Skip to main content
Log in

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

  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

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 K m of 52.1 μM. 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).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Bradford, M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein dye binding. Anal. Biochem. 72: 248-254.

    Google Scholar 

  • Chan, B. S., Satriano, J. A., Pucci, M., and Schuster, V. L. (1998). Mechanism of prostaglandin E2 transport across the plasma membrane of HeLa cells and Xenopus oocytes expressing the prostaglandin transporter “PGT”. J. Biol. Chem. 273: 6689-6697.

    Google Scholar 

  • Dehouck, M.-P., Jolliet-Riant, P., Brée, F., Fruchart, J.-C., Cecchelli, R., and Tillement, J.-P. (1992). Drug transfer across the blood-brain barrier: Correlation between in vitro and in vivo models. J. Neurochem. 58: 1790-1797.

    Google Scholar 

  • Ennis, S. R., Ren, X., and Betz, A. L. (1996). Mechanisms of sodium transport at the blood-brain barrier studied with in situ perfusion of rat brain J. Neruochem. 66: 756-763.

    Google Scholar 

  • Follette, P. (2003). Prion disease treatment's early promise unravels. Science 299: 191-192.

    Google Scholar 

  • Friedrich, A., George, R. L., Bridges, C. C., Prasad, P. D., and Ganapathy, V. (2001). Transport of cholin and its relationship to the expression of organic cation transporters in a rat brain microvessel cell line (RBE4). Biochim. Biophys. Acta 1512: 299-307.

    Google Scholar 

  • Friedrich, A., Prasad, P. D., Freyer, D., Ganapathy, V., and Brust, P. (2003). Molecular cloning and functional characterization of the OCTN2 transporter at the RBE4 cells, an in vitro model of the blood-brain barrier. Brain Res. 968: 69-79.

    Google Scholar 

  • Gorboulev, V., Ulzheimer, J. C., Akhoundova, A., Ulzheimer-Teuber, I., Karbach, U., Quester, S., Baumann, C., Lang, F., Busch, A. E., and Koepsell, H. (1997). Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 16: 871-881.

    Google Scholar 

  • Grundemann, D., Gorboulev, V., Gambaryan, M., Vehyhl, M., and Koepsell, H. (1994). Drug excretion mediated by a new prototype of polyspecific transporter. Nature 372: 549-552.

    Google Scholar 

  • Kekuda, R., Prasad, P. D., Wu, X., Wang, H., Fei, Y. J., Leibach, F. H., and Ganapathy, V. (1998). Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta. J. Biol. Chem. 273: 15971-15979.

    Google Scholar 

  • Koepsell, H. (1998). Organic cation transporters in intestine, kidney, liver, and brain. Annu. Rev. Physiol. 60: 243-266.

    Google Scholar 

  • Korth, C., May, B. C. H., Cohen, F. E., and Prusiner, S. B. (2001). Acridine and phenothiazine derivatives as pharmacotherapeutics for prion disease. Proc. Natl. Acad. Sci. U.S.A. 98: 9836-9841.

    Google Scholar 

  • Maegawa, H., Kato, M., Inui, K., and Hori, R. (1988). pH sensitivity of H+/organic cation antiport system in rat renal brush-border membranes. J. Biol. Chem. 263: 11150-11154.

    Google Scholar 

  • Miller, D. S., Villalobos, A. R., and Pritchard, J. B. (1999). Organic cation transport in rat choroid plexus cells studied by fluorescence microscopy. Am. J. Physiol. 276: C955-C968.

    Google Scholar 

  • Okuda, N., Saito, H., Urakami, Y., Takano, M., and Inui, K. I. (1996). cDNA cloning and functional expression of a novel rat kidney organic cation transporter. Biochem. Biophys. Res. Commun. 224: 500-507.

    Google Scholar 

  • Sawada, N., Takanaga, H., Matsuo, H., Naito, M., Tsuruo, T., and Sawada, Y. (1999). Choline uptake by mouse brain capillary endothelial cells in culture. J. Pharm. Pharmacol. 51: 847-852.

    Google Scholar 

  • Sweet, D. H., and Pritchard, J. (1999). rOCT2 is a basolateral potential-driven carrier, not an organic cation/proton exchanger. Am. J. Physiol. 277: F890-F898.

    Google Scholar 

  • Tamai, I., Ohashi, R., Nezu, J., Sai, Y., Kobayashi, D., Oku, A., Shimane, M., and Tsuji, A. (2000). Molecular and functional characterization of organic cation/carnitine transporter family in mice. J. Biol. Biochem. 275: 40064-40072.

    Google Scholar 

  • Tamai, I., Yabuuchi, H., Nezu, J., Sai, Y., Oku, A., Shimane, M., and Tsuji, A. (1997). Cloning and characterization of a novel human pH-dependent organic cation transporter, OCTN1. FEBS Lett. 419: 107-111.

    Google Scholar 

  • Tatsuta, T., Naito, M., Mikami, K., and Tsuruo, T. (1994). Enhanced expression by the brain matrix of P-glycoprotein in brain capillary endothelial cells. Cell Growth Differ. 5: 1145-1152.

    Google Scholar 

  • Tatsuta, T., Naito, M., Oh-hara, T., Sugawara, I., and Tsuruo, T. (1992). Functional involvement of P-glycoprotein in blood-brain barrier. J. Biol. Chem. 267: 20383-20391.

    Google Scholar 

  • Wu, X., George, R. L., Huang, W., Wang, H., Conway, S. J., Leibach, F. H., and Ganapathy, V. (2000). Structural and functional characteristics and tissue distribution pattern of rat OCTN1, an organic cation transporter, cloned from placenta. Biochim. Biophys. Acta 1466: 315-327.

    Google Scholar 

  • Wu, X., Huang, W., Prasad, P. D., Seth, P., Rajan, D. P., Leibach, F. H., Chen, J., Conway, S. J., and Ganapathy, V. (1999). Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter. J. Pharmacol. Exp. Ther. 290: 1482-1492.

    Google Scholar 

  • Wu, X., Prasad, P. D., Leibach, F. H., and Ganapathy, V. (1998). cDNA sequence, transport function, and genomic organization of human OCTN2, a new member of the organic cation transporter family. Biochem. Biophys. Res. Commun. 246: 589-595.

    Google Scholar 

  • Yabuuchi, H., Tamai, I., Nezu, J., Sakamoto, K., Oku, A., Shimane, M., Sai, Y., and Tsuji, A. (1999). Novel membrane transporter OCTN1 mediates multispecific, bidirectional, and pH-dependent transport of organic cations. J. Pharmacol. Exp. Ther. 289: 768-773.

    Google Scholar 

  • Yamaoka, K., Tanigawara, Y., Nakagawa, T., and Uno, T. (1981). A pharmacokinetic analysis program (MULTI) for microcomputer. J. Pharmacobiodyn. 4: 879-885.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dohgu, S., Yamauchi, A., Takata, F. et al. Uptake and Efflux of Quinacrine, a Candidate for the Treatment of Prion Diseases, at the Blood-Brain Barrier. Cell Mol Neurobiol 24, 205–217 (2004). https://doi.org/10.1023/B:CEMN.0000018617.21378.95

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:CEMN.0000018617.21378.95

Navigation