Multidrug resistance in epilepsy: Rats with drug-resistant seizures exhibit enhanced brain expression of P-glycoprotein compared with rats with drug-responsive seizures

Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.
Brain (Impact Factor: 9.2). 07/2005; 128(Pt 6):1358-68. DOI: 10.1093/brain/awh437
Source: PubMed


Medical intractability, i.e. the absence of any response to anti-epileptic drug (AED) therapy, is an unresolved problem in many patients with epilepsy. Mechanisms of intractability are not well understood, but may include alterations of pharmacological targets and poor penetration of AEDs into the brain because of increased expression of multiple drug-resistance proteins, such as P-glycoprotein (Pgp; ABCB1), capable of active brain extrusion of various drugs, including AEDs. Increased expression of Pgp has been reported in brain tissue of patients with refractory epilepsy, but there is a lack of adequate controls, i.e. brain tissue from patients with drug-responsive epilepsy. In the present study, we used a rat model of temporal lobe epilepsy to examine whether AED responders differ from non-responders in their expression of Pgp in the brain. In this model, spontaneous recurrent seizures develop after status epilepticus induced by prolonged electrical stimulation of the basolateral amygdala. The frequency of these seizures was recorded by continuous video-EEG monitoring before, during and after daily treatment with phenobarbital, which was given at maximum tolerated doses for 2 weeks. Based on their individual response to phenobarbital, rats were grouped into responders (n = 7) and non-responders (n = 4). Pgp expression was studied by immunohistochemistry and showed striking overexpression in non-responders compared with responders in limbic brain regions, including the hippocampus. The Pgp overexpression was confined to brain capillary endothelial cells which form the blood-brain barrier. The present data are the first to demonstrate that rats with drug-resistant spontaneous seizures differ from rats with drug-responsive seizures in their Pgp expression in the brain, thereby substantiating the multidrug transporter hypothesis of intractable epilepsy.

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Available from: Holger Andreas Volk
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    • "As such, the present k 2 and BP ND findings concur with the greater tariquidar sensitivity of K 1 in the nonresponders, insofar as the changes are a consequence of greater tracer delivery to brain. Therefore, the present results clearly support the finding of enhanced P-glycoprotein expression and transport in phenobarbital nonresponders (Volk & Loscher, 2005; Brandt et al., 2006), insofar as the impact of tariquidar was more pronounced in the animals with the higher level of P-glycoprotein expression. It must be emphasized that our experimental design precluded the evaluation of P-glycoprotein expression levels in the responder and nonresponder groups at the time of microPET scanning. "
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    ABSTRACT: Based on experimental findings, overexpression of P-glycoprotein at the blood-brain barrier has been suggested to be a contributor to pharmacoresistance of the epileptic brain. We test a technique for evaluation of interindividual differences of elevated transporter function, through microPET analysis of the impact of the P-glycoprotein modulator tariquidar. The preclinical study is intended for eventual translation to clinical research of patients with pharmacoresistant seizure disorders. We made a microPET evaluation of the effects of tariquidar on the brain kinetics of the P-glycoprotein substrate [(18) F]MPPF in a rat model with spontaneous recurrent seizures, in which it has previously been demonstrated that phenobarbital nonresponders exhibit higher P-glycoprotein expression than do phenobarbital responders. Mean baseline parametric maps of the [(18) F]MPPF unidirectional blood-brain clearance (K(1) ; ml/g per min) and the efflux rate constant (k(2) ; per min) did not differ between the nonresponder and responder group. Tariquidar pretreatment increased the magnitude of [(18) F]MPPF K(1) in hippocampus by a mean of 142% in the nonresponders, which significantly exceeded the 92% increase observed in the responder group. The same treatment decreased the mean magnitude of [(18) F]MPPF k(2) in hippocampus by 27% in nonresponders, without comparable effects in the responder group. These results constitute a proof-of-concept for a novel imaging approach to evaluate blood-brain barrier P-glycoprotein function in animals. By extension, [(18) F]MPPF positron emission tomography (PET) with tariquidar pretreatment may be amenable for clinical applications exploring further the relevance of P-glycoprotein overexpression, and for enabling the rational design of pharmacotherapy according to individual differences in P-glycoprotein expression.
    Full-text · Article · Sep 2010 · Epilepsia
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    • "Development of approaches that target transporter regulatory pathways of course requires an in-depth understanding of the signaling mechanisms that contribute to activation of transporter expression in the epileptic brain. Identification of Targets Involved in P-Glycoprotein Regulation As already stated, experimental data indicate that seizure activity is the main factor upregulating P-glycoprotein in the epileptic brain (Rizzi et al., 2002; Seegers et al., 2002a,b; van Vliet et al., 2004, 2005; Volk et al., 2005; Hoffmann et al., 2006; Liu et al., 2007). Some studies have indicated that antiepileptic drugs might contribute to the induction. "
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    ABSTRACT: 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.
    Preview · Article · Aug 2010 · Epilepsia
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    • "Most of the attention has centered on the mechanisms by which AEDs penetrate the blood–brain barrier (BBB) and how these mechanisms might be compromised in patients with refractory epilepsy [4]. Convergent experimental and clinical findings support that intrinsic or acquired overexpression of multidrug transporters in the BBB can produce pharmacoresistance in epilepsy , for AED concentrations would be reduced to the level that is insufficient to cause anti-epileptic activity [4] [5] [6] [7] [8] [9]. "
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    ABSTRACT: As a common human disorder, epilepsy affects about 0.5% of the population. In many patients with epilepsy, seizures are well-controlled with currently available anti-epileptic drugs, but around 35% of patients with epilepsy continue to have seizures despite carefully optimized drug treatment. Recently, intrinsic or acquired overexpression of multidrug transporters in the blood-brain barrier has been suggested to result in producing pharmacoresistance in epilepsy, for anti-epileptic drugs concentrations would be reduced to the level that is insufficient to cause anti-epileptic activity. Intranasal administration provides a direct transport pathway to brain tissue that circumvents the blood-brain barrier for many drugs and neuropeptides. These significant conditions support the hypothesis that intranasal anticonvulsive treatment may be a prospective management of intractable epilepsy. Unfortunately, there are few studies on intranasal anticonvulsive treatment conducted in the field of intractable epilepsy. Our hypothesis provides not only a new alternative treatment for intractable epilepsy but also has potential for investigating the mechanisms underlying the development of pharmacoresistance in epilepsy.
    Full-text · Article · Aug 2008 · Medical Hypotheses
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