ABC Transporters during Epilepsy and Mechanisms Underlying Multidrug Resistance in Refractory Epilepsy

Abstract

Summary: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 vesselrelated 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 99m Tc-hexakis-2-methoxyisobutylisonitrile ( 99m Tc-MIBI) (a P-gp substrate), and the surgically treated cases showed Pgp brain overexpression. These results suggest the systemic hyperactivity of P-gp in RE patients, including brain P-gp overexpression 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 ( ψ 0 = −10 to -20) compared to normal physiological ψ 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. Key Words: Refractory epilepsy-MDR-BCRP-MVP99m Tc-MIBI.

Evidence for epistatic interactions in antiepileptic drug resistance

“…This phenomenon is thought to be caused by overexpression of drug efflux transporter genes, such as MDR1 at the blood-brain barrier, that limit AED access to the brain. 16,17 The target hypothesis, on the other hand, contends that target receptor sites are somehow altered in the epileptic brain so that they are much less sensitive to the anticonvulsant effects of systemically administered drugs. So far, a reduction in drug target sensitivity in chronic human and experimental epilepsy has been suggested for the voltage-gated sodium channel and the GABA-A receptor.…”

“…The candidate genes with a potential influence on AED response tested in this study were as follows: (1) genes encoding drug transporters, MDR1 (ABCB1), MRP2 (ABCC2) and BCRP (ABCG2), as overexpression of these genes has been observed in the brains of patients with refractory epilepsy 16,17 and (2) genes encoding drug targets such as voltage-gated neuronal sodium channels (SCN1A, SCN1B and SCN2A), potassium channels (KCNQ2, KCNQ3 and KCNQ5), calcium channels (CACNA1H), chloride channels (CLCN2), acetylcholine receptors (CHRNA4 and CHRNB2) and g-aminobutyric acid (GABA) receptors (GABRA1 and GABRG2), as they are the main therapeutic targets of AEDs and are known to be causative of familial epilepsy syndromes, 10,18,19 and (3) genes encoding neurotransmitter transporters (EAAT1, EAAT2, EAAT3, VGLUT1, VGLUT2, VGLUT3, GAT1 and GAT3), as they are the potential therapeutic targets of AEDs. 20 …”

The complexity of roles of P-glycoprotein in refractory epilepsy: Pharmacoresistance, epileptogenesis, SUDEP and relapsing marker after surgical treatment

“…The "transporter`s hypothesis" to explain the refractoriness in epilepsy need not only a functional up-regulation of these transporters at BBB level to clean/export AEDs, but also they should be expressed on previously non-expressing cell as neurons. The inducible properties of these transporters as well as the the pharmacoresistant phenotype [9] links pharmacoresistance with epileptogenesis, as discussed below.…”

“…Interestingly, through the axis glutamate/NMDA receptor/cyclooxygenase-2 (COX-2) signaling, glutamate can induces overexpression of P-glycoprotein (P-gp) in brain [7,8]. The efflux of drugs by the multidrug transporters, particularly P-gp (ABCB1-transporter) is one of the principal means by which several patients with pharmacoresistant epilepsy develops refractoriness to a wide spectrum of antiepileptic drugs (AEDs) [9,10].…”

Modulation of Immunity and the Inflammatory Response: A New Target for Treating Drug-resistant Epilepsy

“…It has been suggested that P-gp overexpression at the BBB lead to therapeutic failure of AEDs by several studies using rodent epilepsy models and human epileptic tissue [96, 97]. Adding a P-gp inhibitor to the anti-epileptic treatment regimens has been shown to reverse the drug-resistant phenotype [98]. The generations of inhibitors of P-gp, such as tariquidar, have been examined in preclinical and clinical studies; however, these trials have largely failed to demonstrate an improvement in therapeutic efficacy [99].…”