Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Drug
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Target Concepts:
Gene/Protein
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Enzyme
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Query: EC:3.6.3.44 (
P-glycoprotein
)
13,344
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Recently, it has been reported that continuous treatment with cyclosporin A or tacrolimus induces
encephalopathy
in transplant patients. The mechanism of immunosuppressant-induced
encephalopathy
is unclear. We investigated the cytotoxicity to brain capillary endothelial cells and the effect of these two drugs on
P-glycoprotein
function using mouse brain capillary endothelial (MBEC4) cells. The transcellular transport of [3H]sucrose was significantly increased and the cellular viability, based on 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and trypan blue exclusion test, was decreased by cyclosporin A (approximately 50% at 5 microM; P<0.005), while tacrolimus showed a much smaller effect. These findings indicate that the toxicity of cyclosporin A was greater than that of tacrolimus. The uptake of [3H]vincristine, a substrate of
P-glycoprotein
, was increased by these two drugs. The expression of
P-glycoprotein
in MBEC4 cells was reduced, but there was no effect on mdr1b mRNA levels. The decrease in the expression of
P-glycoprotein
may be due to the inhibition of the turnover of
P-glycoprotein
, which involves translation. In conclusion, the direct cytotoxic effect on the brain capillary endothelial cells and the inhibition of
P-glycoprotein
may be partly involved in the occurrence of immunosuppressant-induced
encephalopathy
.
...
PMID:Effect of cyclosporin A or tacrolimus on the function of blood-brain barrier cells. 1039 24
There is evidence to suggest that integrity of the neurovascular unit may be compromised in acute liver failure (ALF). In order to address this issue from a molecular standpoint, expression of an array of genes coding for key cerebrovascular endothelial cell and tight junction proteins were measured by reverse transcription-polymerase chain reaction in cerebral cortex of rats with ischemic liver failure resulting from hepatic devascularization (portacaval anastomosis followed 24h later by hepatic artery ligation) compared to appropriate sham-operated controls. Expression of
P-glycoprotein
, endothelin-1, von Willebrand factor, caveolin-1, occludin, and the endothelial nitric oxide synthase isoform (eNOS) were measured in brain extracts from rats with ALF at coma/edema stages of
encephalopathy
. The effects of mild hypothermia (35 degrees C) sufficient to prevent cerebral edema in ALF animals on the expression of these genes were also studied. Brain edema and hepatic coma in normothermic ALF rats was accompanied by selective increases in expression of eNOS. Expression of occludin and von Willebrand factor mRNAs were decreased at coma/edema stages of
encephalopathy
in ALF rats whereas, expression of other cerebrovascular endothelial cell markers endothelin-1,
P-glycoprotein
, and caveolin-1 were unaffected. Mild hypothermia led to normalization of brain water content and of eNOS mRNA. However, the correlation between increased eNOS expression and
encephalopathy
/edema grade was poor suggesting the existence of additional mechanisms. These findings underscore the multifactorial nature of brain edema/
encephalopathy
mechanisms in ALF and question the role of BBB breakdown as a major pathogenetic factor.
...
PMID:Alterations in expression of genes coding for proteins of the neurovascular unit in ischemic liver failure. 2020 Nov 30
Infantile spasms are a severe epileptic
encephalopathy
with a variety of etiologies that occur in infancy and early childhood. Subjects with infantile spasms are at a higher risk for evolving into intractable epileptic spasms, tending to be refractory to conventional antiepileptic drugs. Genetic polymorphisms of the
P-glycoprotein
-encoding gene ABCB1 are suspected to be associated with pharmacoresistance phenotypes in epilepsy patients. Conflicting findings have been reported in different populations; few studies have explored whether this apparent association is affected by other host factors, such as specific epilepsy syndrome. We performed a case-control study to determine whether the risk of infantile spasms is influenced by common ABCB1 polymorphisms in a Han Chinese children's population consisting of 91 patients and 368 healthy individuals. DNA was isolated from whole blood, and three genetic polymorphisms (C1236T, G2677T/A, and C3435T) were assayed by PCR-RFLP. There were significant differences in the distributions of 3435TT [P = 0.001; odds ratio = 2.47; 95% confidence interval (CI) = 1.44-4.27] and 3435CT [P < 0.001; odds ratio = 0.28; 95% CI = 0.15-0.54] genotypes between infantile spasm cases and controls. No significant differences were observed in allelic and haplotypic frequencies of ABCB1 polymorphisms between the two groups. This study demonstrated that variations in the C3435T gene play an important role in the pathogenesis of infantile spasms in the Han Chinese population; 3435TT is associated with increased risk of having this epilepsy syndrome.
...
PMID:Common ABCB1 polymorphisms associated with susceptibility to infantile spasms in the Chinese Han population. 2203 38
The fruits of Euodia rutaecarpa (Euodiae Fructus, EF), the widely used traditional Chinese medicine, have various central nervous system effects. Alkaloids following as evodiamine (EDM), rutaecarpine (RCP) and dehydroevodiamine (DEDM) are the major substances in EF. The MDCK-pHaMDR cell monolayer model was utilized as a blood-brain barrier (BBB) surrogate model to study their BBB permeability. The transport samples were analyzed by high performance liquid chromatography and the apparent permeability coefficients (P
app
) were calculated. EDM and RCP showed high permeability through BBB by passive diffusion, while DEDM showed moderate permeability with efflux mechanism related to
P-glycoprotein
(
P-gp
). EDM and RCP could also reduce the efflux of DEDM probably by inhibiting
P-gp
. The neuroprotective effects of the three alkaloids were then studied on the PC12 cell line injured by 1-methyl-4-phenylpyridinium ion (MPP
+
) or hydrogen peroxide (H
2
O
2
). EDM could significantly reduce MPP
+
or H
2
O
2
-induced cell injury dose-dependently. RCP could increase the cell viability in MPP
+
treated group while DEDM showed a protective effect against H
2
O
2
injury. This study predicted the permeability of EDM, RCP and DEDM through BBB and discovered the neuroprotective substance basis of EF as a potential
encephalopathy
drug.
...
PMID:Blood-brain barrier permeability and neuroprotective effects of three main alkaloids from the fruits of Euodia rutaecarpa with MDCK-pHaMDR cell monolayer and PC12 cell line. 2924 70
Despite the availability of many antiepileptic drugs (AEDs) (old and newly developed) and, as recently suggested, their optimization in the treatment of patients with uncontrolled seizures, more than 30% of patients with epilepsy continue to experience seizures and have drug-resistant epilepsy; the management of these patients represents a real challenge for epileptologists and researchers. Resective surgery with the best rates of seizure control is not an option for all of them; therefore, research and discovery of new methods of treating resistant epilepsy are of extreme importance. In this article, we will discuss some innovative approaches, such as
P-glycoprotein
(
P-gp
) inhibitors, gene therapy, stem cell therapy, traditional and novel antiepileptic devices, precision medicine, as well as therapeutic advances in epileptic
encephalopathy
in children; these treatment modalities open up new horizons for the treatment of patients with drug-resistant epilepsy.
...
PMID:Novel therapies for epilepsy in the pipeline. 3128 59
The clinical phenotype linked with mutations in ABCB1, encoding
P-glycoprotein
, has never been reported. Here, we describe twin sisters with biallelic mutations in ABCB1 who showed recurrent reversible
encephalopathy
accompanied by acute febrile or afebrile illness. Whole-exome sequencing was performed on one of the twin and her healthy parents, and revealed compound heterozygous loss-of-function variants in ABCB1. The patient brains displayed substantial loss of xenobiotic clearance ability, as demonstrated by [
11
C]verapamil positron emission tomography (PET) study, linking this phenotype with ABCB1 function. The endogenous cytokine clearance from the brain was also decreased in LPS-treated ABCB1 knockout mice compared to controls. The results provide insights into the physiological requirement of ABCB1 in maintaining homeostasis of various compounds for normal brain function.
...
PMID:Biallelic mutations in ABCB1 display recurrent reversible encephalopathy. 3262 53
