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)

Pregnenolone sulfate (PS) is an endogenous neurosteroid known to antagonize GABA(A) receptor-mediated inhibitory responses and potentiate NMDA receptor-mediated excitatory responses in vitro. To assess the actions of the steroid as a modulator of seizure susceptibility in vivo, PS (30-300 nmol) was administered intracerebroventricularly in mice. At doses of 50 to 150 nmol, PS elicited seizures characterized by head jerks, rearing and falling, severe forelimb and hindlimb clonus, opisthotonos and explosive running. The seizures increased in severity and frequency with time and eventually progressed to status epilepticus, tonic hindlimb extension and death. The doses producing convulsions in 50% (CD(50)) and 97% (CD(97)) of animals were 92 and 205 nmol, respectively. A subconvulsant dose of PS (50 nmol) significantly increased the convulsant potencies of systemically administered pentylenetetrazol (30-50 mg/kg) and NMDA (50-100 mg/kg). Systemically administered PS at doses as high as 100 mg/kg failed to induce seizures or alter the convulsant potencies of pentylenetetrazol and NMDA. Protection against PS (205 nmol)-induced seizures and lethality was conferred by the GABA(A) receptor positive allosteric modulators clonazepam and allopregnanolone, and by the NMDA receptor antagonists dizocilpine and (R)-CPP. The overall pharmacological profile suggests that the convulsant actions of PS are mediated predominantly via its effects on GABA(A) receptors, and also possibly by effects on NMDA receptors.
 ...
PMID:Convulsant actions of the neurosteroid pregnenolone sulfate in mice. 1041 90

We have previously shown that NMDA receptor activation during status epilepticus (SE) is required to produce epilepsy in in vitro and in vivo models. As in human symptomatic epilepsy, the epilepsy in these models is permanent, suggesting that the pathological activation of NMDA receptors causes permanent plasticity changes in the brain. Ca(2+) influx through NMDA receptors is known to transiently activate a key transcription factor, serum response factor (SRF). Thus, we investigated whether this factor, in terms of its expression and ability to bind to the consensus serum response element, was altered long term in the pilocarpine model of epilepsy. In hippocampal nuclear extracts, SRF binding to DNA was significantly increased over saline-injected control rats at 24 hr and at 8 weeks after the onset of SE. This increase was shown to be the result of significantly elevated levels of SRF. DNA binding was also persistently increased in the cortical, but not in the cerebellar, extracts. Hippocampal expression of SRF was localized to neurons using immunohistochemistry. NMDA receptor activation during SE was required for these changes to take place, and the spontaneous seizures seen in epileptic rats did not appear to be responsible for the increase in SRF. The results demonstrate that SRF is persistently elevated after SE in the pilocarpine model of epilepsy and support the theory that long-term gene changes in this model occur and are associated with the long-lasting plasticity changes that are initiated during epileptogenesis.
 ...
PMID:Persistent increased DNA-binding and expression of serum response factor occur with epilepsy-associated long-term plasticity changes. 1049 24

Severe temporal lobe epilepsy in humans is often associated with loss of neurons in the hippocampus and memory deficits. In Experiment 1, 60 min of continuous electrical stimulation of the perforant path sufficient to produce seizures resembling status epilepticus and loss of hilar and pyramidal cells in the hippocampus, produced a deficit in spatial mapping in the Morris water tank. In particular, the previously stimulated rats took longer and swam farther to find a hidden, but not a visually cued, platform, and, in contrast to the unstimulated control rats, were not disrupted by movement of the platform to a new location. In Experiment 2, a single injection of the non-competitive NMDA receptor antagonist, MK-801 (1.0 mg/kg), just prior to the perforant path stimulation reduced the seizures, hippocampal neuronal loss, and deficit in spatial mapping. These data suggest that temporal lobe seizures can induce deficits in spatial memory by selectively destroying neurons within the hippocampus, and that the mechanism by which this occurs involves the activation of NMDA receptors, and, perhaps, consequent excitotoxicity.
 ...
PMID:Perforant path stimulation in rats produces seizures, loss of hippocampal neurons, and a deficit in spatial mapping which are reduced by prior MK-801. 1062 30

NMDA receptor activation during status epilepticus (SE) has previously been shown to be required for epileptogenesis as well as the persistent upregulation of serum response factor (SRF) in the in vivo pilocarpine model of epilepsy. SRF is established as a regulator of the FosB gene which expresses FosB and DeltaFosB components of the AP-1 transcription factor complex. Therefore we investigated whether DeltaFosB expression and AP-1 DNA binding were also persistently elevated in pilocarpine-treated rats which chronically displayed spontaneous seizures. Using hippocampal nuclear extracts, DeltaFosB expression and AP-1 DNA binding were significantly elevated for up to one year in the epileptic animals. The expression of other fos and jun proteins was not persistently altered in epilepsy. Neuronal upregulation of DeltaFosB was correlated with regions of the brain that were involved in seizure generation and propagation. The increase in AP-1 DNA binding was shown to be dependent on NMDA receptor activation during SE. Hippocampal DeltaFosB immunostaining was seen predominately in the neuronal nuclei as opposed to other cell types. The data indicate that recurrent seizures which persistently occur in this model were not responsible for the increased DeltaFosB expression. Chronic DeltaFosB expression in epilepsy may be playing a role in the altered expression of other genes in this model and may be involved in some of the neuronal plasticity changes associated with epileptogenesis.
 ...
PMID:Chronic DeltaFosB expression and increased AP-1 transcription factor binding are associated with the long term plasticity changes in epilepsy. 1092 51

Substance P, which modulates synaptic excitability, can be induced by a variety of stimuli. We studied the expression of hippocampal substance P in rats in using lithium-pilocarpine model of status epilepticus during development. Status epilepticus resulted in an age-specific manner of substance P expression that was anatomically distinctive in hippocampal subfields. Maximal induction of substance P immunoreactivity was seen in the CA1 region of the two-week-old rats, and progressively decreased in the three-, four-week-old rats and adults. Meanwhile, the number of substance P-immunoreactive neurons in the CA3 region and dentate granule cell layer was minimal in the two-week-old animals, but approximated the adult level in the three- and four-week-old rats. No substance P-immunoreactive axon terminals were seen in the strata pyramidale and lucidum in the CA3 region of the two-week-old rats, but they were found to progressively increase in the three-, four-week-old rats and adults. To confirm substance P expression after status epilepticus, we studied the expression of preprotachykinin-A mRNA in the hippocampus of the three-week-old rats by in situ hybridization. Two hours following injection of lithium-pilocarpine, preprotachykinin-A mRNA dramatically increased in the granule cells, as well as in the CA3 and CA1 pyramidal cell layers of the hippocampus. To evaluate the relationship between behavioral seizures and substance P induction, we used the NMDA receptor antagonist MK-801. Injection of MK-801 completely blocked lithium-pilocarpine-induced behavioral seizures and SP induction in the two-week-old rats. These results indicate that seizure activity selectively evokes age-dependent and region-selective expression of substance P.
 ...
PMID:Patterns of status epilepticus-induced substance P expression during development. 1107 53

Systemic administration of kainic acid (KA) induces status epilepticus (SE) that causes neurodegeneration and may subsequently lead to spontaneous recurrent seizures. We investigated the effects of KA-induced SE on tyrosine phosphorylation and solubility properties of the NMDA receptor. Following 1 h of SE, total protein tyrosine phosphorylation was elevated in both the hippocampus and frontal cortex relative to controls. Tyrosine phosphorylation of the NMDA receptor subunits NR2A and NR2B was also enhanced following SE. Animals that received KA but did not develop SE, did not exhibit increased tyrosine phosphorylation. SE resulted in a decrease in the solubility of NMDA receptor subunits and of PSD-95 in 1% deoxycholate. In contrast, the detergent solubility of AMPA and kainate receptors was not affected. These findings demonstrate that SE alters tyrosine phosphorylation of the NMDA receptor, and indicate that the interaction of the NMDA receptor with other components of the NMDA receptor complex are altered as a consequence of seizure activity.
 ...
PMID:Seizure activity results in increased tyrosine phosphorylation of the N-methyl-D-aspartate receptor in the hippocampus. 1168 75

A paired-pulse (PP) stimulation protocol was used to examine changes in field potentials (fEPSPs), locally evoked in CA1 via Schaffer/ commissural fiber stimulation and in the dentate gyrus (DG) through angular bundle stimulation, in freely moving epileptic rats. This epilepsy model is characterized by recurrent spontaneous seizures that occur after a latent period of 1-2 weeks following an electrically induced status epilepticus (SE). In the control period, i.e., before induction of SE, the PP stimulation protocol given at the appropriate intensity evoked fEPSPs with a pronounced paired-pulse depression (PPD). In the acute period, immediately after SE, the fEPSPs in the CA1 and DG areas were generally depressed. During the latent period in the CA1 stratum radiatum, the negative fEPSP was followed by a large positive potential that remained for the rest of the recording period. CA1 PPD, observed during the control period, was changed to paired-pulse facilitation (PPF) that remained for the rest of the recording period. Also during the latent period, a broad late component appeared in DG fEPSPs. The initial decrease in PPD was partly restored in the following weeks. Timm staining at different time points after SE showed an increase of mossy-fiber sprouting in the inner molecular layer within 6 days, which was robust within 6 weeks. We noted Timm granules positioned on parvalbumin immunoreactive neurons in the granule-cell layer of rats that had survived SE, suggesting that restoration of PPD could be partly due to reinnervation of a population of GABAergic neurons. The broad late component of DG fEPSPs, which was sensitive to the NMDA receptor antagonist ketamine, was still present for at least 6 weeks into the chronic epileptic phase, indicating lasting increased excitability. These observed changes indicate a lasting increased excitability in CA1 and DG networks that could play a role in the recurrence of spontaneous seizures.
 ...
PMID:Long-lasting increased excitability differs in dentate gyrus vs. CA1 in freely moving chronic epileptic rats after electrically induced status epilepticus. 1209 83

Most patients with temporal lobe epilepsy (TLE), the most common type of epilepsy, show pronounced loss of neurons in limbic brain regions, including the hippocampus. The massive neurodegeneration in the hippocampus is known as hippocampal sclerosis, and is considered one of the hallmarks of this type of difficult-to-treat epilepsy. There is a long and ongoing debate on whether this sclerosis is the result of an initial pathological event, such as a status epilepticus (S.E.), stroke or head trauma, which often precedes the development of TLE, or is caused by the spontaneous recurrent seizures (SRS) once epilepsy has developed. At present, pharmacological prevention of limbic sclerosis is not available. In a clinical situation, such prevention would only be possible if delayed cell death developing after an initial pathological event is involved. Assuming that sclerotic brain lesions provoke epileptogenesis and that delayed cell death is involved in these lesions, it should be possible to prevent both the lesions and the epilepsy by a prophylactic treatment after an initial insult such as an S.E. In order to test this hypothesis, we used a rat model of TLE in which limbic brain lesions and epilepsy with SRS develop after a kainate-induced S.E. A single low dose of the N-methyl-D-aspartate (NMDA) receptor blocker dizocilpine (MK-801) significantly reduced the damage in limbic regions, including the hippocampus and piriform cortex, and completely protected several rats from such damage when given after an S.E. of 90 min induced by kainate, strongly suggesting that delayed cell death is involved in the damage. This was substantiated by the use of molecular and immunohistochemical markers of delayed active ("programmed") cell death. However, the neuroprotection by dizocilpine did not prevent the development of SRS after the S.E., suggesting that structures not protected by dizocilpine may play a role in the genesis of SRS or that epileptogenesis is not the consequence of structural lesions in the limbic system. The only brain regions that exhibited neuronal damage in all rats with SRS were the hilus of the dentate gyrus and the mediodorsal thalamus, although treatment with dizocilpine reduced the severity of damage in the latter region. The data indicate that NMDA receptor blockade immediately after a prolonged S.E. is an effective means to reduce the damage produced by a sustained S.E. in several brain regions, including the hippocampus, but show that this partial neuroprotection of the limbic system does not prevent the development of epilepsy.
 ...
PMID:N-methyl-D-aspartate receptor blockade after status epilepticus protects against limbic brain damage but not against epilepsy in the kainate model of temporal lobe epilepsy. 1271 Sep 80

X11 alpha or Mint1 is a protein containing an N-terminal sequence, which binds to Munc-18 protein, a middle phosphotyrosine-binding domain (PTB) and two C-terminal PDZ (Post-synaptic density/Discs large/Zone Occludens-1) domains. The PDZ domains, which mediate protein-protein interactions have been shown to be involved in the organization of synaptic signaling pathways. Mint1 plays an important role in vesicle synaptic transport toward the active zone at the pre-synaptic site, and also participates in the transport of NR2B subunit of the NMDA receptor, to the post-synaptic site. To investigate the participation and distribution of this protein in the hippocampal subfield of rats submitted to the pilocarpine model of epilepsy, Mint1 was analyzed using Western blotting and immunohistochemistry. Animals of 5 h of status epilepticus showed decreased levels of this protein in the hippocampus when compared to the control animals. In contrast, animals from seizure-free period (silent group) and during spontaneous seizures phase (chronic group) showed increased Mint1 immunostaining in all hippocampal subfields, mainly in the dentate gyrus, when compared to the control group. The blotting confirmed the results obtained by immunohistochemistry. The present work suggests that Mint1 may be related to hippocampal plasticity during epileptogenesis in the pilocarpine model of temporal lobe epilepsy.
 ...
PMID:Levels of the synaptic protein X11 alpha/mint1 are increased in hippocampus of rats with epilepsy. 1470 32

Three different classes of NMDA receptor antagonists were compared for their effectiveness in terminating prolonged status epilepticus (SE), induced by continuous hippocampal stimulation. Animals were treated after 150 min of SE by intraperitoneal administration of increasing doses of 3-((R,S)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), MK-801 (dizocilpine), ifenprodil, or saline. EEG recordings were used to determine seizure termination. The first experiment (n = 57 animals) determined the most effective anticonvulsant dose of each agent by determining its ability to terminate SE within the next 300 min. Five control rats treated with normal saline after 150 min of SE continued to exhibit continuous seizures for the next 300 min. All drugs were administered after 150 min of SE. CPP terminated seizures with an ED(50) of 6.4 mg/kg; the maximal effective dose was 15 mg/kg. MK-801 has an ED(50) of 1.4 mg/kg; the maximal effective dose was 2 mg/kg. Ifenprodil was maximally effective at 30 mg/kg. However, an ED(50) could not be calculated. In a subsequent experiment, the NMDA antagonists were compared for their ability to terminate prolonged SE within 60 min of their administration at the most effective dose. MK-801 (2.0 mg/kg) terminated SE in 6 of 10 animals within 60 min, CPP (15 mg/kg) terminated it in 1 of 9 animals; ifenprodil (30 mg/kg) did not terminate it in any of 9 animals treated. In the 300 min following administration, CPP (6/9) and MK-801 (6/10) were equally efficacious in terminating SE but ifenprodil (2/7) was less effective (P = 0.065, chi-square test). The results indicate that the non-competitive NMDA receptor antagonist MK-801 was superior to the competitive antagonist CPP and the pH-sensitive site antagonist ifenprodil, in terminating prolonged experimental SE.
 ...
PMID:A comparison of three NMDA receptor antagonists in the treatment of prolonged status epilepticus. 1513 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>