Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P-glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs. Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models. Moreover, the impact of a cyclooxygenase-2 inhibitor on expression of the efflux transporter and on brain delivery of an antiepileptic drug was evaluated in rats with recurrent spontaneous seizures. The highly selective cyclooxygenase-2 inhibitors SC-58236 and NS-398 both counteracted the status epilepticus-associated increase in P-glycoprotein expression in the parahippocampal cortex and the ventral hippocampus. In line with our working hypothesis, a sub-chronic 2-week treatment with SC-58236 in the chronic epileptic state kept P-glycoprotein expression at control levels. As described previously, enhanced P-glycoprotein expression in chronic epileptic rats was associated with a significant reduction in the brain penetration of the antiepileptic drug phenytoin. Importantly, the brain delivery of phenytoin was significantly enhanced by sub-chronic cyclooxygenase-2 inhibition in rats with recurrent seizures. In conclusion, the data substantiate targeting of cyclooxygenase-2 in the chronic epileptic brain as a promising strategy to control the expression levels of P-glycoprotein despite recurrent seizure activity. Cyclooxygenase-2 inhibition may therefore help to increase concentrations of antiepileptic drugs at the target sites in the epileptic brain. It needs to be further evaluated whether the approach also enhances efficacy.
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PMID:COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats. 1978 37

Epilepsy affects more than 60 million people worldwide. While most patients can be treated with antiepileptic drugs, up to 40% of patients respond poorly to pharmacotherapy. This drug resistance is not well understood and presents a major clinical problem. In this short review we provide background information on one potential cause of antiepileptic drug resistance, namely, upregulation of the drug efflux transporter P-glycoprotein at the blood-brain barrier. We summarize recent findings that connect antiepileptic drug resistance with P-glycoprotein upregulation and show a mechanistic link between seizures and upregulation of this transporter. We provide an overview of results demonstrating that glutamate released during seizures signals through N-methyl-Daspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) to increase P-glycoprotein. In this context we discuss the NMDA receptor and COX-2 as potential therapeutic targets and provide information on current clinical trials on drugresistant epilepsy involving blood-brain barrier efflux transporters. Finally, we provide a perspective on future research that could help improve the treatment of drug-resistant epilepsy.
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PMID:Signaling to P-glycoprotein-A new therapeutic target to treat drug-resistant epilepsy? 1989 Apr 96

The mechanisms underlying the refractory temporal lobe epilepsy (TLE) are not well understood. Several explanations for refractory TLE are (1) an overexpression of P-glycoprotein (P-gp) encoded by multiple drug resistance 1 (MDR1) gene and other efflux transporters such as multidrug resistance protein (MRP) in the cerebrovascular endothelium in or around the region of the epileptic focus may lead to drug resistance in epilepsy; (2) the loss of antiepileptic drug sensitivity at certain target sites in the brain, including the sodium ion channel and the gamma aminobutyric acid (GABA)A receptor; and (3) seizures beget seizures by means of a cascade of events that include various types of neuronal damage, sprouting of neuronal axons and new synapse formations that establish aberrant glutamatergic synapses. TLE may be a progressive neurological disorder that requires early and effective treatment. Early recognition of refractory TLE and referral for epilepsy surgery may prevent years of unnecessary seizure activity and its consequences.
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PMID:The mechanisms of medically refractory temporal lobe epilepsy. 1996 Sep 58

Surgery is recommended for pharmacoresistant temporal lobe epilepsy (TLE), but seizures recur in approximately one third of patients postsurgery. P-glycoprotein is an efflux multidrug transporter that is overexpressed in a range of epileptogenic pathologies. We hypothesized that increased expression of P-glycoprotein in the epileptogenic temporal lobe might be a marker for recurrence of pharmacoresistant seizures postsurgery. We performed immunohistochemistry on temporal lobe tissues resected from 69 patients who underwent anterior temporal lobectomy for pharmacoresistant TLE with histopathological proven hippocampal sclerosis. P-glycoprotein expression was rated by three pathologists independently. Patients with seizure recurrence (n=22) had greater number of positively stained capillaries (p=0.001) and higher P-glycoprotein immunoreactive score in capillaries (p=0.002) in the white matter of resected temporal lobe. The differences remained significant in multivariate analysis (p=0.002 and 0.006, respectively). The results suggest that P-glycoprotein expression in temporal lobe may be associated with seizure recurrence after surgery for pharmacoresistant TLE.
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PMID:Association between temporal lobe P-glycoprotein expression and seizure recurrence after surgery for pharmacoresistant temporal lobe epilepsy. 2040 41

Over-expression of efflux transporter P-glycoprotein (PgP) encoded by ABCB1 gene has been implicated in poor responsive epilepsy. Several genetic variants have been shown to influence the expression levels of P-glycoprotein. The aim of the present study was to investigate the role of ABCB1 polymorphisms: C1236T, G2677T/A and C3435T in determining drug response to first line antiepileptic drugs (AEDs) namely phenobarbitone, phenytoin, carbamazepine and valproate in North Indian cohort of epilepsy patients. DNA samples were obtained from 392 consecutive epilepsy patients, out of which 228 had completed follow-up evaluation at 12 months. After attaining steady state of the AEDs in the first two months of study, 133 patients showed complete freedom from seizures (no-seizure group) and 95 patients continued to have seizures (recurrent-seizures group) in the remaining period of study. Comparison of "no-seizure" and "recurrent-seizures" groups revealed no significant differences in allelic, genotypic and haplotypic frequencies for all the studied variants. In conclusion, our finding disproves a general association between ABCB1 polymorphisms and drug response in epilepsy patients.
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PMID:Absence of a general association between ABCB1 genetic variants and response to antiepileptic drugs in epilepsy patients. 2041 80

Enhanced brain efflux of antiepileptic drugs by the blood-brain barrier transporter P-glycoprotein is discussed as one mechanism contributing to pharmacoresistance of epilepsies. P-glycoprotein overexpression has been proven to occur as a consequence of seizure activity. Therefore, blocking respective signaling events should help to improve brain penetration and efficacy of P-glycoprotein substrates. A series of recent studies revealed key signaling factors involved in seizure-associated transcriptional activation of P-glycoprotein. These data suggested several interesting targets, including the N-methyl-d-aspartate (NMDA) receptor, the inflammatory enzyme cyclooxygenase-2, and the prostaglandin E2 EP1 receptor. These targets have been further evaluated in rodent models, demonstrating that targeting these factors can control P-glycoprotein expression, improve antiepileptic drug brain penetration, and help to overcome pharmacoresistance. In general, the approach offers particular advantages over transporter inhibition as it preserves basal transporter function. In this review the different strategies for blocking P-glycoprotein upregulation, including their therapeutic promise and drawbacks are discussed. Moreover, pros and cons of the approach are compared to those of alternative strategies to overcome transporter-associated resistance. Regarding future perspectives of the novel approach, there is an obvious need to more clearly define the clinical relevance of transporter overexpression. In this context current efforts are discussed, including the development of imaging tools that allow an evaluation of P-glycoprotein function in individual patients.
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PMID:Modulating P-glycoprotein regulation: future perspectives for pharmacoresistant epilepsies? 2047 44

Drug development in neuro-oncology remains a challenge for neoplasms of the central nervous system (CNS). Drugs can be administered peripherally (i.e., oral or intravenous) or locally (into the tumor or the adjacent neuropil). Each of these routes has advantages and disadvantages. Like the treatment for non-CNS cancers, peripheral side effects are encountered (i.e., diarrhea, myelosuppression, rash); however, there also may be neural-specific side effects for patients that may be acute or delayed (i.e., seizures, somnolence, hearing loss). The nervous system is also a privileged site protected by the blood-brain barrier, so many agents developed for peripheral administration will not penetrate into the CNS due to issues of size, charge, or lack of lipid solubility. In addition, the abnormal vasculature, increased interstitial pressure, and inherent mechanisms of tumor resistance (methyl-guanine-methyl transferase [MGMT], P-glycoprotein, etc.) within brain neoplasms reduce the efficacy of many agents designed for neuro-oncologic indications. Each of these issues alone, and all of them in aggregate, are reasons for the limited success of therapeutic agents directed against CNS tumors despite promising data acquired using cell lines and animal models.
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PMID:Issues in developing drugs for primary brain tumors: barriers and toxicities. 2114 33

It is proposed that overexpression of P-glycoprotein (P-gp), encoded by the ABC subfamily B member 1 (ABCB1) gene, is involved in resistance to antiepileptic drugs (AEDs) in about 30% of patients with epilepsy. Genetic variation and haplotype patterns are population specific which may cause different phenotypes such as response to AEDs. Although several studies examined the link between the common polymorphisms in the ABCB1 gene with resistance to AEDs, the results have been conflicting. This controversy may be caused by the effect of some confounders such as ethnicity and polytherapy. Moreover, expression of the ABCB1 gene is under the control of pregnane X receptor (PXR). Evidence showed that PXR gene contribute to the response to treatment. The aim of this study was to assess the association of ABCB1 and PXR genetic polymorphisms with response to the carbamazepine (CBZ) or sodium valproate (VPA) monotherapy in epilepsy. Genotypes were assessed in 685 Chinese, Indian, and Malay epilepsy patients for ABCB1 (C1236T, G2677T, C3435T) and PXR (G7635A) polymorphisms. No association between these polymorphisms and their haplotypes, and interaction between them, with response to treatment was observed in the overall group or in the Chinese, Indian, and Malay subgroups. Our data showed that these polymorphisms may not contribute to the response to CBZ or VPA monotherapy treatment in epilepsy.
Seizure 2011 Jun
PMID:Lack of association of ABCB1 and PXR polymorphisms with response to treatment in epilepsy. 2131 68

Approximately one third of newly treated epilepsy patients do not respond to antiepileptic drugs (AEDs). Overexpression of P-glycoprotein (P-gp) efflux transporter has been proposed to have a critical role in causing resistance to AEDs. P-gp is a product of the ATP-binding cassette subfamily B member 1 (ABCB1) gene. The purpose of this study was to investigate a possible link between ABCB1 rs3789243 C>T, C1236T, G2677T/A, rs6949448 C>T, and C3435T haplotypes with response to carbamazepine (CBZ) or sodium valproate (VPA) monotherapy in Malaysian epilepsy patients. No ABCB1 haplotype association was found with response to either CBZ or VPA monotherapy in the Chinese, Indian, and Malay patients. C3435 allele carriers of the Indian males with cryptogenic epilepsy were more prone to resistance to either CBZ or VPA than carriers of T allele. Moreover, rs3789243T allele carriers of Malay females with symptomatic epilepsy were more resistant to either CBZ or VPA than C allele carriers. Our findings suggest that the ABCB1 rs3789243 C>T, C1236T, G2677T/A, rs6949448 C>T, and C3435T haplotypes do not contribute to response to AED treatment in epilepsy.
Seizure 2011 Sep
PMID:Lack of association of ABCB1 haplotypes on five loci with response to treatment in epilepsy. 2153 Mar 24

One of the shortcomings of current treatment of nerve agent poisoning is that oximes hardly penetrate the blood-brain barrier (BBB), whereas nerve agents easily do. Increasing the concentration of oximes in the brain, would therefore provide an attractive approach to improve medical countermeasures. An explanation for limited penetration might be that oximes are substrates for the active P-glycoprotein (Pgp) efflux transporter located in the BBB. Using quantitative brain microdialysis in rats, the effect of i.v. injected tariquidar, a non-competitive, specific Pgp-inhibitor, on HI-6 levels in blood and brain was investigated. It appeared that tariquidar enhanced HI-6 levels in the brain approximately 2-fold during the first hour after HI-6 administration, whereas plasma levels did not differ between the treatment groups. A subsequent proof-of-concept study in rats showed that soman-induced seizures and convulsions were prevented almost completely when they were, in addition to HI-6 and atropine, pretreated with tariquidar. Moreover, twice as much AChE activity was present in their brains as compared to control rats. These results in rats indicate that modulation of the BBB by a drug like tariquidar, which is non-toxic by itself, is of great value in enhancing the efficacy of oximes.
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PMID:Increasing oxime efficacy by blood-brain barrier modulation. 2160 Feb 73


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