippocampal cell death after treatment with kainate in zinc deficiency. 1616 25

Perinatal asphyxia is an important cause of neonatal mortality and subsequent serious sequelae such as motor and cognitive deficits and seizures. Recent studies have demonstrated that short peptides derived from activity-dependent neurotrophic factor (ADNF) and activity-dependent neuroprotective protein (ADNP) are neuroprotective at femtomolar concentrations. However, the effect of these peptides on the hypoxic-ischemic brain injury model is unknown. The aim of this study is to investigate the effects of the peptides ADNF-9 and NAP on neurodegeneration and cerebral nitric oxide (NO) production in a neonatal rat model of hypoxic-ischemic brain injury. Seven-day-old Wistar Albino rat pups have been used in the study (n=42). Experimental groups in the study were: sham-operated group, ADNF-9-treated hypoxia-ischemia group, NAP-treated hypoxia-ischemia group, ADNF-9+NAP-treated hypoxia-ischemia group, and vehicle-treated group. In hypoxia-ischemia groups, left common carotid artery was ligated permanently on the seventh postnatal day. Two hours after the procedure, hypoxia (92% nitrogen and 8% oxygen) was applied for 2.5 h. ADNF-9, NAP, and ADNF-9+NAP were injected (intraperitoneally; i.p.) as a single dose immediately after the hypoxia period. Brain nitrite levels, neuronal cell death, and apoptosis were evaluated in both hemispheres (carotid ligated or nonligated) 72 h after the hypoxic-ischemic insult. Histopathological evaluation demonstrated that ADNF-9 and NAP significantly diminished number of "apoptotic cells" in the hippocampal CA1, CA2, CA3, and gyrus dentatus regions in both hemispheres (ligated and nonligated). When compared with vehicle-treated group, combination treatment with ADNF-9+NAP did not significantly reduce "apoptotic cell death" in any of the hemispheres. ADNF-9 and NAP, when administered separately, significantly preserved the number of neurons CA1, CA2, CA3, and dentate gyrus regions of the hippocampus, when compared with vehicle-treated group. The density of the CA1, CA2, and dentate gyrus neurons was significantly higher when combination therapy with ADNF-9+NAP was used in the carotid ligated hemispheres. In the nonligated hemispheres, combination therapy preserved the number of neurons only in the CA1 and dentate gyrus regions. Brain nitrite levels were evaluated by Griess reagent and showed that hypoxic-ischemic injury caused a significant increase in NO production. Brain nitrite levels in ADNF-9+NAP-treated animals were not different in carotid ligated or nonligated hemispheres. The peptides ADNF-9 and NAP significantly decreased NO overproduction in the hypoxic-ischemic hemisphere, whereas no significant change appeared in hypoxia alone and also in the sham-operated group. These results suggest the beneficial neuroprotective effect of ADNF-9 and NAP in this model of neonatal hypoxic-ischemic brain injury. To our knowledge, this is the first study that demonstrates a protective effect of these peptides against hypoxia-ischemia in the developing brain.
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PMID:Neuroprotective effect of the peptides ADNF-9 and NAP on hypoxic-ischemic brain injury in neonatal rats. 1693 77

Temporal lobe epilepsy (TLE) with hippocampal sclerosis is associated with high extracellular glutamate levels, which could trigger seizures. Down-regulation of glial glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) in sclerotic hippocampi may account for such increases. Their distribution was compared immunohistochemically in non-sclerotic and sclerotic hippocampi and localized only in astrocytes, with weaker immunoreactivity for both transporters in areas associated with pronounced neuronal loss, especially in CA1, but no decrease or even an increase in areas with less neuronal loss, like CA2 and the subiculum in the sclerotic group. Such compensatory changes in immunoreactivity may account for the lack of differences between the groups in immunoblot studies as blots show the average concentrations in the samples. These data suggest that differences in glial glutamate transporter distribution between the two groups of hippocampi may be an insufficient explanation for the high levels of extracellular glutamate in sclerotic seizure foci observed through in vivo dialysis studies.
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PMID:Changes in glial glutamate transporters in human epileptogenic hippocampus: inadequate explanation for high extracellular glutamate during seizures. 1711 31

We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1-CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls [no mesial temporal sclerosis (no MTS); n = 34, 19%]. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies.
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PMID:A new clinico-pathological classification system for mesial temporal sclerosis. 1722 Dec 3

The megencephaly mice show dramatic progressive increase in brain size and seizures. The overgrowth affects primarily the hippocampus and ventral cortex. The phenotype originates from a mutation in the Shaker-like voltage-gated potassium channel Kv1.1 brain, which results in a malfunctioning protein. A key question in elucidating the mechanism behind the unique brain overgrowth is whether it is caused by an increase in cell number. By applying stereological techniques, we found that the number of both neurons and astrocytes, as well as structure volume, was increased approximately two-fold within dentate gyrus (DG), CA2/3, and hilus of 12-week-old mceph/mceph versus wild type mice. In CA1, there was a tendency toward an increase in volume and in number of astrocytes. The volume estimates in newborn and p14 mice suggest that the overgrowth in mceph/mceph hippocampus starts between birth and the second week of life. To investigate the hyperplasia, cell proliferation was studied within the subgranular zone of the DG using BrdU and Ki67. There was a three-fold increase in proliferation in mceph/mceph mice compared to wild type mice at an age before onset of epileptic symptoms (3 weeks), and these new mceph/mceph neurons showed increased migration and had a 6-week survival rate as the new neurons in wild type DG. Also when seizures were frequent in mceph/mceph (9 weeks old), the proliferation rate was three-fold higher than in wild type. The number of TUNEL-positive cells in hippocampus was lower in mceph/mceph supporting additional overgrowth mechanism than induced by seizures. In conclusion, lack of a functional Kv1.1 ion channel subunit in the mceph/mceph mice causes a unique neuronal hyperplasia in distinct hippocampal regions and consequently hippocampal enlargement from 2 to 3 weeks of age. This phenotype is a result, at least in DG, from increased proliferation, neurogenesis, and enhanced general hippocampal cell survival.
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PMID:Lack of potassium channel induces proliferation and survival causing increased neurogenesis and two-fold hippocampus enlargement. 1731 99

The dipeptide N-acetylaspartylglutamate (NAAG) has been recently implicated in numerous neurological disorders. NAAG binds and stimulates group II metabotropic glutamate receptors producing a down-modulation of synaptic glutamate release. In the present immunohistochemical study, we compare the distribution of NAAG-containing (NAAGergic) neurons between the hippocampus of control and chronic epileptic rats obtained with the pilocarpine model of temporal lobe epilepsy. In the hippocampal formation, NAAGergic neurons comprise a subpopulation of GABAergic neurons. Examination by light microscopy revealed a significant reduction of NAAG-immunoreactive neurons in CA3 stratum oriens (35.8%) and CA1 stratum oriens (78.87%), stratum pyramidale (40%), and stratum radiatum (56.6%). Similar loss of NAAGergic neurons was observed in the subiculum characterized by 71.82% and 77.53% reduction in the stratum oriens and radiatum, respectively, when compared with controls. NAAGergic neurons in CA2 and dentate gyrus were apparently resistant to seizure-related cell loss but appeared more complex and exhibited numerous NAAG-positive puncta. Our findings indicate a selective vulnerability of NAAGergic neurons in temporal lobe epilepsy.
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PMID:Selective vulnerability of hippocampal NAAGergic neurons in experimental temporal lobe epilepsy. 1734 83


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