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)

Several recent studies have shown that the multidrug transporter P-glycoprotein (PGP) is over-expressed in endothelial cells from brain blood vessels of patients with refractory temporal lobe epilepsy (TLE), suggesting that altered drug permeability across the blood-brain barrier (BBB) may be involved in pharmacoresistance to antiepileptic drugs (AEDs). Furthermore, over-expression of PGP has been found in astrocytes of epileptogenic tissue. However, it is not known in which regions of the temporal lobe PGP over-expression occurs and whether the over-expression is a result of uncontrolled seizures, of the mechanisms underlying epilepsy, or of chronic administration of AEDs. In the present study, we used the rat kainate model of TLE to study the time-course of PGP expression in capillary endothelium and parenchyma of the hippocampus and several other limbic brain regions thought to be involved in TLE. Kainate was administered at a dose which produced a generalized convulsive status epilepticus (SE), which was limited to a duration of 90 min by diazepam. PGP was detected by immunohistochemistry either 24 h or 10 days after SE, using a monoclonal PGP antibody. In both kainate-treated rats and controls, PGP staining was observed mainly in microvessel endothelial cells and, to a much lesser extent, in parenchymal cells. Twenty-four hours after SE, significant increases in PGP expression were determined in endothelial cells of the dentate gyrus and in parenchymal cells of the CA1 and CA3 sectors of the hippocampus. Furthermore, increased PGP expression was observed in the amygdala, piriform, and parietal cortex, but not in the substantia nigra. Ten days after the kainate-induced SE, except for an increase in parenchymal PGP expression in the dentate hilus and CA1 sector, no significant differences to controls were determined, indicating that most PGP increases seen 24 h after SE were only transient. The data indicate that PGP over-expression is a transient result of seizures and occurs in several regions of the temporal lobe. Seizure-induced over-expression of PGP in capillary endothelial cells of the BBB is likely to reduce the penetration of AEDs into brain parenchyma, which could explain the drug-refractoriness of seizures in TLE.
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PMID:Transient increase of P-glycoprotein expression in endothelium and parenchyma of limbic brain regions in the kainate model of temporal lobe epilepsy. 1239 76

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.
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PMID:Neuronal expression of the drug efflux transporter P-glycoprotein in the rat hippocampus after limbic seizures. 1470 87

There is recent evidence that increased expression of multidrug transporters, such as P-glycoprotein (P-gp), may lead to reduced antiepileptic drug (AED) concentrations in the brain, shortly after status epilepticus (SE), thereby suggesting a possible mechanism for drug-resistance. To get insights on whether increased P-gp expression is a consequence of the initial insult, or evolves more gradually as a result of recurrent spontaneous seizures, we used a rat model of temporal lobe epilepsy in which spontaneous seizures develop after an electrically induced SE. We investigated the temporal and region-specific expression of two isoforms of the multidrug resistance gene (mdr1a and mdr1b, both encoding for P-gp) in two regions within the temporal lobe (the dentate gyrus (DG) and the parahippocampal cortex (PHC)). Using real-time PCR, we found that the mdr1b isoform was increased in the temporal lobe, 1 week after SE; however, this increase was reversible in dentate gyrus while it persisted in the parahippocampal cortex of chronic epileptic rats. Mdr1b upregulation was related to the occurrence of spontaneous seizures, since this isoform was unchanged in rats that were stimulated, but that did not develop SE (non-SE). The mdr1a isoform was transiently upregulated in the dentate gyrus. P-gp immunostaining was enhanced in endothelial and glia-like cells, 1 week after SE. In chronic epileptic rats, the number of strongly P-gp positive glia-like cells was much lower than 1 week after SE, and it was mainly present in the most ventral part of the temporal lobe. These cells were in close apposition to strongly stained blood vessels. These findings show that both mdr1a and mdr1b are induced by SE, although the increase in mdr1b isoform was more persistent. More importantly, increased P-gp expression is still present in chronic epileptic rats.
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PMID:Selective and persistent upregulation of mdr1b mRNA and P-glycoprotein in the parahippocampal cortex of chronic epileptic rats. 1538 May 64

Medical intractability, i.e. the absence of any response to anti-epileptic drug (AED) therapy, is an unresolved problem in many patients with epilepsy. Mechanisms of intractability are not well understood, but may include alterations of pharmacological targets and poor penetration of AEDs into the brain because of increased expression of multiple drug-resistance proteins, such as P-glycoprotein (Pgp; ABCB1), capable of active brain extrusion of various drugs, including AEDs. Increased expression of Pgp has been reported in brain tissue of patients with refractory epilepsy, but there is a lack of adequate controls, i.e. brain tissue from patients with drug-responsive epilepsy. In the present study, we used a rat model of temporal lobe epilepsy to examine whether AED responders differ from non-responders in their expression of Pgp in the brain. In this model, spontaneous recurrent seizures develop after 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 (n = 7) and non-responders (n = 4). Pgp expression was studied by immunohistochemistry and showed striking overexpression in non-responders compared with responders in limbic brain regions, including the hippocampus. The Pgp overexpression was confined to brain capillary endothelial cells which form the blood-brain barrier. The present data are the first to demonstrate that rats with drug-resistant spontaneous seizures differ from rats with drug-responsive seizures in their Pgp expression in the brain, thereby substantiating the multidrug transporter hypothesis of intractable epilepsy.
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PMID:Multidrug resistance in epilepsy: rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures. 1571 4

Multidrug resistance proteins (MRPs; symbol ABCC) are membrane glycoproteins that mediate the ATP-dependent export of a wide range of substrates from cells and thereby affect the bioavailability and disposition of many drugs. MRP2 (ABCC2) is expressed on the apical domain of hepatocytes, enterocytes of the proximal small intestine, and proximal renal tubular cells, but its location in the brain is a matter of debate. Most previous studies failed to determine MRP2 mRNA or protein in the brain or cell preparations from the brain of different species including humans. Based on our previous experience with the drug efflux transporter P-glycoprotein, we evaluated whether the immunohistochemical determination of MRP2 expression is sensitive to fixation and staining variables. Furthermore, we examined whether the MRP2 protein is overexpressed after experimentally induced seizures in rats, using the pilocarpine model of temporal lobe epilepsy. The MRP2 expression in the liver was used as positive control. MRP2 deficient TR- rats were used as negative controls. Despite various modifications in tissue fixation and immunohistochemical staining as well as use of different commercially available MRP2 antibodies, we never observed any unequivocal MRP2 staining in the brain of normal rats. However, after a pilocarpine-induced convulsive status epilepticus, clear MRP2 staining became visible in brain capillary endothelial cells and, less frequently, perivascular astroglia and neurons in various brain regions. In view of our recent data on brain access of antiepileptic drugs in MRP2 deficient TR- rats, seizure-induced over-expression of MRP2 in the blood-brain barrier is likely to impair drug penetration into the brain, thereby contributing to drug resistance in epilepsy.
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PMID:Expression of the multidrug transporter MRP2 in the blood-brain barrier after pilocarpine-induced seizures in rats. 1650 77

Recent studies have suggested that overexpression of the multidrug transporter P-glycoprotein (P-gp) in the hippocampal region leads to decreased levels of antiepileptic drugs and contributes to pharmacoresistance that occurs in a subset of epileptic patients. Whether P-gp expression and function is affected in other brain regions and in organs that are involved in drug metabolism is less studied. Therefore, we investigated P-gp expression in different brain regions and liver of chronic epileptic rats, several months after electrically induced status epilepticus (SE), using Western blot analysis. P-gp function was determined by measuring phenytoin (PHT) levels in these brain regions using high-performance liquid chromatography, in the absence and presence of a P-gp-specific inhibitor, tariquidar (TQD). In addition, the pharmacokinetic profile of PHT was determined. PHT concentration was reduced by 20 to 30% in brain regions that had P-gp overexpression (temporal hippocampus and parahippocampal cortex) and not in brain regions in which P-gp expression was not changed after SE. Inhibition of P-gp by TQD significantly increased the PHT concentration, specifically in regions that showed P-gp overexpression. Despite increased P-gp expression in the liver of epileptic rats, pharmacokinetic analysis showed no significant change of PHT clearance in control versus epileptic rats. These findings show that overexpression of P-gp at the blood-brain barrier of specific limbic brain regions causes a decrease of local PHT levels in the rat brain.
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PMID:Region-specific overexpression of P-glycoprotein at the blood-brain barrier affects brain uptake of phenytoin in epileptic rats. 1739 2

Increased expression of drug efflux transporters at the blood-brain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-d-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders.
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PMID:Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling. 1831 94

Refractory status epilepticus (RSE) is a major medical emergency, defined as severe form of SE that does not respond to first (benzodiazepines) and second (phenytoin, phenobarbital) treatment efforts with antiepileptic drugs (AEDs). Understanding the mechanisms of RSE is important to prevent or reverse its development. Based on both clinical experience and data from rat models of SE, seizures that last more than 30 min become very hard to control by AEDs. Experimental studies have shown that the prolonged seizures of SE lead to progressive alterations of GABAA receptors, including reduced surface expression of these receptors by receptor trafficking, which would explain the loss of efficacy of benzodiazepines. In addition to AED target alterations, SE-induced overexpression of drug efflux transporters, such as P-glycoprotein (Pgp), in the brain may be involved in the resistance to AEDs (including phenytoin and phenobarbital) that are Pgp substrates. However, recent experiments of our group did not indicate that Pgp plays any important role in drug resistance of SE. Improved understanding the molecular mechanisms underlying AED resistance in SE will ultimately provide new treatment options for RSE.
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PMID:Mechanisms of drug resistance in status epilepticus. 1833 7

About 30% of patients with epilepsy do not respond adequately to drug therapy, making pharmacoresistance a major problem in the treatment of this common brain disorder. Mechanisms of intractability are not well understood, but may include limitation of antiepileptic drug access to the seizure focus by overexpression of the drug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier. Increased expression of Pgp has been determined both in epileptogenic brain tissue of patients with intractable epilepsy and in rodent models of temporal lobe epilepsy, including the pilocarpine model. The mechanisms underlying the increase of Pgp after seizures are unclear. We have recently suggested that the excitatory neurotransmitter glutamate, which is excessively released by seizures, is involved in the seizure-induced overexpression of Pgp in the brain. This hypothesis was evaluated in the present study in the pilocarpine model in rats. After 90 min of status epilepticus (SE), diazepam was administered, followed by either vehicle or the glutamate receptor antagonist MK-801 (dizocilpine). Following SE in vehicle treated rats, Pgp expression in brain capillary endothelial cells increased about twofold in the hippocampus, which was completely prevented by MK-801. Furthermore, neurodegeneration developing in the hippocampus and parahippocampal regions was reduced by the glutamate antagonist. In contrast, the Pgp inhibitor tariquidar did not affect the SE-induced overexpression of Pgp or neurodegeneration in most regions examined. The data indicate that seizure-induced glutamate release is involved in the regulation of Pgp expression, which can be blocked by MK-801. The finding that MK-801 counteracts both Pgp overexpression and neuronal damage when administered after SE may offer a clinically useful therapeutic option in patients with refractory SE.
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PMID:Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain. 1839 57

Status epilepticus (SE) is a neurological emergency, characterized by continuous or intermittent seizures without full recovery of consciousness between seizures, which can result in death or neurological sequelae. In about one third of patients, SE is unresponsive to sequential treatment with first- and second-line antiepileptic drugs (AEDs). At least in part, this drug resistance may be due to AED target alterations induced by SE, such as reduced membrane expression of GABA(A) receptors. Apart from target alterations by receptor trafficking, SE is known to increase the brain expression of drug efflux transporters such as P-glycoprotein (Pgp), which might reduce concentrations of AEDs at their brain targets. However, it is not known whether overexpression of Pgp develops rapidly enough after onset of SE to be of any functional consequence for drug treatment. Therefore, we studied whether overexpression of Pgp at the blood-brain barrier is involved in refractory SE. Two rat SE models were used, the lithium/pilocarpine model and induction of SE by sustained electrical stimulation of the basolateral amygdala (BLA). Four AEDs, diazepam (DZP), phenobarbital (PB) and phenytoin (PHT) or fosphenytoin (FPHT) were administered at different times after onset of SE. In the pilocarpine model, once self-sustained SE was established, none of the AEDs alone was effective in terminating SE, but sequential injection of PB and DZP stopped SE. Administration of the Pgp inhibitor tariquidar did not prevent or counteract resistance to AEDs. In the BLA model, DZP and PB terminated SE in the majority of rats, whereas PHT or FPHT were ineffective. Immunohistochemical staining of Pgp did not indicate any increase of Pgp expression in brain capillary endothelial cells during SE, whereas significant overexpression was determined in both models 48 h after SE. The data suggest that, at least under the conditions of the present study, alterations in Pgp are not critically involved in refractory SE.
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PMID:Resistance to antiepileptic drugs and expression of P-glycoprotein in two rat models of status epilepticus. 1876 Sep 5


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