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Seizure-induced up-regulation of P-glycoprotein at the blood-brain barrier through glutamate and cyclooxygenase-2 signaling

Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig-Maximilians-University Munich, Koeniginstr. 16, 80539 Munich, Germany.
Molecular pharmacology (Impact Factor: 4.12). 06/2008; 73(5):1444-53. DOI: 10.1124/mol.107.041210
Source: PubMed

ABSTRACT Increased expression of drug efflux transporters at the blood-brain barrier accompanies epileptic seizures and complicates therapy with antiepileptic drugs. This study is concerned with identifying mechanistic links that connect seizure activity to increased P-glycoprotein expression at the blood-brain barrier. In this regard, we tested the hypothesis that seizures increase brain extracellular glutamate, which signals through an N-methyl-d-aspartate (NMDA) receptor and cyclooxygenase-2 (COX-2) in brain capillaries to increase blood-brain barrier P-glycoprotein expression. Consistent with this hypothesis, exposing isolated rat or mouse brain capillaries to glutamate for 15 to 30 min increased P-glycoprotein expression and transport activity hours later. These increases were blocked by 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801), an NMDA receptor antagonist, and by celecoxib, a selective COX-2 inhibitor; no such glutamate-induced increases were seen in brain capillaries from COX-2-null mice. In rats, intracerebral microinjection of glutamate caused locally increased P-glycoprotein expression in brain capillaries. Moreover, using a pilocarpine status epilepticus rat model, we observed seizure-induced increases in capillary P-glycoprotein expression that were attenuated by administration of indomethacin, a COX inhibitor. Our findings suggest that brain uptake of some antiepileptic drugs can be enhanced through COX-2 inhibition. Moreover, they provide insight into one mechanism that underlies drug resistance in epilepsy and possibly other central nervous system disorders.

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    • "Multidrug transporter Model Time after insult Region of overexpression References ABCB1/P-gp Intra cerebroventricular kainic acid rat model 1 d, 3 d, 5 d, 1 w, 2 w, 3 w, 4 w, 6 w, 10 w Hippocampus Zhang et al. (1999) ABCB1/P-gp Intra-hippocampus glutamate rat model 1 d Hippocampus Bauer et al. (2008) ABCB1/P-gp Kainic acid mouse SE model 3 h, 6 h, 24 h Hippocampus Rizzi et al. (2002) ABCB1/P-gp ABCC1/MRP1 Angular bundle stimulation rat SE model 1 d, 1 w, 4–9 m Hippocampus Parasubiculum Entorhinal cortex Piriform cortex Perirhinal cortex Somatosensory cortex Claustrum Amygdala Septum Van Vliet et al. (2004b) Van Vliet et al. (2007b) Van Vliet et al. (2006) Van Vliet et al. (2005) Van Vliet et al. (2010) Rizzi et al. (2002) ABCC2/MRP2 ABCG2/BCRP ABCB1/P-gp Amygdala kindling model rat 8 h after 10 consecutive fully kindled stage 5 seizures Hippocampus Cortex Volk et al. (2004b) ABCB1/P-gp Amygdala stimulation rat SE model 2 d, 2 m Hippocampus Piriform cortex Volk and Loscher (2005) Bankstahl and Loscher (2008) ABCB1/P-gp Kainic acid rat SE model 1 d, 10 d Hippocampus Amygdala Volk et al. (2004a) Seegers et al. (2002a) Seegers et al. (2002b) ABCB1/P-gp Pilocarpine rat SE model 18 h, 1 d, 2 d, 1 w Hippocampus Piriform cortex Amygdala Thalamus, Substantia nigra Van Vliet et al. (2010) Volk et al. (2004a) Marchi et al. (2006) Bauer et al. (2008) Pekcec et al. (2009) "
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    • "Multidrug transporter Model Time after insult Region of overexpression References ABCB1/P-gp Intra cerebroventricular kainic acid rat model 1 d, 3 d, 5 d, 1 w, 2 w, 3 w, 4 w, 6 w, 10 w Hippocampus Zhang et al. (1999) ABCB1/P-gp Intra-hippocampus glutamate rat model 1 d Hippocampus Bauer et al. (2008) ABCB1/P-gp Kainic acid mouse SE model 3 h, 6 h, 24 h Hippocampus Rizzi et al. (2002) ABCB1/P-gp ABCC1/MRP1 Angular bundle stimulation rat SE model 1 d, 1 w, 4–9 m Hippocampus Parasubiculum Entorhinal cortex Piriform cortex Perirhinal cortex Somatosensory cortex Claustrum Amygdala Septum Van Vliet et al. (2004b) Van Vliet et al. (2007b) Van Vliet et al. (2006) Van Vliet et al. (2005) Van Vliet et al. (2010) Rizzi et al. (2002) ABCC2/MRP2 ABCG2/BCRP ABCB1/P-gp Amygdala kindling model rat 8 h after 10 consecutive fully kindled stage 5 seizures Hippocampus Cortex Volk et al. (2004b) ABCB1/P-gp Amygdala stimulation rat SE model 2 d, 2 m Hippocampus Piriform cortex Volk and Loscher (2005) Bankstahl and Loscher (2008) ABCB1/P-gp Kainic acid rat SE model 1 d, 10 d Hippocampus Amygdala Volk et al. (2004a) Seegers et al. (2002a) Seegers et al. (2002b) ABCB1/P-gp Pilocarpine rat SE model 18 h, 1 d, 2 d, 1 w Hippocampus Piriform cortex Amygdala Thalamus, Substantia nigra Van Vliet et al. (2010) Volk et al. (2004a) Marchi et al. (2006) Bauer et al. (2008) Pekcec et al. (2009) "
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