Drug Resistance in Epilepsy: The Role of the Blood–Brain Barrier

Abbott, N. Joan; Khan, E.U.; Rollinson, Christopher; Reichel, Andreas; Janigro, Damir; Dombrowski, Stephen; Dobbie, Michael S.; Begley, David J.

doi:10.1002/0470846356.ch4

Cited by 90 publications

(45 citation statements)

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“…Moreover, in chronic inactive lesions, P-gp expression was absent from the brain vasculature. In both types of MS lesions we observed an increased P-gp expression on hypertrophic astrocytes, which has previously been suggested to represent a second line defense mechanism as a result of BBB dysfunction [31]. The expression of GLUT-1 remained unaffected in various MS lesions indicating that there is a selective loss of endothelial P-gp during MS pathology.…”

Section: Discussionsupporting

confidence: 59%

T lymphocytes impair P-glycoprotein function during neuroinflammation

Kooij

Horssen

Lange

et al. 2010

Journal of Autoimmunity

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Section: Discussionsupporting

confidence: 59%

T lymphocytes impair P-glycoprotein function during neuroinflammation

Kooij

Horssen

Lange

et al. 2010

Journal of Autoimmunity

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“…Mdr1, also called P-glycoprotein, has been widely studied in this context, and knockout mice show an increase in a wide variety of small lipophilic drugs entering the brain, as well as endogenous molecules (Schinkel et al 1994(Schinkel et al , 1995(Schinkel et al , 1996. Up-regulation of Mdr1 has also been associated with drug-resistant epilepsy and tumors (Potschka et al 2001;Abbott et al 2002). An important avenue of research uses structural modeling to predict substrates of these efflux transporters to develop therapeutics that can avoid efflux and, thus, gain entry to the CNS.…”

Section: Tight Junctionsmentioning

confidence: 99%

The Blood–Brain Barrier

Daneman

Prat

2015

Cold Spring Harb Perspect Biol

2,248

1,660

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Blood vessels are critical to deliver oxygen and nutrients to all of the tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier, which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and also protects the neural tissue from toxins and pathogens, and alterations of these barrier properties are an important component of pathology and progression of different neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the endothelial cells (ECs) that form the walls of the blood vessels, and these properties are regulated by interactions with different vascular, immune, and neural cells. Understanding how these different cell populations interact to regulate the barrier properties is essential for understanding how the brain functions during health and disease.

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“…Apart from the wide range of permeabilities related to the nature of the tumor, these efflux transporters actively reduce uptake of the drug [9][10][11]. Similar considerations apply to the treatment of epilepsy [12] and HIV-1 infection [13]. MDR1 in leukocytes reduces the cell uptake of protease inhibitors [14], and permeation of protease inhibitors across the BBB in neuroAIDS would encounter the same challenge.…”

Section: Introductionmentioning

confidence: 99%

TNF Activates P-Glycoprotein in Cerebral Microvascular Endothelial Cells

Kastin

et al. 2007

Cell Physiol Biochem

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Background/Aims: Multidrug resistance proteins (MDRs, including P-glycoproteins) are efflux pumps that serve important biological functions but hinder successful drug delivery to the CNS. Many chemotherapeutic agents, anti-epileptics, anti-HIV drugs, and opiates are substrates for MDRs. Therefore, understanding the regulation of MDRs in the endothelial cells composing the blood-brain barrier has therapeutic implications. Methods: We used microarray, real time RT-PCR, Western blotting, and uptake of vinblastine by RBE4 cerebral endothelial cells to test the effects of tumor necrosis factor alpha (TNF) on the expression and functions of P-glycoprotein (MDR1). Results: The proinflammatory cytokine TNF specifically induced the expression and enhanced the function of MDR1 in RBE4 cells. The persistent upregulation of MDR1 mRNA was shown by cDNA microarray at 6, 12, and 24 h after TNF treatment. This was confirmed by real-time RT-PCR between 2 and 24 h. MDR1 protein expression was increased 6 to 24 h after TNF treatment and resulted in a significant reduction in the cellular uptake of ³H-vinblastine. Conclusion: The drug efflux transporter in cerebral endothelial cells can be upregulated by TNF. This suggests that adjunctive anti-TNF treatment has novel therapeutic potential in conditions such as brain cancer, epilepsy, neuroAIDS, and chronic pain.

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Drug Resistance in Epilepsy: The Role of the Blood–Brain Barrier

Cited by 90 publications

References 0 publications

T lymphocytes impair P-glycoprotein function during neuroinflammation

T lymphocytes impair P-glycoprotein function during neuroinflammation

The Blood–Brain Barrier

TNF Activates P-Glycoprotein in Cerebral Microvascular Endothelial Cells

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