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)

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

The variability of P-glycoprotein expression in individuals is linked to a C3435T polymorphism of the multidrug-resistance 1 (MDR1) gene, and the CC genotype at the C3435T polymorphism was reported to be associated with multidrug resistance in epilepsy patients. Since population frequencies of polymorphic genes depend on ethnic specificity, we investigated functional significance of the C3435T polymorphism of the MDR1 gene in Korean epilepsy patients. One hundred and eight patients with drug-responsive epilepsy, 63 patients with drug-resistant epilepsy, and 219 control migraine subjects were studied, but the analysis for C3435T allele showed no significant association between the CC genotype and the multidrug-resistant epilepsy. We suggest that influence of the C3435T polymorphism in the multidrug-resistant epilepsy may not be significant in Korean populations and further investigations in various ethnic populations would be necessary to clarify the effect of C3435T polymorphism on the mutidrug resistance in epilepsy patients.
Seizure 2006 Jul
PMID:Lack of association between C3435T nucleotide MDR1 genetic polymorphism and multidrug-resistant epilepsy. 1654 58

We examined the blood-brain barrier (BBB) function in methylazoxymethanol acetate (MAM)-treated rats, a model of human developmental brain malformations. We found aberrant vessels morphology and serum albumin leakage in the heterotopic (malformed) hippocampus; these changes were associated with a significant increase in endothelial P-glycoprotein (P-gp) expression. Seizures exacerbated BBB leakage and greatly augmented P-gp expression in vessels and additionally in perivascular/parenchymal astrocytes. The effects of seizures were observed to a much larger extent in malformed than in normal brain tissue. The intrinsic changes in BBB function in MAM-exposed rats were associated with increased blood-to-brain penetration of ondansetron, a P-gp substrate. However, a marked reduction in drug brain levels was provoked by seizures, and this effect was reversed by selective blockade of P-gp activity with tariquidar. Changes in BBB function may critically contribute to determine the brain uptake and distribution of P-gp substrates in epileptic tissue associated with developmental malformations.
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PMID:Determinants of drug brain uptake in a rat model of seizure-associated malformations of cortical development. 1702 74

The present work was undertaken to examine the central pharmacokinetics of phenytoin (PHT) in an experimental model of epilepsy, induced by administration of 3-mercaptopropionic acid (MP), and possible participation of P-glycoprotein in this model of epilepsy. Repeated seizures were induced in male Wistar rats by injection of 3-MP (45 mg kg(-1), i.p.) during 10 days. Control rats (C) were injected with saline solution. In order to monitor extracellular PHT levels, either a shunt microdialysis probe or a concentric probe was inserted into carotid artery or hippocampus, respectively. All animals were administered with PHT (30 mg kg(-1), i.v.) 30 min after intraperitoneal administration of vehicle (V) or nimodipine (NIMO, 2 mg kg(-1)). No differences were found in PHT plasma levels comparing all experimental groups. In pre-treated rats with V, hippocampal PHT concentrations were lower in MP (maximal concentration, C(max): 2.7+/-0.3 microg ml(-1), p<0.05 versus C rats) than in C animals (C(max): 5.3+/-0.9 microg ml(-1)). Control rats pre-treated with NIMO showed similar results (C(max): 4.5+/-0.8 microg ml(-1)) than those pre-treated with V. NIMO pre-treatment of MP rats showed higher PHT concentrations (C(max): 6.8+/-1.0 microg ml(-1), p<0.05) when compared with V pre-treated MP group. Our results indicate that central pharmacokinetics of PHT is altered in MP epileptic rats. The effect of NIMO on hippocampal concentrations of PHT suggests that P-glycoprotein has a role in reduced central bioavailability of PHT in our epileptic refractory model.
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PMID:Nimodipine restores the altered hippocampal phenytoin pharmacokinetics in a refractory epileptic model. 1724 61

One of the major neurobiological mechanisms proposed in drug resistant epilepsy is removal of anti-epileptic drugs (AEDs) from the epileptogenic tissue through excessive expression of multi-drug efflux transporters such as P-glycoprotein (P-gp). P-gp, the encoded product of the human multi-drug resistance-1 (MDR-1; ABCB1) gene, is of particular clinical relevance in the emergence of multi-drug resistance (MDR), which may play an important role in preventing treatment response of some tumors and infectious diseases to chemotherapeutic agents and antibiotics. It has been shown that MDR-1 is over-expressed in brain tissue (hippocampal neurons) in patients with refractory temporal lobe epilepsy. For direct evidence that drug transporters such as P-gp are responsible for drug resistance, an experiment can be conducted to determine whether seizure control is improved when P-gp inhibitors are administered in addition to existing AEDs in patients with medically refractory epilepsy. In comparison with first and second-generation of P-gp inhibitors, third-generation inhibitors such as pyronaridine (PND) have advantages, such as higher potency and specificity for P-gp, lack of non-specific cytotoxicity, relatively long duration of action with reversibility, and good oral bioavailability. We suggest that a pilot study be conducted to determine whether adding of PND to existing AEDs decreases seizure frequency in patients with drug resistant epilepsy, and should this show promise, that a double-blind randomized controlled trial be designed to test the efficacy of PND.
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PMID:Potentiation of anti-epileptic drugs effectiveness by pyronaridine in refractory epilepsy. 1736 47

There is accumulating evidence to suggest that overexpression of efflux drug transporters at the blood-brain barrier, by reducing antiepileptic drug (AED) accumulation in the seizure foci, contributes to drug resistance in epilepsy. P-glycoprotein, encoded by the ABCB1 gene, is the most studied drug transporter. There are conflicting data as to whether the CC genotype of the ABCB1 3435C>T polymorphism is associated with drug resistance in Caucasian patients with epilepsy. We investigated this association in ethnic Chinese. ABCB1 3435C>T was genotyped in 746 Han Chinese patients with epilepsy and 179 controls. Patients with drug-resistant epilepsy were more likely to have the TT genotype compared with those with drug-responsive epilepsy (16.7% vs 7.4%, odds ratio=2.5, 95% confidence interval=1.4-4.6, P=0.0009). Our results contrast with those of studies of Caucasians, and highlight the complexity of the possible role of this polymorphism in AED response in different ethnic populations.
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PMID:Association between ABCB1 C3435T polymorphism and drug-resistant epilepsy in Han Chinese. 1752 63

It is estimated 20-25% of the epileptic patients fails to achieve good control with the different antiepileptic drugs (AEDs) treatments, developing refractory epilepsy (RE). Discovered first in cancer, the activity of P-glycoprotein (P-gp) and others ABC transporters as multidrug-resistance-associated proteins (MRPs) and breast cancer resistant protein (BCRP) are directly related with the refractoriness. We have observed the overexpression of these all transporters in the brain of patients with RE, and according with other authors, all these data suggests an active drug efflux from brain. Both constitutive and seizure induced brain P-gp overexpression was also suggested. As confirmation of these clinical evidences, different models of experimental epilepsy have demonstrated P-gp overexpression on blood brain barrier (BBB) and brain parenchyma cells, as astrocytes and neurons. In our model, early P-pg detection in vessel-related cells and later additional P-gp detection in neurons, correlated with the gradual loss of protective effect of phenytoin. The progressive neuronal P-gp expression, depending on intensity and time-constancy of seizure-injury, was in agreement with the development of "P-gp-positive seizure-axis" proposed by Kwan & Brodie, who also showed that the development of RE directly correlated with the number and frequency of seizures before initiation of drug therapy. P-gp expression in excretory organs suggests that P-gp have a central role in drug elimination. Persistent low levels of AEDs in plasma and P-gp brain overexpression in several RE pediatric patients were reported. We also observed in adult RE patients, an increased liver clearance of 99mTc-hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) (a P-gp substrate), and the surgically treated cases showed P-gp brain overexpression. These results suggest the systemic hyperactivity of P-gp in RE patients, including brain P-gp over-expression should be suspected when persistent subtherapeutic levels of AEDs in plasma are detected. P-gp neuronal expression described in both clinical and experimental reports indicates that additional mechanisms could be operative from seizure-affected P-gp-positive neurons, due to AEDs targets are expressed at membrane level. An alternative mechanism was demonstrated in P-gp-expressed cells that exhibit lower membrane potential (Deltapsi(0)=-10 to -20) compared to normal physiological Deltapsi(0) of -60 mV. Under this situation and irrespective to the P-gp pharmacoresistant property or type of drug treatment selected, P-gp-expressed neurons could increase their sensitivity to new seizures perhaps as an epileptogenic mechanism. The understanding of properties of these ABC transporters can offer new tools for better selection of more effective preventive or therapeutic strategies and avoid the invasive surgical treatments for RE.
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PMID:ABC transporters during epilepsy and mechanisms underlying multidrug resistance in refractory epilepsy. 1791 May 94

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


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