Further, for NF-κB p65, MDR1, P-gp and apoptosis-associated protein levels detection, miR-542-3p mimic showed a suppressive effect on these KA-induced protein levels, whereas TLR4 overexpression ameliorated the miR-542-3p-induced these protein levels in KA-treated epilepsy rats.
Our data provide key signaling steps underlying seizure-induced P-gp up-regulation and suggest that mPGES-1 inhibitors could potentially prevent P-gp up-regulation in epilepsy.-Soldner, E. L. B., Hartz, A. M. S., Akanuma, S.-I., Pekcec, A., Doods, H., Kryscio, R. J., Hosoya, K.-I., Bauer, B. Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier.
Neuroinflammation due to high levels of glutamate has been identified as one of the causes of P-gp upregulation, and several studies in animal models of epilepsy suggest that antiinflammatory drugs might prevent P-gp overexpression and, thus, avoid the development of refractory epilepsy.
Our data support the hypothesis that glutamate signals cPLA2 activation, resulting in overexpression of blood-brain barrier P-gp and BCRP.-Hartz, A. M. S., Rempe, R. G., Soldner, E. L. B., Pekcec, A., Schlichtiger, J., Kryscio, R., Bauer, B. Cytosolic phospholipase A2 is a key regulator of blood-brain barrier function in epilepsy.
Indeed, many genes, including genes encoding drug transporters (ABCB1), drug targets (SCN1A), drug-metabolizing enzymes (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins, may regulate the mechanisms of drug resistance in epilepsy.
This study investigates the effect of the Pgp inhibitor verapamil on the anticonvulsant effect of CBZ and its nanoparticulate formulation in the rat model of isoniazid-induced epilepsy.
This study aimed to assess whether [<sup>11</sup>C]flumazenil is a P-glycoprotein substrate in humans and to what extent increased P-glycoprotein function in epilepsy may confound interpretation of clinical [<sup>11</sup>C]flumazenil studies used to assess gamma-aminobutyric acid A receptors.
The genetic polymorphism of ABCB1rs1045642 was found to be associated with normalized OXC concentration and therapeutic efficacy in patients with epilepsy (P<0.05).
By compared to the epilepsy model group, the P-gp expression was not markedly attenuated by the inhibition of NF-κB activity with PDTC treatment, nevertheless with a decrease of NF-κB expression in this intervention group.
Hence, our findings support the combination of flavonoid-type P-gp inhibitors and P-gp substrate antiepileptic drugs as a potential therapeutic strategy for the management of pharmacoresistant epilepsy.
Exposing isolated rat brain capillaries to glutamate ex vivo upregulated P-gp expression to levels that were similar to those in capillaries isolated from rats that had status epilepticus or chronic epilepsy.
The expression levels of P-gp and its encoded gene mdr1a/b were significantly up-regulated on the brain of KA-induced chronic epilepsy rats or the epilepsy rats treated with CBZ for 1 week, meanwhile with a high expression of PXR.
C3435T polymorphism of MDR1 gene was analysed by the high resolution melting technique in a group of patients with drug-resistant (n = 106) and drug-responsive epilepsy (n = 67), as well as in non-epileptic children (n = 98) hospitalised at the Department of Neurology, Polish Mother's Memorial Hospital in Lodz.
The present study attempted to evaluate association of polymorphisms of CYP2C9, CYP2C19, and ABCB1, and P-gp activity with treatment response in patients with epilepsy.
In this case-control study, we have investigated the role of ABCB1rs1045642 and rs2032582 and ABCC2 rs2273697 and rs717620 single nucleotide polymorphisms in antiepileptic drug-resistance in patients with epilepsy.
The association between the non-synonymous polymorphism G2677T/A in the coding region of the ABCB1 gene, and the risk of resistance to anti-epileptic drugs (AEDs) in epilepsy remains controversial.
Previous studies reported the associations between the ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1) polymorphisms and their haplotypes with risk of response to antiepileptic drugs in epilepsy, however, the results were inconclusive.
rs776746 and rs15524 in the CYP3A5 gene tend to affect CBZ metabolism, and rs2032582, rs10234411 in the ABCB1 gene may contribute to inter-individual variation in CBZ and in CBZ-E transport among patients with epilepsy using CBZ in combination with PHT or PB.
These findings rule out the MDR1 c.3435C>T polymorphism having a major role or increasing the risk of drug-resistance suggesting a revision is required to determine the contribution of this polymorphism in predicting drug response in epilepsy.