COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats

Vliet, Erwin A. van; Zibell, Guido; Pekcec, Anton; Schlichtiger, Juli; Edelbroek, Peter M.; Holtman, Linda; Aronica, Eleonora; Gorter, Jan A.; Potschka, Heidrun

doi:10.1016/j.neuropharm.2009.09.012

Cited by 127 publications

(124 citation statements)

References 31 publications

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“…In the field of epileptology, studies in rodent and human brain capillaries have revealed that glutamate can upregulate P-glycoprotein via an N-methyl-D-aspartic acid (NMDA) receptor/cyclooxygenase-2 signaling pathway (Bauer et al, 2008b;Zibell et al, 2009;van Vliet et al, 2010;Avemary et al, 2013). Considering the excessive extracellular glutamate concentrations reached during epileptic seizures, this signaling pathway explains the overexpression of P-glycoprotein, which has been repeatedly found in the epileptic brain (Tishler et al, 1995;Thomas et al, 2003Thomas et al, , 2004Thomas et al, , 2005Aronica et al, 2004;Kubota et al, 2006;Ak et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Glutamate-Mediated Upregulation of the Multidrug Resistance Protein 2 in Porcine and Human Brain Capillaries

Luna-Munguía

Salvamoser

Pascher

et al. 2014

J Pharmacol Exp Ther

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As a member of the multidrug-resistance associated protein (MRP) family, MRP2 affects the brain entry of different endogenous and exogenous compounds. Considering the role of this transporter at the blood-brain barrier, the regulation is of particular interest. However, there is limited knowledge regarding the factors that regulate MRP2 in neurologic disease states. Thus, we addressed the hypothesis that MRP2 might be affected by a glutamateinduced signaling pathway that we previously identified as one key mechanism in the regulation of P-glycoprotein.

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Section: Introductionmentioning

confidence: 99%

Glutamate-Mediated Upregulation of the Multidrug Resistance Protein 2 in Porcine and Human Brain Capillaries

Luna-Munguía

Salvamoser

Pascher

et al. 2014

J Pharmacol Exp Ther

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“…Direncin yalnızca ilaç taşıyıcı ve hedef duyarlılığı ile açıkla-Epilepsi 2015;21(2): [43][44][45][46][47][48][49][50][51][52][53] ilaç yanıt değişkenliğini açıklayabilir. [51,52] NAT-2 enzimi bazı kimselerde genetik polimorfizm nedeni ile karaciğerde normal kimselere göre daha az miktarda oluşabilir ve ilaçların metabolizmasını etkileyebilir.…”

Section: İntrensek şIddet Hipotezi ("Intrinsic Severity Hypothesis")unclassified

“…Nöbetle ilişkili P-gp indüksiyonunu önlemek için PGE2 EP1 reseptör antagonistleri ve COX2 inhibitörleri denenmektedir. [44,79,80] COX2 inhibisyonu ile kronik epileptik sıçanda, fenitoinin beyine penetrasyonun arttığı ve fenobarbitale duyarlılığının şekillendiği gözlenmiştir. [80] Bu ön-leyici stratejiler P-gp salınımını, bazal transport fonksiyonu bozulmayacak şekilde kontrollü olarak düzenler.…”

Section: Epilepside İlaç Direnciyle İlişkili Diğer öNemli Konular Staunclassified

Drug Resistance and Resistance Mechanisms in Epilepsy

Taşkıran¹

2015

Epilepsi

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SummaryEpilepsy is a commonly encountered disorder among neurological disorders in our country and in the world. Almost 30% of seizures persist in spite of medical treatment. Resistance to medical treatment is important with regard to cognitive and psychosocial problems, and increased risk in mortality and morbidity. It may emerge due to the type of epilepsy, underlying epileptogenic process, and individual differences. Immunological, genetic and plasticity-related mechanisms are most relevant. The literature related to this subject is growing constantly, and increased understanding of the underlying mechanisms of drug resistance will play an important role in the development of more efficient treatment strategies. Contributing to this body of work, this article discusses drug resistance in epilepsy, its underlying mechanisms and accompanying clinical issues.Key words: Resistance mechanisms; epilepsy; drug resistance; pseudoresistance. ÖzetEpilepsi ülkemizde ve dünyada sık görülen nörolojik hastalıklardan biridir. Hastaların yaklaşık %30'unda nöbetler ilaç tedavisine rağmen devam etmektedir. Tedaviye direnç kognitif ve psikososyal sorunlar ile mortalite ve morbidite riskinde artışa neden olması açısından önem taşımaktadır. Tedaviye direnç, epilepsi tipi, altta yatan epileptogenez süreci ve bireysel farklılıklar nedeni ile gelişebilir. Başlıca mekanizmalar immünolojik, genetik ve plastisite ile ilişkili olmak üzere dikkat çekmekte ve gün geçtikçe bilgi birikimimiz artmaktadır. Daha etkin tedavi ve yaklaşımlarının geliştirilebilmesi için, ilaç direncinin altında yatan mekanizmaların anlaşılması önem taşımaktadır. Bu amaçla, epilepside ilaç direnci, altta yatan mekanizmalar ile bunlara eşlik eden klinik sorunlar ele alınmıştır.

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“…The other study [100] demonstrated that glutamate could cause localized up-regulation of P-gp via COX-2. COX-2 inhibition by SC-58236 and NS-398 may therefore help to increase concentrations of antiepileptic drugs at the target sites in the epileptic brain.…”

Section: Roles Of Immune and Inflammation In Drementioning

confidence: 99%

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

Líu²,

Qin³

2013

Current Neuropharmacology

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Until recently, epilepsy medical therapy is usually limited to anti-epileptic drugs (AEDs). However, approximately 1/3 of epilepsy patients, described as drug-resistant epilepsy (DRE) patients, still suffer from continuous frequent seizures despite receiving adequate AEDs treatment of sufficient duration. More recently, with the remarkable progress of immunology, immunity and inflammation are considered to be key elements of the pathobiology of epilepsy. Activation of inflammatory processes in brain tissue has been observed in both experimental seizure animal models and epilepsy patients. Anti-inflammatory and immunotherapies also showed significant anticonvulsant properties both in clinical and in experimental settings. The above emerging evidence indicates that modulation of immunity and inflammatory processes could serve as novel specific targets to achieve potential anticonvulsant effects for the patients with epilepsy, especially DRE. Herein we review the recent evidence supporting the role of inflammation in the development and perpetuation of seizures, and also discuss the recent achievements in modulation of inflammation and immunotherapy applied to the treatment of epilepsy. Apart from medical therapy, we also discuss the influences of surgery, ketogenic diet, and electroconvulsive therapy on immunity and inflammation in DRE patients. Taken together, a promising perspective is suggested for future immunomodulatory therapies in the treatment of patients with DRE.

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COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats

Cited by 127 publications

References 31 publications

Glutamate-Mediated Upregulation of the Multidrug Resistance Protein 2 in Porcine and Human Brain Capillaries

Glutamate-Mediated Upregulation of the Multidrug Resistance Protein 2 in Porcine and Human Brain Capillaries

Drug Resistance and Resistance Mechanisms in Epilepsy

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

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