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The Efflux Transport of Choline through Blood-Brain Barrier is Inhibited by Alzheimer's Disease Therapeutics

  • Lee, Na-Young (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University) ;
  • Kang, Young-Sook (College of Pharmacy and Research Institute of Pharmaceutical Sciences, Sookmyung Women's University)
  • Published : 2008.09.30

Abstract

In the present study, we examined the effects of several therapeutics of Alzheimer's disease, such as donepezil hydrochloride, tacrine and $\alpha$-phenyl-n-tert-butyl nitrone (PBN) on choline efflux from brain to circulating blood. The brain-to-blood efflux of [$^3H$]choline in rats was significantly inhibited by tacrine and PBN. Also the [$^3H$]choline efflux was reduced by tacrine and donepezil hydrochloride in the TR-BBB cells, in vitro the blood-brain barrier (BBB) model. These results suggest that these drugs may influence choline efflux transport from brain to blood and regulate the choline level in brain resulting in the increase of acetylcholine synthesis.

Keywords

References

  1. Allen, D.D., and Smith, Q.R. (2001) Characterization of the blood-brain barrier choline transporter using the in situ rat brain perfusion technique. J. Neurochem. 76, 1032-1041 https://doi.org/10.1046/j.1471-4159.2001.00093.x
  2. Blusztajn, J.K., and Wurtman, R.J. (1983) Choline and cholinergic neurons. Science 221, 614-620 https://doi.org/10.1126/science.6867732
  3. Cohen, B.M., Renshaw, P.F., Stoll, A.L., Wurtman, R.J., Yurgelun- Todd, D., and Babb, S.M. (1995) Decreased brain choline uptake in older adults: an in vivo proton magnetic resonance spectroscopy study. J. Am. Med. Assoc. 274, 902-907 https://doi.org/10.1001/jama.1995.03530110064037
  4. Cornford, E.M., Braun, L.D., and Oldendorf, W.H. (1978) Carrier mediated blood-brain barrier transport of choline and certain analogs. J. Neurochem. 30, 299-308 https://doi.org/10.1111/j.1471-4159.1978.tb06530.x
  5. Cornford, E.M. (1985) The blood-brain barrier, a dynamic regulatory interface. Mol. Physiol. 7, 219-259
  6. Dolezal, V., and Tucek, S. (1992) Investigation of the mechanism of the effect of tacrine (tetrahydroaminoacridine) on the metabolism of acetylcholine and choline in brain cortical prisms. J. Neural. Transm. Park. Dis. Dement. Sect. 4, 303-318 https://doi.org/10.1007/BF02260079
  7. Grason, S.I. (1996) Evaluation of tacrine hydrochloride (Cognex) in two parallel-group studies. Acta. Neurol. Scand. Suppl. 165, 114-122
  8. Hosoya, K.I., Takashima, T., Tetsuka, K., Nagura, T., Ohtsuki, S., Takanaga, H., Ueda, M., Yanai, N., Obinata, M., and Terasaki, T. (2000) mRNA expression and transport characterization of conditionally immortalized rat brain capillary endothelial cell lines, a new in vitro BBB model for drug targeting. J. Drug Target. 8, 357-370 https://doi.org/10.3109/10611860008997912
  9. Kakee, A., Terasaki, T., and Sugiyama, Y. (1996) Brain efflux index as a novel method of analyzing efflux transport at the blood-brain barrier. J. Pharmacol. Exp. Ther. 277, 1550-1559
  10. Kang, Y.S., Terasaki, T., Ohnishi, T., and Tsuji, A. (1990) In vivo and in vitro evidence for a common carrier mediated transport of choline and basic drugs through the blood-brain barrier. J. Pharmacobiodyn. 13, 353-360 https://doi.org/10.1248/bpb1978.13.353
  11. Kang, Y.S., Lee, K.E., Lee, N.Y., and Terasaki, T. (2005) Donepezil, tacrine and alpha-phenyl-n-tert-butyl nitrone (PBN) inhibit choline transport by conditionally immortalized rat brain capillary endothelial cell lines (TR-BBB). Arch. Pharm. Res. 28, 443-450 https://doi.org/10.1007/BF02977674
  12. Knapp, M.J., Knopman, D.S., Solomon, P.R., Pendlebury, W.W., Davis, C.S., and Gracon, S.I. (1994) A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer's disease. J. Am. Med. Assoc. 271, 985-991 https://doi.org/10.1001/jama.1994.03510370037029
  13. Knecht, K.T., and Mason, R.P. (1993) In vivo spin trapping of xenobiotic free radical metabolites. Arch. Biochem. Biophys. 303, 185-194 https://doi.org/10.1006/abbi.1993.1272
  14. Lee, N.Y., and Kang, Y.S. (2006) In vivo brain-to-blood efflux transport of choline at the blood-brain barrier. J. Appl. Pharmacol. 14, 45-49
  15. MaNally, W.P., Pool, W.F., Sinz, M.W., Dehart, P., Ortwine, D.F., Huang, C.C., Chang, T., and Woolf, T.F. (1996) Distribution of tacrine and metabolites in rat brain and plasma after single- and multiple-dose regimens; Evidence for accumulation of tacrine in brain tissue. Drug Metab. Dispos. 24, 628-633
  16. Matsui, K., Mishima, M., Nagai, Y., Yuzuriha, T., and Yoshimura, T. (1999) Absorption, Distribution, Metabolism, and Excretion of Donepezil (Aricept) after a Single Oral Administration to Rat. Drug Metab. Dispos. 27, 1406-1414
  17. Metting, T.L., Burgio, D.E., Terry, A.V., Beach, J.W., Mccurdy, C.R., and Allen, D.D. (1998) Inhibition of brain choline uptake by isoarecolone and lobeline derivatives: implications for potential vector-mediated brain drug delivery. Neurosci. Let. 258, 25-28 https://doi.org/10.1016/S0304-3940(98)00871-4
  18. Nitsch, R.M., Blusztajn, J.K., Pittas, A.G., Slack, B.E., Growdon, J.H., and Wurtman, R.J. (1992) Evidence for a membrane defect in Alzheimer disease brain. Proc. Natl. Acad. Sci. USA 89, 1671-1675 https://doi.org/10.1073/pnas.89.5.1671
  19. Ohtsuki, S., and Terasaki T. (2007) Contribution of carrier-mediated transport systems to the blood-brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm. Res. 24, 1745-1758 https://doi.org/10.1007/s11095-007-9374-5
  20. Pardridge, W.M. (1988) Recent advances in blood-brain barrier transport. Annu. Rev. Pharmacol. Toxicol. 28, 25-39 https://doi.org/10.1146/annurev.pa.28.040188.000325
  21. Rho, J.P., and Lipson, L.G. (1997) Focus on donepezil: A reversible acetylcholinesterase inhibitor for the treatment of Alzheimer's disease. Formulary 32, 677-678
  22. 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 https://doi.org/10.1211/0022357991773050
  23. Smith, Q.R. (1993) Drug delivery to brain and the role of carriermediated transport. Adv. Exp. Med. Biol. 331, 83-93 https://doi.org/10.1007/978-1-4615-2920-0_14
  24. Spector, R. (1989) Micronutrient homeostasis in mammalian brain and cerebrospinal fluid. J. Neurochem. 53, 1667-1674 https://doi.org/10.1111/j.1471-4159.1989.tb09229.x
  25. Takada, Y., Vistica, D.T., Greig, N.H., Purdon, D., Rapoport, S.I., and Smith, Q.R. (1992) Rapid high affinity transport of a chemotherapeutic amino acid across the blood-brain barrier. Cancer Res. 52, 2191-2196
  26. Takanaga, H., Ohtsuki, S., Hosoya, K., and Terasaki, T. (2001) GAT2/BGT-1 as a system responsible for the transport of gamma-aminobutyric acid at the mouse blood-brain barrier. J. Cereb. Blood Flow Metabol. 21, 1232-1239 https://doi.org/10.1097/00004647-200110000-00012
  27. Wurtman, R.J. (1992) Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurosci. 15, 117-122 https://doi.org/10.1016/0166-2236(92)90351-8
  28. Zhao, Q., Pahlmark, K., Smith, M.L., and Siesjo, B.K. (1994) Delayed treatment with the spin trap $\alpha$-phenyl-n-tert-butyl nitrone (PBN) reduces infarct size following transient middle cerebral artery occlusion in rats. Acta Physiol. Scand. 152, 349-350 https://doi.org/10.1111/j.1748-1716.1994.tb09816.x

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