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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The central histaminergic neuron system inhibits epileptic seizures, which is suggested to occur mainly through histamine 1 (H1) and histamine 3 (H3) receptors. However, the importance of histaminergic neurons in seizure-induced cell damage is poorly known. In this study, we used an organotypic coculture system and confocal microscopy to examine whether histaminergic neurons, which were verified by immunohistochemistry, have any protective effect on kainic acid (KA)-induced neuronal damage in the developing hippocampus. Fluoro-Jade B, a specific marker for degenerating neurons, indicated that, after the 12 h KA (5 microM) treatment, neuronal damage was significantly attenuated in the hippocampus cultured together with the posterior hypothalamic slice containing histaminergic neurons [HI plus HY (POST)] when compared with the hippocampus cultured alone (HI) or with the anterior hypothalamus devoid of histaminergic neurons. Moreover, alpha-fluoromethylhistidine, an inhibitor of histamine synthesis, eliminated the neuroprotective effect in KA-treated HI plus HY (POST), and extracellularly applied histamine (1 nM to 100 microM) significantly attenuated neuronal damage only at 1 nM concentration in HI. After the 6 h KA treatment, spontaneous electrical activity registered in the CA1 subregion contained significantly less burst activity in HI plus HY (POST) than in HI. Finally, in KA-treated slices, the H3 receptor antagonist thioperamide enhanced the neuroprotective effect of histaminergic neurons, whereas the H1 receptor antagonists triprolidine and mepyramine dose-dependently decreased the neuroprotection in HI plus HY (POST). Our results suggest that histaminergic neurons protect the developing hippocampus from KA-induced neuronal damage, with regulation of neuronal survival being at least partly mediated through H1 and H3 receptors.
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PMID:Histaminergic neurons protect the developing hippocampus from kainic acid-induced neuronal damage in an organotypic coculture system. 1643 94

Mesio-temporal lobe epilepsy (MTLE) is often accompanied by granule cell dispersion (GCD), a widening of the granule cell layer. The molecular determinants of GCD are poorly understood. Here, we used an animal model to study whether GCD results from an increased dentate neurogenesis associated with an abnormal migration of the newly generated granule cells. Adult mice were given intrahippocampal injections of kainate (KA) known to induce focal epileptic seizures and GCD, comparable to the changes observed in human MTLE. Ipsilateral GCD progressively developed after KA injection and was paralleled by a gradual decrease in the expression of doublecortin, a marker of newly generated granule cells, in the dentate subgranular layer. Staining with Fluoro-Jade B revealed little cell degeneration in the subgranular layer on the KA-injected side. Labeling with bromodeoxyuridine showed an early, transient increase in mitotic activity in the dentate gyrus of the KA-injected hippocampus that gave rise to microglial cells and astrocytes but not to new neurons. Moreover, at later time points, there was a virtually complete cessation of mitotic activity in the injected hippocampus (where GCD continued to develop), but not on the contralateral side (where no GCD was observed). Finally, a significant decrease in reelin mRNA synthesis in the injected hippocampus paralleled the development of GCD, and neutralization of reelin by application of the CR-50 antibody induced GCD. These results show that GCD does not result from increased neurogenesis but reflects a displacement of mature granule cells, most likely caused by a local reelin deficiency.
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PMID:Reelin deficiency and displacement of mature neurons, but not neurogenesis, underlie the formation of granule cell dispersion in the epileptic hippocampus. 1664 Dec 51

The present study has examined the effect of free radical spin trap N-tert-butyl-alpha-phenylnitrone (PBN) in the model of seizures induced in immature 12-day-old rats by bilateral intracerebroventricular infusion of dl-homocysteic acid (dl-HCA, 600 nmol/side). PBN was given i.p. in two doses (100 mg/kg each), 30 min prior and 30 min after dl-HCA infusion. PBN did not significantly influence the severity of seizures, evident both from the behavioral symptoms and EEG recordings. PBN normalized decreased ATP levels in the hippocampus, occurring during the acute phase of seizures ( approximately 45-50 min after infusion) and persisting until the end of the 24-h recovery period. PBN also led to normalization of decreased glucose levels and to a significant reduction of lactate accumulation in the cerebral cortex and hippocampus. The neuroprotective effect of PBN was evaluated after 24 h and 6 days of survival following dl-HCA-induced seizures (Nissl and Fluoro-Jade B staining). The administration of PBN resulted in a partial amelioration of severe damage observed in many brain regions following infusion of dl-HCA alone. The data suggest that increased free radical production is apparently occurring during seizures induced in immature rats by homocysteic acid. Free radical scavenger PBN had a clear-cut protective effect, evident as the improved recovery of brain energy status and as a partial, but significant, attenuation of neuronal degeneration associated with this model of seizures.
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PMID:Effect of free radical spin trap N-tert-butyl-alpha-phenylnitrone (PBN) on seizures induced in immature rats by homocysteic acid. 1675 75

Hippocampal kindling, a model of mesial temporal lobe epilepsy, is developed through repetitive stimulation of the hippocampus and leads to increased after-discharges as measured by EEG and an enduring seizure-prone state. Synthesis of new proteins is thought to form the basis for sustained seizure-induced physiological and/or pathological changes in synaptic reorganization and apoptotic/necrotic neuronal death. Here we examined the effect of kindling on stimulus-induced c-Jun N-terminal kinase (JNK) and p38 phosphorylation, events postulated to lie upstream of seizure-induced changes in gene transcription. We found that stimulus-induced phosphorylation of JNK, but not of p38, is significantly enhanced in kindled animals compared with their naive counterparts in the CA1 subregion of the hippocampus. Immunofluorescent staining confirmed this region-specific pattern of JNK activation and revealed that reactive astrocytes mediate this effect. Astrocyte proliferation and hypertrophy, as well as upregulation of vimentin protein levels, common markers of astrogliosis, were present after 4 d of kindling. Moreover, this reactive astrogliosis was associated with neuronal death as visualized with Fluoro-jade B and anti-active caspase-3 staining. Stimulus-induced phosphorylation of the JNK substrate paxillin was enhanced in kindled animals, but not that of c-Jun. Moreover, a pan-antibody against MAPK/CDK (mitogen-activated protein kinases/cyclin-dependent kinase) substrates indicated the presence of phosphorylated proteins in cytosolic, membrane, and nuclear fractions. The consequence of these phosphorylation events is not completely understood, but these findings suggest a selective astrocytic signaling response to aberrant synaptic activity, signaling that may modulate kindling progression and/or neuronal death.
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PMID:c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes. 1689 24

Histological examination of brain after a single high (40 mg/kg) dose of D-methamphetamine (METH) was used to determine the relationships between blood-brain barrier (BBB) disruption, hyperthermia, intense seizure activity, and extensive degeneration that this exposure often produces. In very hyperthermic mice (body temperatures > 40.5 degrees C) exhibiting status epilepticus, increase in mouse IgG immunoreactivity (IgGIR) in the medial and ventral amygdala was observed within 90 min after METH exposure. In a few instances, where body temperature was in the 40.0 degrees C range, such IgGIR was also seen in animals that had exhibited status epilepticus. Variable increases in IgGIR, which correlated with neurodegeneration, also occurred within 12 h in the hippocampus, indicating BBB disruption in this region also. Degenerating neurons, Fluoro-Jade C (FJ-C) labeled, were first detected 4 h after METH in the amygdala and hippocampus. Extensive neurodegeneration occurred in the amygdaloid and hippocampal pyramidal cell regions in animals with marked IgGIR increase in these regions by 12 and 24 h after METH. A very rapid activation of brain microglia and/or infiltration of macrophages in regions of notable IgGIR increase with intense neurodegeneration were seen within 24 h. The phagocytosis rate of neurons in the hippocampus was so rapid that FJ-C labeling was virtually nonexistent 3 days after METH. METH did not produce IgGIR increase or neurodegeneration in the limbic regions in the absence of hyperthermia and seizures. Thus, high doses of METH can cause damage to the BBB when hyperthermia occurs, resulting in rapid and extensive hippocampal and amygdalar damage. The BBB disruption in the medial amygdala occurs first, and may well be contributing to the induction and severity of seizures, while BBB disruption in the hippocampus is likely a result of the seizures and hyperthermia. This hippocampal damage should be sufficient to compromise learning and memory.
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PMID:High doses of methamphetamine that cause disruption of the blood-brain barrier in limbic regions produce extensive neuronal degeneration in mouse hippocampus. 1695 62

Pharmacoresistant epilepsy arising from the dominant temporal region in patients with intact memory and normal anatomical imaging, presents major challenges in the preoperative definition of the epileptogenic zone, and the planning of the extent of the surgical resection. We report on the case of a 42-year-old, right-handed male who presented with recurrent daily seizures that were resistant to antiepileptic drugs. Multiple, non-invasive (scalp) video-EEG evaluations revealed focal epilepsy arising from the left fronto-temporal region. Multiple high resolution MRIs that were performed at multiple Epilepsy Centers failed to show any abnormality. Fluoro-deoxyglucose PET scan showed extensive, left antero-mesial temporal hypometabolism, and ictal SPECT showed increased perfusion in the left insula in addition to the left mesial and anterior temporal pole. Neuropsychological testing and intracarotid methohexital testing revealed excellent memory to the left, dominant side. A two-stage invasive evaluation with subdural grid electrodes followed by depth electrode recordings allowed the localization of the epileptogenic region to the temporal pole. A selective resection of the left temporal pole (that spared the hippocampal formation) resulted in a seizure-free outcome (one year follow-up) with no significant consequences on memory function. We conclude that targeted, invasive recording techniques should be used for the accurate localization and delineation of the extent of the epileptogenic zone in cases of suspected, non-lesional, dominant hemisphere, temporal lobe epilepsy with preserved memory function. The use of the staged invasive approach may increase the chances for memory (function) sparing through tailored, temporal resection.
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PMID:Definition of the epileptogenic zone in a patient with non-lesional temporal lobe epilepsy arising from the dominant hemisphere. 1701 70

This report presents unusual positron emission tomography findings in an 11-year-old male with Rasmussen's encephalitis. This patient underwent fluorine-18 fluorodeoxyglucose positron emission tomography to localize his ictal focus before surgical consideration. Positron emission tomography disclosed marked hypermetabolism in the left cerebral hemisphere and basal ganglia with subnormal right cerebral activity and crossed cerebellar diaschisis. The heterogeneous distribution of metabolism suggests a combination of areas in different stages of ictal and postictal involvement. The hypermetabolic region in the left hemisphere was larger in size and extent (now including the left frontoparietal lobe) than the sole hypermetabolic left temporal lobe on his positron emission tomography from 2 years ago. While this positron emission tomography pattern of progression appears most commonly in Rasmussen's encephalitis case studies, few serial reports exist. The complex positron emission tomography findings of this case emphasize the importance of knowing the history of recent seizures, seizure type, clinical status at time of injection, and electroencephalographic correlation before interpreting functional neuroimaging studies. Finally, positron emission tomography studies can help clarify whether patients with Rasmussen's encephalitis with dominant hemisphere involvement are appropriate candidates for surgery or not.
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PMID:Positron emission tomography in Rasmussen's encephalitis. 1727 63

Sodium fluoroacetate was introduced as a rodenticide in the US in 1946. However, its considerable efficacy against target species is offset by comparable toxicity to other mammals and, to a lesser extent, birds and its use as a general rodenticide was therefore severely curtailed by 1990. Currently, sodium fluoroacetate is licensed in the US for use against coyotes, which prey on sheep and goats, and in Australia and New Zealand to kill unwanted introduced species. The extreme toxicity of fluoroacetate to mammals and insects stems from its similarity to acetate, which has a pivotal role in cellular metabolism. Fluoroacetate combines with coenzyme A (CoA-SH) to form fluoroacetyl CoA, which can substitute for acetyl CoA in the tricarboxylic acid cycle and reacts with citrate synthase to produce fluorocitrate, a metabolite of which then binds very tightly to aconitase, thereby halting the cycle. Many of the features of fluoroacetate poisoning are, therefore, largely direct and indirect consequences of impaired oxidative metabolism. Energy production is reduced and intermediates of the tricarboxylic acid cycle subsequent to citrate are depleted. Among these is oxoglutarate, a precursor of glutamate, which is not only an excitatory neurotransmitter in the CNS but is also required for efficient removal of ammonia via the urea cycle. Increased ammonia concentrations may contribute to the incidence of seizures. Glutamate is also required for glutamine synthesis and glutamine depletion has been observed in the brain of fluoroacetate-poisoned rodents. Reduced cellular oxidative metabolism contributes to a lactic acidosis. Inability to oxidise fatty acids via the tricarboxylic acid cycle leads to ketone body accumulation and worsening acidosis. Adenosine triphosphate (ATP) depletion results in inhibition of high energy-consuming reactions such as gluconeogenesis. Fluoroacetate poisoning is associated with citrate accumulation in several tissues, including the brain. Fluoride liberated from fluoroacetate, citrate and fluorocitrate are calcium chelators and there are both animal and clinical data to support hypocalcaemia as a mechanism of fluoroacetate toxicity. However, the available evidence suggests the fluoride component does not contribute. Acute poisoning with sodium fluoroacetate is uncommon. Ingestion is the major route by which poisoning occurs. Nausea, vomiting and abdominal pain are common within 1 hour of ingestion. Sweating, apprehension, confusion and agitation follow. Both supraventricular and ventricular arrhythmias have been reported and nonspecific ST- and T-wave changes are common, the QTc may be prolonged and hypotension may develop. Seizures are the main neurological feature. Coma may persist for several days. Although several possible antidotes have been investigated, they are of unproven value in humans. The immediate, and probably only, management of fluoroacetate poisoning is therefore supportive, including the correction of hypocalcaemia.
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PMID:Sodium fluoroacetate poisoning. 1728 93

Incidence of human epilepsy in infants and children is high and prolonged seizures in the early developmental period can cause brain damage and lead to serious consequences later in the life. The present study was aimed to investigate potential protective effect of (R, S)-4-phosphonophenylglycine ((R, S)-PPG), a potent and selective group III mGluR agonist, on brain damage associated with homocysteic acid-induced seizures in immature 12-day-old rats. This compound does not exhibit any proconvulsive effect. Moreover, (R, S)-PPG was shown to protect NMDA and quinolinic acid-induced lesions in rats. Seizures were induced by bilateral intracerebroventricular (i.c.v.) infusion of homocysteic acid (DL-HCA, 600 nmol/side). (R, S)-PPG was given by bilateral i.c.v. infusions (5 nmol/side) at 15- to 20-min time intervals prior to administration of DL-HCA. After 1 or 6 days of survival, animals in all experimental groups (13-day-old and 18-day-old) were perfused transcardially under deep ether anaesthesia with heparinized normal saline and subsequently with the fixation solution (4% paraformaldehyde in the phosphate buffer, pH 7.4, both solutions at room temperature). Two histological methods were used in our study. Fluoro-Jade B dye is an anionic fluorescein derivative useful for the histological staining of neurons undergoing degeneration and staining with bis-benzimide (Hoechst 33342) was used to detect apoptotic cells according nuclei with condensed and/or fragmented DNA. Animals perfused 1 day after the treatment (13-day-old): After only (R, S)-PPG application, no obvious pathological changes were found. After only DL-HCA application, distinct destruction of the hippocampal region both in the dorsal and ventral hippocampus was observed. Particularly affected were cells in the CA1 and CA3 regions. In addition, neurons with segmented or fragmented nuclei were found in the granule cell layer of the dentate gyrus. (R, S)-PPG + DL-HCA administration resulted in a lower number of Fluoro-Jade B positive cells. All areas of the hippocampus were protected by (R, S)-PPG pre-treatment. Animals perfused 6 days after the treatment (18-day-old): In the group where only (R, S)-PPG has been applied, no obvious pathological changes were found in the hippocampal area. After only DL-HCA administration almost complete destruction of the hippocampal region both in the dorsal and ventral hippocampus was observed. Particularly affected were the cells in the CA1 and CA3 regions, granule cells of the dentate gyrus and many interneurons in all hippocampal areas. (R, S)-PPG + DL-HCA administration resulted in lower number of Fluoro-Jade B positive cells. All areas of the hippocampus have been protected by (R, S)-PPG pre-treatment. In conclusion, the present data support the hypothesis that (R, S)-PPG can have a beneficial effect in those disorders where excitotoxicity is one of the dominant pathogenetic mechanisms.
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PMID:Neuroprotective effect of (R, S)-4-phosphonophenylglycine against neuronal damage associated with homocysteic acid-induced seizures in immature rats. 1740 55

Status epilepticus may cause long-term functional and structural consequences possibly resulting in brain dysfunctions such as chronic epilepsy. In epileptogenesis, the dentate gyrus plays a key role in regulating the excitability of highly vulnerable and potentially epileptogenic downstream structures in the hippocampus proper. One, four and eight weeks after electrically induced status epilepticus, excitability and neuronal degeneration in the rat dentate gyrus were examined with intracerebral electrodes and Fluoro Jade (FJ) staining, respectively. Half of the animals had developed chronic epilepsy by 8 weeks after status epilepticus. Sham-operated controls did not exhibit seizures, and the excitatory parameters remained unchanged. Compared to controls, 8 weeks after status epilepticus the population spike latency in the dentate gyrus was significantly reduced (p<0.05) and substantial neuronal degeneration was seen (p<0.05). In summary, status epilepticus results in functional and morphological alterations in the dentate gyrus likely contributing to epileptogenesis.
Seizure 2008 Jan
PMID:Functional and morphological changes in the dentate gyrus after experimental status epilepticus. 1772 57


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