Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition

ArticleinNeuropharmacology 56(5):849-55 · February 2009with12 Reads
DOI: 10.1016/j.neuropharm.2009.01.009 · Source: PubMed
Abstract
In the epileptic brain, seizure activity induces expression of the blood-brain barrier efflux transporter, P-glycoprotein, thereby limiting brain penetration and therapeutic efficacy of antiepileptic drugs. We recently provided the first evidence that seizures drive P-glycoprotein induction through a pathway that involves glutamate-signaling through the NMDA receptor and cyclooxygenase-2 (COX-2). Based on these data, we hypothesized that selective inhibition of COX-2 could prevent seizure-induced P-glycoprotein up-regulation. In the present study, we found that the highly selective COX-2 inhibitors, NS-398 and indomethacin heptyl ester, blocked the glutamate-induced increase in P-glycoprotein expression and transport function in isolated rat brain capillaries. Importantly, consistent with this, the COX-2 inhibitor, celecoxib, blocked seizure-induced up-regulation of P-glycoprotein expression in brain capillaries of rats in vivo. To explore further the role of COX-2 in signaling P-glycoprotein induction, we analyzed COX-2 protein expression in capillary endothelial cells in brain sections from rats that had undergone pilocarpine-induced seizures and in isolated capillaries exposed to glutamate and found no change from control levels. However, in isolated rat brain capillaries, the COX-2 substrate, arachidonic acid, significantly increased P-glycoprotein transport activity and expression indicating that enhanced substrate flux to COX-2 rather than increased COX-2 expression drives P-glycoprotein up-regulation. Together, these results provide the first in vivo proof-of-principle that specific COX-2 inhibition may be used as a new therapeutic strategy to prevent seizure-induced P-glycoprotein up-regulation at the blood-brain barrier for improving pharmacotherapy of drug-resistant epilepsy.

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    • "This metabolite is converted to prostaglandin E2 (PGE2) by cyclooxygenase 2 (COX2) and released to extracellular space by efflux activity of MRP, likely MRP4 (Bauer et al., 2008). Extracellular PGE2 binds to a prostaglandin E receptor 1 (EP-1R), which then signals NF-κB activation and increased P-gp expression (Bauer et al., 2008; Pekcec et al., 2009; Zibell et al., 2009). In contrast to a well-defined effect of glutamate on P-gp expression, BCRP expression at BBB after exposure to high levels of glutamate is controversial. "
    [Show abstract] [Hide abstract] ABSTRACT: The strength of the blood-brain barrier (BBB) in providing protection to the central nervous system from exposure to circulating chemicals is maintained by tight junctions between endothelial cells and by a broad range of transporter proteins that regulate exchange between CNS and blood. The most important transporters that restrict the permeability of large number of toxins as well as therapeutic agents are the ABC transporters. Among them, P-gp, BCRP, MRP1 and MRP2 are the utmost studied. These efflux transporters are neuroprotective, limiting the brain entry of neurotoxins; however, they could also restrict the entry of many therapeutics and contribute to CNS pharmacoresistance. Characterization of several regulatory pathways that govern expression and activity of ABC efflux transporters in the endothelium of brain capillaries have led to an emerging consensus that these processes are complex and contain several cellular and molecular elements. Alterations in ABC efflux transporters expression and/or activity occur in several neurological diseases. Here, we review the signaling pathways that regulate expression and transport activity of P-gp, BCRP, MRP1 and MRP2 as well as how their expression/activity changes in neurological diseases. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jul 2015
    • "It has also been shown that COX-2 inhibitors may improve pharmacotherapy in treatment-resistant epilepsy by decreasing the upregulation of P-glycoprotein, which limits penetration of AEDs in the BBB [61]. P-glycoproteins are upregulated during seizures, serving as a mechanism of drug resistance by limiting AED BBB penetrance and AED efficacy [61]. ICE/caspase-1 inhibitors and IL-1b receptor antagonists as potential therapeutics in epilepsy ICE/caspase-1 is an intracellular protease that cleaves the precursors of IL-1b into active cytokines. "
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this article is to review recent advances in the treatment of epilepsy. It includes five antiepileptic drugs that have been recently added to the pharmacologic armamentarium and surgical techniques that have been developed in the last few years. Finally, we review ongoing research that may have a potential role in future treatments of epilepsy.
    Full-text · Article · May 2015
    • "In accordance with our previous results, Jeong et al. (9) reported that acetylsalicylic acid treatment also leads to increased death among epileptic animals. In contrast, several authors have shown that COX2 inhibition can control P-glycoprotein (PgP) expression, improving the penetration of antiepileptic drugs into the brain and restoring the pharmacosensitivity to these drugs (10,11). Additionally, COX2 deficiency reduces excitotoxic damage to the epileptic brain (12). "
    [Show abstract] [Hide abstract] ABSTRACT: OBJECTIVE: Refractory status epilepticus is one of the most life-threatening neurological emergencies and is characterized by high morbidity and mortality. Additionally, the use of anti-inflammatory drugs during this period is very controversial. Thus, this study has been designed to analyze the effect of a low dose of indomethacin (a COX inhibitor) on the expression of inflammatory molecules. METHOD: The hippocampus of rats submitted to pilocarpine-induced long-lasting status epilepticus was analyzed to determine the expression of inflammatory molecules with RT-PCR and immunohistochemistry. RESULTS: Compared with controls, reduced levels of the kinin B2 receptors IL1β and TNFα were found in the hippocampus of rats submitted to long-lasting status epilepticus and treated with indomethacin. CONCLUSIONS: These data show that low doses of indomethacin could be employed to minimize inflammation during long-lasting status epilepticus.
    Full-text · Article · Sep 2014
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