Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038220 (status epilepticus)
 7,272 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The temporal evolution of irreversible neuronal damage from pilocarpine-induced seizures was studied by light microscopy. Neuronal cell death was judged on a 0-3 scale by estimating the percentage of acidophilic neurons in each of 23 brain regions. In addition, in the dorsal dentate hilus (CA4), quantitative cell counts of normal and acidophilic neurons were also performed. A few dead neurons (grade 0.5 damage) appeared in ventral hippocampal CA1 and CA3 regions after 20-min status epilepticus (SE). Slight-to-mild damage (grades 0.5-1.5) occurred in 14 and 12 brain regions after 40-min and 1-h SE respectively, and slight-to-moderate damage (grades 0.5-2.0) was found in 15 regions after 3-h SE. Twenty-four h and 72 h after 3-h SE, there was slight-to-severe damage (grade 0.5-3.0) in 22 and 21 regions respectively. Three-h SE produced more severe damage to 7 brain regions compared to 1-h SE, and 16 regions had more pronounced neuronal injury 24 h after rather than 0-4 h after 3-h SE. Eight brain regions had less damage 72 h compared to 24 h after SE, probably because of progressive neuronal lysis and dropout, but in mediodorsal and lateroposterior thalamic nuclei damage worsened from 24 to 72 h after SE. Neuronal cell counting revealed 20% acidophilic neurons in dorsal dentate hilus after 40-min SE and no difference between the 1-h and 3-h seizure groups (31% vs. 43% acidophilic neurons respectively). Among the 3 groups of rats with 3-h SE and varying recovery periods, the 24-h and 72-h recovery groups had higher percentages of acidophilic neurons (65% and 54% respectively) than the 0-4-h group (43%). Finally, the hippocampal CA2 region and dentate granule cell layer and the caudate-putamen, considered resistant to seizure-induced cell injury, were all damaged from SE lasting 40 min or more.
 ...
PMID:The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. 882 81

We studied the time course and possible mechanisms of the development of chronic epilepsy following unilateral stimulation of the perforant path. After 24 h of perforant path stimulation by a modified Sloviter method, lesions were restricted to the hippocampus, except for 2 of 24 rats with minimal entorhinal neuronal injury in layer 3. Lesions were exclusively ipsilateral in the polymorph layer of the hilus and in CA4-CA3C, predominantly ipsilateral in CA3, in CA1 and in the granule cell layer. Feedforward and feedback inhibition were studied by paired pulse stimulation. In the week following inhibition, there was complete loss of GABAA-mediated, short interstimulus interval (ISI)-dependent inhibition and frequency-dependent inhibition, and also of GABAB-mediated long ISI-dependent inhibition. Yet no spontaneous seizures were observed at that time. In the next four weeks, we saw no evidence of increasing excitatory drive such as would be expected from recurrent mossy fiber sprouting. On the contrary, there was progressive return of inhibition. By four weeks post-lesion, the majority of animals had developed spontaneous recurrent seizures, and/or seizures on 2 Hz stimulation (never seen in controls), in spite of complete or near-complete recovery of short ISI-dependent, GABAA-mediated inhibition. A small but significant loss of frequency-dependent inhibition persisted, but individual animals with complete recovery of frequency-dependent inhibition showed spontaneous seizures, suggesting that loss of GABAA-mediated inhibition was not the direct cause of chronic epilepsy. GABAB-mediated, long ISI-dependent inhibition continued to show a significant loss. The ratio of the population spike amplitude at 250 microA to the maximal population spike amplitude, a measure of granule cell excitability, was unchanged immediately after stimulation, but increased in the next few weeks in a manner identical to that seen in kindling, suggesting the possibility that during the transient loss of inhibition, spontaneous kindling had occurred. Intracellular recordings from granule cells in hippocampal slices prepared from these animals showed a significant loss of GABAB-mediated slow inhibitory postsynaptic potentials (IPSPs). These data show that the sequellae of unilateral status epilepticus with damage restricted to the hippocampus are sufficient to cause chronic recurrent seizures. There is a possibility that chronic epilepsy is not the direct result of the loss of inhibitory drive or of a sprouting-induced increase in excitatory drive, but represents plastic changes akin to spontaneous kindling, possibly facilitated by loss of GABAB-mediated inhibition.
 ...
PMID:Chronic epilepsy with damage restricted to the hippocampus: possible mechanisms. 898 5

Kainic acid-induced multifocal status epilepticus in the rat is a model of medically intractable complex partial seizures and neurotoxicity. The exact mechanisms of kainic acid epileptogenic and neurotoxic effects are unknown, but enhanced glutamate release seems to be an important factor. PNU-151774E ((S)-(+)-2-(4-(3-fluorobenzyloxy) benzylamino) propanamide, methanesulfonate) is a broad-spectrum new anticonvulsant with Na+ channel-blocking and glutamate release inhibiting properties. We have examined the effect of pretreatment with this compound on both seizure activity and hippocampal neuronal damage induced by systemic injection of kainic acid in rats. Lamotrigine, a recently developed anticonvulsant with similar glutamate release inhibitory properties, was tested for comparison, together with diazepam as reference standard, on the basis of its anticonvulsant and neuroprotectant properties in this animal model. PNU-151774E, lamotrigine (10, 30 mg/kg; i.p.) and diazepam (20 mg/kg; i.p.) were administered 15 min before kainic acid (10 mg/kg; i.p.). In the vehicle-treated group, kainic acid injection caused status epilepticus in 86% of animals. Hippocampal neuronal cell loss was 66% in the CA4 hippocampal area at 7 days after kainic acid administration. Diazepam inhibited both seizures and neurotoxicity. Lamotrigine reduced hippocampal neuronal cell loss at both doses, even when it did not protect from seizures, although it showed a trend toward protection. On the other hand PNU-151774E protected from both hippocampal neurodegeneration and status epilepticus. Thus, these data support the concept that seizure prevention and neuroprotection might not be tightly coupled. Glutamate release inhibition may play a major role in neuroprotection, but an additional mechanism(s) of action might be relevant for the anticonvulsant activity of PNU-151774E in this model.
 ...
PMID:PNU-151774E protects against kainate-induced status epilepticus and hippocampal lesions in the rat. 983 Dec 89

There is considerable controversy whether aberrant fascia dentata (FD) mossy fiber sprouting is an epiphenomena related to neuronal loss or a pathologic abnormality responsible for spontaneous limbic seizures. If mossy fiber sprouting contributes to seizures, then reorganized axon circuits should alter postsynaptic glutamate receptor properties. In the pilocarpine-status rat model, this study determined if changes in alpha amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and n-methyl-D-aspartic acid (NMDA) receptor subunit mRNA levels correlated with mossy fiber sprouting. Sprague-Dawley rats were injected with pilocarpine (320 mg/kg; i.p.) and maintained in status epilepticus for 6 to 8 hours (pilocarpine-status). Rats were killed during the: (1) latent phase after neuronal loss but before spontaneous limbic seizures (day 11 poststatus; n = 7); (2) early seizure phase after their first seizures (day 25; n = 7); and (3) chronic seizure phase after many seizures (day 85; n = 9). Hippocampi were studied for neuron counts, inner molecular layer (IML) neo-Timm's staining, and GluR1-3 and NMDAR1-2b mRNA levels. Compared with controls, pilocarpine-status rats in the: (1) latent phase showed increased FD GluR3, NMDAR1, and NMDAR2b; greater CA4 and CA1 NMDAR1; and decreased subiculum GluR1 hybridization densities; (2) early seizure phase showed increased FD GluR3, increased CA1 NMDAR1, and decreased subiculum NMDAR2b densities; and (3) chronic seizure phase showed increased FD GluR2; increased FD and CA4 GluR3; decreased CA1 GluR2; and decreased subiculum GluR1, GluR2, NMDAR1, and NMDAR2b levels. In multivariate analyses, greater IML neo-Timm's staining: (1) positively correlated with FD GluR3 and NMDAR1 and (2) negatively correlated with CA1 and subiculum GluR1 and GluR2 mRNA levels. These results indicate that: (1) hippocampal AMPA and NMDA receptor subunit mRNA levels changed as rats progressed from the latent to chronic seizure phase and (2) certain subunit alterations correlated with mossy fiber sprouting. Our findings support the hypothesis that aberrant axon circuitry alters postsynaptic hippocampal glutamate receptor subunit stoichiometry; this may contribute to limbic epileptogenesis.
 ...
PMID:Hippocampal AMPA and NMDA mRNA levels correlate with aberrant fascia dentata mossy fiber sprouting in the pilocarpine model of spontaneous limbic epilepsy. 985 58

We have performed a detailed time-course analysis of cell death in the hippocampal formation, basal forebrain and amygdala following a single intraseptal injection of kainate in adult rats. Acetylcholinesterase histochemistry revealed a profound loss of staining in the medial septum but not in the diagonal band, and cholinergic fiber density was highly reduced in the hippocampus and amygdala at 10 days postinjection. Terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphatebiotin nick end labeling (TUNEL) histochemistry was performed for precise location of apoptotic cells. Both the medial septum and amygdala exhibited numerous TUNEL-positive nuclei after the intraseptal injection of kainate, while the lateral septum exhibited a lower but significant incidence in terms of apoptotic cells. In the medial septum, the presence of apoptotic cells was at a location displaying acetylcholinesterase staining. TUNEL histochemistry revealed a time-dependent sequential apoptotic cell death in hippocampal pyramidal cells. During the first two days postinjection, apoptosis in the hippocampus was only evident in the CA3 region. At five days postinjection, the entire CA4 region became apoptotic. At 10 days postinjection, the whole extent of the CA1 pyramidal cell layer exhibited numerous TUNEL-positive nuclei. The time-course of kainate-induced apoptosis in Ammons's horn correlated with the disappearance of hippocampal pyramidal neurons as detected by Nissl staining, which is suggestive of a prominent apoptotic death for these cells. The temporal delayed distant damage to CA4 and CA1 hippocampal subfields after a single intraseptal kainate injection is not seen in other models employing kainate and may be a valuable tool for exploring the cellular mechanisms leading to cell death in conditions of status epilepticus.
 ...
PMID:Delayed apoptotic pyramidal cell death in CA4 and CA1 hippocampal subfields after a single intraseptal injection of kainate. 1062 49

It is shown in the present study that metyrapone (100 mg/kg), an inhibitor of corticosterone synthesis, given twice, 30 min before and 6 h after kainic acid (10 mg/kg) administration, blocks the kainic acid-evoked induction of heat shock proteins 72 kDa (HSP 70). Specifically, it was observed that metyrapone completely prevented kainic acid-induced appearance of HSP 70 in the rat amygdala, habenula, parietal cortex, and significantly decreased the number of HSP 70-positive neurons in the CA1, CA3, and CA4 subregions of hippocampus. The reduction in HSP 70 induction was paralleled by a complete prevention of the kainic acid-induced rise in the circulating corticosterone level by metyrapone; however, in applied doses metyrapone evoked slight enhancement of blood corticosterone. Despite the fact that metyrapone blocked/attenuated the kainic acid-evoked induction of HSP 70, its administration did not affect the behavioral effects of kainic acid, regarded as "limbic status epilepticus." It is concluded that the blockade of corticosterone synthesis might have neuroprotective effects in the pathological states associated with the overstimulation of glutamatergic receptors.
 ...
PMID:Metyrapone, an inhibitor of corticosterone synthesis, blocks the kainic acid-induced expression of HSP 70. 1101 88

In the brain, the efflux transporter P-glycoprotein (Pgp) is predominantly located on the luminal membrane of endothelial cells lining brain microvessels and forming the blood-brain barrier. Many lipophilic drugs, including antiepileptic drugs, are potential substrates for Pgp. Overexpression of Pgp in endothelial cells of the blood-brain barrier has been determined in patients with drug resistant forms of epilepsy such as temporal lobe epilepsy and rodent models of temporal lobe epilepsy and suggested to lead to reduced penetration of antiepileptic drugs into the brain. Expression of Pgp after seizures has also been described in astrocytes, whereas it is not clear whether neurons can express Pgp. In the present study, Pgp expression was studied by immunohistochemistry in rats 24 h after a status epilepticus induced by either pilocarpine or kainate, widely used models of temporal lobe epilepsy. Unexpectedly, in addition to endothelial Pgp staining, intense Pgp staining was found in neurons in the CA3c/CA4 sectors and hilus of the hippocampus formation, but not in other brain regions examined. The neuronal Pgp staining was confirmed by two different Pgp antibodies. Double immunolabeling and confocal microscopy showed that Pgp was colocalized with the neuronal marker neuronal nuclear antigen, but not with the glial marker glial fibrillary acidic protein. No neuronal Pgp staining was seen in control rats. The expression of Pgp in neurons after limbic seizures was substantiated by determining Pgp encoding genes (mdr1a, mdr1b) in neurons by real time quantitative RT-PCR. Increased Pgp expression in hippocampal neurons is likely to affect the action of drugs with intraneuronal targets and, in view of recent evidence from other cell types, could be associated with prevention of apoptosis which is involved in neuronal damage developing after seizures such as produced by pilocarpine.
 ...
PMID:Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures. 1470 87

This report describes a previously healthy 28 year old patient with a 5 month period of intractable generalised status epilepticus (SE) of unknown aetiology with fatal outcome. Repeated magnetic resonance imaging (MRI) showed no pre-existing abnormality, but did show progressive cortical and hippocampal atrophy and T2 hyperintensity in both hippocampal formations, suggestive of progressive tissue damage. Post-mortem histopathological analysis revealed substantial neuronal cell loss including CA1 and CA4 sectors of the hippocampus compatible with bilateral hippocampal sclerosis. There was no evidence of systemic complications including arterial hypotension and hypoxia, hypoglycaemia, hyperpyrexia, or other confounding factors to account for these findings. This case provides further evidence of SE induced hippocampal damage in humans.
 ...
PMID:Evolution of MRI changes and development of bilateral hippocampal sclerosis during long lasting generalised status epilepticus. 1514 10

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.
 ...
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 disabling seizures associated with mesial temporal lobe epilepsy (TLE) are often resistant to antiepileptic drugs (AEDs). The biological basis of this refractoriness is unknown but may include alterations in AED targets in the epileptogenic brain tissue, reduced AED penetration to the seizure focus, and neuropathological brain alterations such as hippocampal sclerosis typically found in patients with refractory TLE. In the present study, we used a rat model of TLE to examine whether AED responders differ from non-responders in their structural alterations and GABA(A) receptor characteristics in the hippocampal formation. In this model, spontaneous recurrent seizures develop after a status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video/EEG monitoring before, during, and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders and non-responders. The severity or duration of the initial brain insult (the status epilepticus) did not differ between responders and non-responders, indicating that the difference between the two subgroups is genetically determined. Subsequent histological examination showed a significant loss of neurons in the CA1, CA3c/CA4, and dentate hilus of non-responders, whereas responders did not differ in this respect from non-epileptic controls. The morphological alterations in the non-responders were associated with striking alterations in autoradiographic imaging of diazepam-sensitive and diazepam-insensitive GABA(A) receptor binding in the dentate gyrus with a significant shift to enhanced diazepam-insensitive binding. The present data indicate that neurodegeneration and associated GABA(A) receptor changes in the dentate gyrus are critically involved in the mechanisms underlying refractoriness of seizures in TLE.
 ...
PMID:Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. 1625 58


<< Previous 1 2 3 Next >>