Uptake and Efflux of Quinacrine, a Candidate for the Treatment of Prion Diseases, at the Blood-brain Barrier

Overview

Journal Cell Mol Neurobiol

Publisher Springer

Specialties Cell Biology
Molecular Biology
Neurology

Date 2004 Jun 5

PMID 15176436

Citations 9

Authors

Shinya Dohgu

Atsushi Yamauchi

Fuyuko Takata

Yasufumi Sawada

Shun Higuchi

Mikihiko Naito

Takashi Tsuruo

Susumu Shirabe

Masami Niwa

Shigeru Katamine

Yasufumi Kataoka

Affiliations

Soon will be listed here.

Abstract

1. A clinical trial of quinacrine in patients with Creutzfeldt-Jakob disease is now in progress. The permeability of drugs through the blood-brain barrier (BBB) is a determinant of their therapeutic efficacy for prion diseases. The mechanism of quinacrine transport across the BBB was investigated using mouse brain endothelial cells (MBEC4). 2. The permeability of quinacrine through MBEC4 cells was lower than that of sodium fluorescein, a BBB-impermeable marker. The basolateral-to-apical transport of quinacrine was greater than its apical-to-basolateral transport. In the presence of P-glycoprotein (P-gp) inhibitor, cyclosporine or verapamil, the apical-to-basolateral transport of quinacrine increased. The uptake of quinacrine by MBEC4 cells was enhanced in the presence of cyclosporine or verapamil. 3. Quinacrine uptake was highly concentrative, this event being carried out by a saturable and carrier-mediated system with an apparent Km of 52.1 microM. Quinacrine uptake was insensitive to Na+-depletion and changes in the membrane potential and sensitive to changes in pH. This uptake was decreased by tetraethylammonium and cimetidine, a substrate and an inhibitor of organic cation transporters, respectively. 4. These findings suggest that quinacrine transport at the BBB is mediated by the efflux system (P-gp) and the influx system (organic cation transporter-like machinery).

Citing Articles

Developing Therapeutics for PrP Prion Diseases.

Giles K, Olson S, Prusiner S Cold Spring Harb Perspect Med. 2017; 7(4).

PMID: 28096242 PMC: 5378016. DOI: 10.1101/cshperspect.a023747.

Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models.

Parks A, Charest-Morin X, Boivin-Welch M, Bouthillier J, Marceau F PeerJ. 2015; 3:e1314.

PMID: 26500823 PMC: 4614855. DOI: 10.7717/peerj.1314.

Convection-enhanced delivery of AAV2-PrPshRNA in prion-infected mice.

Ahn M, Bajsarowicz K, Oehler A, Lemus A, Bankiewicz K, DeArmond S PLoS One. 2014; 9(5):e98496.

PMID: 24866748 PMC: 4035323. DOI: 10.1371/journal.pone.0098496.

Quinacrine promotes replication and conformational mutation of chronic wasting disease prions.

Bian J, Kang H, Telling G Proc Natl Acad Sci U S A. 2014; 111(16):6028-33.

PMID: 24711410 PMC: 4000840. DOI: 10.1073/pnas.1322377111.

Pharmacokinetics of quinacrine efflux from mouse brain via the P-glycoprotein efflux transporter.

Ahn M, Ghaemmaghami S, Huang Y, Phuan P, May B, Giles K PLoS One. 2012; 7(7):e39112.

PMID: 22768295 PMC: 3388068. DOI: 10.1371/journal.pone.0039112.

References

Wu X, Prasad P, Leibach F, Ganapathy V . cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem Biophys Res Commun. 1998; 246(3):589-95. DOI: 10.1006/bbrc.1998.8669. View

Korth C, May B, Cohen F, Prusiner S . Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc Natl Acad Sci U S A. 2001; 98(17):9836-41. PMC: 55539. DOI: 10.1073/pnas.161274798. View

Dehouck M, Bree F, Fruchart J, Cecchelli R, Tillement J . Drug transfer across the blood-brain barrier: correlation between in vitro and in vivo models. J Neurochem. 1992; 58(5):1790-7. DOI: 10.1111/j.1471-4159.1992.tb10055.x. View

Tatsuta T, Naito M, Mikami K, Tsuruo T . Enhanced expression by the brain matrix of P-glycoprotein in brain capillary endothelial cells. Cell Growth Differ. 1994; 5(10):1145-52. View

Yabuuchi H, Tamai I, Nezu J, Sakamoto K, Oku A, SHIMANE M . Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J Pharmacol Exp Ther. 1999; 289(2):768-73. View

Kekuda R, Prasad P, Wu X, Wang H, Fei Y, Leibach F . Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J Biol Chem. 1998; 273(26):15971-9. DOI: 10.1074/jbc.273.26.15971. View

Maegawa H, Kato M, Inui K, Hori R . pH sensitivity of H+/organic cation antiport system in rat renal brush-border membranes. J Biol Chem. 1988; 263(23):11150-4. View

Tamai I, Yabuuchi H, Nezu J, Sai Y, Oku A, SHIMANE M . Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett. 1998; 419(1):107-11. DOI: 10.1016/s0014-5793(97)01441-5. View

Ennis S, Ren X, Betz A . Mechanisms of sodium transport at the blood-brain barrier studied with in situ perfusion of rat brain. J Neurochem. 1996; 66(2):756-63. DOI: 10.1046/j.1471-4159.1996.66020756.x. View

10.

Sawada N, Takanaga H, Matsuo H, Naito M, Tsuruo T, Sawada Y . Choline uptake by mouse brain capillary endothelial cells in culture. J Pharm Pharmacol. 1999; 51(7):847-52. DOI: 10.1211/0022357991773050. View

11.

Grundemann D, Gorboulev V, Gambaryan S, Veyhl M, Koepsell H . Drug excretion mediated by a new prototype of polyspecific transporter. Nature. 1994; 372(6506):549-52. DOI: 10.1038/372549a0. View

12.

Tatsuta T, Naito M, Sugawara I, Tsuruo T . Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem. 1992; 267(28):20383-91. View

13.

Tamai I, Ohashi R, Nezu J, Sai Y, Kobayashi D, Oku A . Molecular and functional characterization of organic cation/carnitine transporter family in mice. J Biol Chem. 2000; 275(51):40064-72. DOI: 10.1074/jbc.M005340200. View

14.

Follette P . New perspectives for prion therapeutics meeting. Prion disease treatment's early promise unravels. Science. 2003; 299(5604):191-2. DOI: 10.1126/science.299.5604.191. View

15.

Wu X, George R, Huang W, Wang H, Conway S, Leibach F . Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim Biophys Acta. 2000; 1466(1-2):315-27. DOI: 10.1016/s0005-2736(00)00189-9. View

16.

Koepsell H . Organic cation transporters in intestine, kidney, liver, and brain. Annu Rev Physiol. 1998; 60:243-66. DOI: 10.1146/annurev.physiol.60.1.243. View

17.

Okuda M, Saito H, Urakami Y, Takano M, Inui K . cDNA cloning and functional expression of a novel rat kidney organic cation transporter, OCT2. Biochem Biophys Res Commun. 1996; 224(2):500-7. DOI: 10.1006/bbrc.1996.1056. View

18.

Bradford M . A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72:248-54. DOI: 10.1016/0003-2697(76)90527-3. View

19.

Sweet D, Pritchard J . rOCT2 is a basolateral potential-driven carrier, not an organic cation/proton exchanger. Am J Physiol. 1999; 277(6):F890-8. DOI: 10.1152/ajprenal.1999.277.6.F890. View

20.

Chan B, Satriano J, Pucci M, Schuster V . Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter "PGT". J Biol Chem. 1998; 273(12):6689-97. DOI: 10.1074/jbc.273.12.6689. View