Glia-Induced Reversible Disruption of Blood–Brain Barrier Integrity and Neuropathological Response of the Neurovascular Unit

Willis, Colin L.

doi:10.1177/0192623310385830

Cited by 54 publications

(41 citation statements)

References 78 publications

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“…The GFAP-fLuc model used here is used primarily to assess astrogliosis associated with neuroinflammation, neurodegeneration, infection, and cancer progression (48)(49)(50)(51)(52). One implication of our finding is that these pathologic conditions are associated with BBB disruption (53,54), which would increase the entry of D-luciferin and bioluminescence.…”

Section: Discussionmentioning

confidence: 70%

Bioluminescent imaging of drug efflux at the blood–brain barrier mediated by the transporter ABCG2

Bakhsheshian

Wei

Chang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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ATP-binding cassette (ABC) transporters are a group of transmembrane proteins that maintain chemical homeostasis through efflux of compounds out of organelles and cells. Among other functions, ABC transporters play a key role in protecting the brain parenchyma by efflux of xenobiotics from capillary endothelial cells at the blood-brain barrier (BBB). They also prevent the entry of therapeutic drugs at the BBB, thereby limiting their efficacy. One of the key transporters playing this role is ABCG2. Although other ABC transporters can be studied through various imaging modalities, no specific probe exists for imaging ABCG2 function in vivo. Here we show that D-luciferin, the endogenous substrate of firefly luciferase, is a specific substrate for ABCG2. We hypothesized that ABCG2 function at the BBB could be evaluated by using bioluminescence imaging in transgenic mice expressing firefly luciferase in the brain. Bioluminescence signal in the brain of mice increased with coadministration of the ABCG2 inhibitors Ko143, gefitinib, and nilotinib, but not an ABCB1 inhibitor. This method for imaging ABCG2 function at the BBB will facilitate understanding of the function and pharmacokinetic inhibition of this transporter. P rovision of nutrients and maintenance of chemical homeostasis in the brain is performed by the endothelial cells of brain capillaries within a neurovascular unit termed the bloodbrain barrier (BBB) (1). In contrast to endothelial cells of capillaries elsewhere in the body, those in the brain are joined by tight junctions forming a physiologic barrier. Drug delivery to the brain depends on physicochemical characteristics such as lipophilicity, molecular weight, and ionic state. For many compounds, brain entry is lower than other tissues/organs because of the presence of ATP-binding cassette (ABC) efflux transporters at the apical surface of endothelial cells at the BBB (2, 3). These transporters maintain chemical homeostasis in the brain, and prevent toxins from interfering with neural processes by regulating the compounds that can enter the brain.ABC transporters contribute to the clinical challenge of drug delivery to the brain, and it has been estimated that only 2% of drug discovery compounds can cross the BBB to reach therapeutic targets (4). ABCG2 (also known as breast cancer resistance protein) and ABCB1 (also called P-glycoprotein) are the two most highly expressed efflux transporters at the BBB (5). Altered expression of ABC transporters at the BBB has been associated with a range of pathophysiological conditions (2, 6). ABC efflux transporters at the BBB also play a major role in limiting effective concentrations of chemotherapeutic agents to treat primary and metastatic tumors in the brain (7). ABCG2 has been shown to work in tandem with ABCB1 at the BBB (8, 9). However, its individual contribution is not understood.Molecular imaging allows the measurement of the individual contribution and function of transporters in vivo (10). Efflux of a substrate by transporters at the BBB is reflected by...

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Section: Discussionmentioning

confidence: 70%

Bioluminescent imaging of drug efflux at the blood–brain barrier mediated by the transporter ABCG2

Bakhsheshian

Wei

Chang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Data are mean7 SD. occurs in brain (Wang et al, 2007;Willis, 2011). In response to the ischemic injury, glial cells quickly become activated and undergo morphological transformations, and are accompanied by functional changes, such as increasing expression of cytokines: interleukins (IL-1b, IL-4, IL-6, IL-10), TNFa, interferons and chemokines (Pickering and O'Connor, 2007;Guo et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of Gualou Guizhi decoction in vivo and in vitro

Zhang¹,

Li²,

Huang³

et al. 2014

Journal of Ethnopharmacology

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“…The neuropil (i.e., the CNS parenchyma) is penetrated by numerous capillaries. The structural specialization of these vascular channels, such as an absence of fenestrations as well as numerous tight and adherens junctions, forms a major anatomic substrate for the blood-brain barrier (BBB; Willis 2011). The CNS ventricular system is an interconnected series of fluid-filled reservoirs within the brain and the spinal cord.…”

Section: Region-specific Structure and Functionmentioning

confidence: 99%

Proliferative and Nonproliferative Lesions of the Rat and Mouse Central and Peripheral Nervous Systems

et al. 2012

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Harmonization of diagnostic nomenclature used in the pathology analysis of tissues from rodent toxicity studies will enhance the comparability and consistency of data sets from different laboratories worldwide. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of four major societies of toxicologic pathology to develop a globally recognized nomenclature for proliferative and nonproliferative lesions in rodents. This article recommends standardized terms for classifying changes observed in tissues of the mouse and rat central (CNS) and peripheral (PNS) nervous systems. Sources of material include academic, government, and industrial histopathology databases from around the world. Covered lesions include frequent, spontaneous, and aging-related changes as well as principal toxicant-induced findings. Common artifacts that might be confused with genuine lesions are also illustrated. The neural nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/).

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Glia-Induced Reversible Disruption of Blood–Brain Barrier Integrity and Neuropathological Response of the Neurovascular Unit

Cited by 54 publications

References 78 publications

Bioluminescent imaging of drug efflux at the blood–brain barrier mediated by the transporter ABCG2

Bioluminescent imaging of drug efflux at the blood–brain barrier mediated by the transporter ABCG2

Neuroprotective effects of Gualou Guizhi decoction in vivo and in vitro

Proliferative and Nonproliferative Lesions of the Rat and Mouse Central and Peripheral Nervous Systems

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