ATP-binding cassette transporters at the zebrafish blood-brain barrier and the potential utility of the zebrafish as an in vivo model

Abstract

The brain is protected from toxins by a tightly regulated network of specialized cells, including endothelial cells, pericytes, astrocyes, and neurons, known collectively as the blood-brain barrier (BBB). This selectively permeable barrier permits only the most crucial molecules essential for brain function to enter and employs a number of different mechanisms to prevent the entry of potentially harmful toxins and pathogens. In addition to a physical barrier comprised of endothelial cells that form tight junctions to restrict paracellular transport, there is an active protective mechanism made up of energy-dependent transporters that efflux compounds back into the bloodstream. Two of these ATP-binding cassette (ABC) transporters are highly expressed at the BBB: Pglycoprotein (P-gp, encoded by the ABCB1 gene) and ABCG2 (encoded by the ABCG2 gene). Although a number of in vitro and in vivo systems have been developed to examine the role that ABC transporters play in keeping compounds out of the brain, all have inherent advantages and disadvantages. Zebrafish (Danio rerio) have become a model of interest for studies of the BBB due to the similarities between the zebrafish and mammalian BBB systems. In this review, we discuss what is known about ABC transporters in zebrafish and what information is still needed before the zebrafish can be recommended as a model to elucidate the role of ABC transporters at the BBB.

Generation and characterization of a zebrafish knockout model of abcb4, a homolog of the human multidrug efflux transporter P-glycoprotein

“…S1). This result indicates that the BBB of zebra sh embryo at 3 dpf is permeable, which agrees with previous studies that the BBB is functionally immature at 3 dpf [13,25]. Interestingly, images of injected embryos after 1.5 hours of circulation showed that the level of rhodamine123 remaining in the parenchyma of Tg[ k1:EGFP];abcb4 −/− was signi cantly higher than that of Tg[ k1:EGFP] (Fig.…”

Knowns and unknowns of TiLV-associated neuronal disease

“…Zebrafish brain endothelial cells have many of the same adaptations as their mammalian counterparts. In addition, they possess homologs for the claudin family of transmembrane tight junction proteins found in mammals that contribute to BBB permeability [ 20 ].…”

Current Strategies to Enhance Delivery of Drugs across the Blood–Brain Barrier

“…ABC transporters, which are significant players in the multidrug-resistant phenotype of glioma and other malignancies, efflux several chemotherapeutics [ 38 ]. As a result, many efforts have been made to improve tumor drug delivery by using competitive or non-competitive inhibitors, and many P-gp and BCRP inhibitors, such as valspodar [ 39 ], dexverapamil [ 40 ], tariquidar [ 41 ], biricodar [ 40 ], and elacridar, have been clinically evaluated for use as adjuvants on chemotherapy to treat non-brain tumors, as well as indirect inhibition by anti-P-gp monoclonal antibodies. Their effectiveness in overcoming the BBB has been tested in both animals and humans.…”