RGD Reference Report - The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. - Rat Genome Database

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The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy.

Authors: Brandt, C  Bethmann, K  Gastens, AM  Loscher, W 
Citation: Brandt C, etal., Neurobiol Dis. 2006 Oct;24(1):202-11. Epub 2006 Aug 22.
RGD ID: 1598560
Pubmed: PMID:16928449   (View Abstract at PubMed)
DOI: DOI:10.1016/j.nbd.2006.06.014   (Journal Full-text)

Resistance to drug treatment is an important hurdle in the therapy of many diseases, including cancer, infectious diseases and brain disorders such as epilepsy. A phenotype that is referred to as multidrug resistance was first described for chemotherapy-resistant cancer cells that overexpressed the drug efflux transporter P-glycoprotein (P-gp). More recently, overexpression of P-gp has been found in capillary endothelial cells of epileptogenic brain tissue from patients with medically intractable epilepsy. Such regionally restricted P-gp overexpression in the blood-brain barrier is likely to reduce the concentration of antiepileptic drugs at epileptic neurons, which would be a plausible explanation for multidrug resistance in epilepsy. However, a definite proof-of-principle for this hypothesis is lacking. In the present study, we used a rat model of temporal lobe epilepsy that allows selecting drug-resistant and drug-responsive subgroups of epileptic rats by prolonged treatment with the antiepileptic drug phenobarbital at maximum tolerated doses. We have shown recently that drug-resistant rats selected from this model exhibit a marked overexpression of P-gp in the hippocampus and other limbic brain regions. This model is thus ideally suited to prove the multidrug transporter hypothesis of drug resistance. For this purpose, we selected a group of phenobarbital-resistant rats, which was subsequently treated by combinations of phenobarbital with the selective P-gp inhibitor tariquidar. Coadministration of tariquidar (15-20 mg/kg) fully restored the anticonvulsant activity of phenobarbital without altering plasma pharmacokinetics or neurotoxicity of the antiepileptic drug. These data demonstrate that inhibiting P-gp in epileptic rats with proven drug resistance counteracts resistance, providing the first proof-of-principle of the multidrug transporter hypothesis of medically refractory epilepsy.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
temporal lobe epilepsy  IDA 1598560 RGD 
temporal lobe epilepsy  ISOAbcb1b (Rattus norvegicus)1598560 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Abcb1b  (ATP-binding cassette, sub-family B member 1B)

Genes (Mus musculus)
Abcb1b  (ATP-binding cassette, sub-family B member 1B)

Objects referenced in this article
Gene ABCB1 ATP binding cassette subfamily B member 1 Homo sapiens

Additional Information