Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Imperatorin is Transported through Blood-Brain Barrier by Carrier-Mediated Transporters

  • Tun, Temdara (College of Pharmacy, Drug Information Research Institute and Research Center for Cell Fate Control, Sookmyung Women's University) ;
  • Kang, Young-Sook (College of Pharmacy, Drug Information Research Institute and Research Center for Cell Fate Control, Sookmyung Women's University)
  • Received : 2017.04.04
  • Accepted : 2017.04.13
  • Published : 2017.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Imperatorin, a major bioactive furanocoumarin with multifunctions, can be used for treating neurodegenerative diseases. In this study, we investigated the characteristics of imperatorin transport in the brain. Experiments of the present study were designed to study imperatorin transport across the blood-brain barrier both in vivo and in vitro. In vivo study was performed in rats using single intravenous injection and in situ carotid artery perfusion technique. Conditionally immortalized rat brain capillary endothelial cells were as an in vitro model of blood-brain barrier to examine the transport mechanism of imperatorin. Brain distribution volume of imperatorin was about 6 fold greater than that of sucrose, suggesting that the transport of imperatorin was through the blood-brain barrier in physiological state. Both in vivo and in vitro imperatorin transport studies demonstrated that imperatorin could be transported in a concentration-dependent manner with high affinity. Imperatorin uptake was dependent on proton gradient in an opposite direction. It was significantly reduced by pretreatment with sodium azide. However, its uptake was not inhibited by replacing extracellular sodium with potassium or N-methylglucamine. The uptake of imperatorin was inhibited by various cationic compounds, but not inhibited by TEA, choline and organic anion substances. Transfection of plasma membrane monoamine transporter, organic cation transporter 2 and organic cation/carnitine transporter 2/1 siRNA failed to alter imperatorin transport in brain capillary endothelial cells. Especially, tramadol, clonidine and pyrilamine inhibited the uptake of [$^3H$]imperatorin competitively. Therefore, imperatorin is actively transported from blood to brain across the blood-brain barrier by passive and carrier-mediated transporter.

Keywords

References

  1. Abad, M. J., de las Heras, B., Silvan, A. M., Pascual, R., Bermejo, P., Rodriquez, B. and Villar, A. M. (2001) Effects of furocoumarins from Cachrys trifida on some macrophage functions. J. Pharm. Pharmacol. 53, 1163-1168. https://doi.org/10.1211/0022357011776432
  2. Andre, P., Debray, M., Scherrmann, J. M. and Cisternino, S. (2009) Clonidine transport at the mouse blood-brain barrier by a new H+ antiporter that interacts with addictive drugs. J. Cereb. Blood Flow Metab. 29, 1293-1304. https://doi.org/10.1038/jcbfm.2009.54
  3. Baek, N. I., Ahn, E. M., Kim, H. Y. and Park, Y. D. (2000) Furanocoumarins from the root of Angelica dahurica. Arch. Pharm. Res. 23, 467-470. https://doi.org/10.1007/BF02976574
  4. Budzynska, B., Boguszewska-Czubara, A., Kruk-Slomka, M., Skalicka-Wozniak, K., Michalak, A., Musik, I. and Biala, G. (2015) Effects of imperatorin on scopolamine-induced cognitive impairment and oxidative stress in mice. Psychopharmacology (Berl.) 232, 931-942. https://doi.org/10.1007/s00213-014-3728-6
  5. Budzynska, B., Kruk-Slomka, M., Skalicka-Wozniak, K., Biala, G. and Glowniak, K. (2012) The effects of imperatorin on anxiety and memory-related behavior in male Swiss mice. Exp. Clin. Psychopharmacol. 20, 325-332. https://doi.org/10.1037/a0028391
  6. Chapy, H., Smirnova, M., Andre, P., Schlatter, J., Chiadmi, F., Couraud, P. O., Scherrmann, J. M., Decleves, X. and Cisternino, S. (2014) Carrier-mediated cocaine transport at the blood-brain barrier as a putative mechanism in addiction liability. Int. J. Neuropsychopharmacol. 18, pyu001.
  7. Chapy, H., Goracci, L., Vayer, P., Parmentier, Y., Carrupt, P. A., Decleves, X., Scherrmann, J. M., Cisternino, S. and Cruciani, G. (2015) Pharmacophore-based discovery of inhibitors of a novel drug/proton antiporter in human brain endothelial hCMEC/D3 cell line. Br. J. Pharmacol. 172, 4888-4904. https://doi.org/10.1111/bph.13258
  8. Cisternino, S., Chapy, H., Andre, P., Smirnova, M., Debray, M. and Scherrmann, J. M. (2013) Coexistence of passive and proton antiporter-mediated processes in nicotine transport at the mouse blood-brain barrier. AAPS J. 15, 299-307. https://doi.org/10.1208/s12248-012-9434-6
  9. Deguchi, Y., Yokoyama, Y., Sakamoto, T., Hayashi, H., Naito, T., Yamada, S. and Kimura, R. (2000) Brain distribution of 6-mercaptopurine is regulated by the efflux transport system in the blood-brain barrier. Life.Sci. 66, 649-662. https://doi.org/10.1016/S0024-3205(99)00637-2
  10. Fujii, S., Hayashi, H., Itoh, K., Yamada, S., Deguchi, Y. and Kawazu, K. (2013) Characterization of the carrier-mediated transport of ketoprofen, a nonsteroidal anti-inflammatory drug, in rabbit corneal epithelium cells. J. Pharm. Pharmacol. 65, 171-180. https://doi.org/10.1111/j.2042-7158.2012.01583.x
  11. Hosoya, K., Makihara, A., Tsujikawa, Y., Yoneyama, D., Mori, S., Terasaki, T., Akanuma, S., Tomi, M. and Tachikawa, M. (2009) Roles of inner blood-retinal barrier organic anion transporter 3 in the vitreous/retina-to-blood efflux transport of p-aminohippuric acid, benzylpenicillin, and 6-mercaptopurine. J. Pharmacol. Exp. Ther. 329, 87-93. https://doi.org/10.1124/jpet.108.146381
  12. Hiasa, M., Matsumoto, T., Komatsu, T., Omote H. and Moriyama, Y. (2007) Functional characterization of testis-specific rodent multidrug and toxic compound extrusion 2, a class III MATE-type polyspecific H+/organic cation exporter. Am. J. Physiol., Cell Physiol. 293, C1437-C1444. https://doi.org/10.1152/ajpcell.00280.2007
  13. 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
  14. Kang, Y. S., Ohtsuki, S., Takanaga, H., Tomi, M., Hosoya, K. and Terasaki, T. (2002) Regulation of taurine transport at the blood-brain barrier by tumor necrosis factor-alpha, taurine and hypertonicity. J. Neurochem. 83, 1188-1195. https://doi.org/10.1046/j.1471-4159.2002.01223.x
  15. Kang, Y. S. (2000) Taurine transport mechanism through the bloodbrain barrier in spontaneously hypertensive rats. Adv. Exp. Med. Biol. 483, 321-324.
  16. Kido, Y., Tamai, I., Ohnari, A., Sai, Y., Kagami, T., Nezu, J., Nikaido, H., Hashimoto, N., Asano, M. and Tsuji, A. (2001) Functional relevance of carnitine transporter OCTN2 to brain distribution of Lcarnitine and acetyl-L-carnitine across the blood-brain barrier. J. Neurochem. 79, 959-969.
  17. Kim, D. K., Lim, J. P., Yang, J. H., Eom, D. O., Eun, J. S. and Leem, K. H. (2002) Acetylcholinesterase inhibitors from the roots of Angelica dahurica. Arch. Pharm. Res. 25, 856-859. https://doi.org/10.1007/BF02977004
  18. Kitamura, A., Higuchi, K., Okura, T. and Deguchi, Y. (2014) Transport characteristics of tramadol in the blood-brain barrier. J. Pharm. Sci. 103, 3335-3341. https://doi.org/10.1002/jps.24129
  19. Koepsell, H., Lips, K. and Volk C. (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm. Res. 24, 1227-1251. https://doi.org/10.1007/s11095-007-9254-z
  20. Koziol, E. and Skalicka-Wozniak, K. (2016) Imperatorin-pharmacological meaning and analytical clues: profound investigation. Phytochem. Rev. 15, 627-649. https://doi.org/10.1007/s11101-016-9456-2
  21. Kubo, Y., Kusagawa, Y., Tachikawa, M., Akanuma, S. and Hosoya, K. (2013) Involvement of a novel organic cation transporter in verapamil transport across the inner blood-retinal barrier. Pharm. Res. 30, 847-856. https://doi.org/10.1007/s11095-012-0926-y
  22. Lee, E., Choi, S. Y., Yang, J. H. and Lee, Y. J. (2016) Preventive effects of imperatorin on perfluorohexanesulfonate-induced neuronal apoptosis via inhibition of intracellular calcium-mediated ERK pathway. Korean J. Physiol. Pharmacol. 20, 399-406. https://doi.org/10.4196/kjpp.2016.20.4.399
  23. Lee, N. Y., Lee, K. B. and Kang, Y. S. (2014) Pharmacokinetics, placenta, and brain uptake of paclitaxel in pregnant rats. Cancer Chemother. Pharmacol. 73, 1041-1045. https://doi.org/10.1007/s00280-014-2439-3
  24. Lee, N. Y. and Kang, Y. S. (2016) In vivo and in vitro evidence for brain uptake of 4-Phenylbutyrate by the monocarboxylate transporter 1 (MCT1). Pharm. Res. 33, 1711-1722. https://doi.org/10.1007/s11095-016-1912-6
  25. Lee, N. Y., Sai, Y., Nakashima, E., Ohtsuki, S. and Kang, Y. S. (2011) 6-Mercaptopurine transport by equilibrative nucleoside transporters in conditionally immortalized rat syncytiotrophoblast cell lines TR-TBTs. J. Pharm. Sci. 100, 3773-3782. https://doi.org/10.1002/jps.22631
  26. Lili, W., Yehong, S., Qi, Y., Yan, H., Jinhui, Z., Yan, L. and Cheng, G. (2013) In vitro permeability analysis, pharmacokinetic and brain distribution study in mice of imperatorin, isoimperatorin and cnidilin in Radix Angelicae Dahuricae. Fitoterapia 85, 144-153. https://doi.org/10.1016/j.fitote.2013.01.007
  27. Miecz, D., Januszewicz, E., Czeredys, M., Hinton, B. T., Berezowski, V., Cecchelli, R. and Nalecz, K. A. (2008) Localization of organic cation/carnitine transporter (OCTN2) in cells forming the bloodbrain barrier. J. Neurochem. 104, 113-123.
  28. Mori, S., Ohtsuki, S., Takanaga, H., Kikkawa, T., Kang, Y. S. and Terasaki, T. (2004) Organic anion transporter 3 is involved in the brain-to-blood efflux transport of thiopurine nucleobase analogs. J. Neurochem. 90, 931-941. https://doi.org/10.1111/j.1471-4159.2004.02552.x
  29. Ohta, K. Y., Inoue, K., Hayashi, Y. and Yuasa, H. (2006) Molecular identification and functional characterization of rat multidrug and toxin extrusion type transporter 1 as an organic cation/H+ antiporter in the kidney. Drug Metab. Dispos. 34, 1868-1874. https://doi.org/10.1124/dmd.106.010876
  30. 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
  31. Okura, T., Hattori, A., Takano, Y., Sato, T., Hammarlund-Udenaes, M., Terasaki, T. and Deguchi, Y. (2008) Involvement of the pyrilamine transporter, a putative organic cation transporter, in blood-brain barrier transport of oxycodone. Drug Metab. Dispos. 36, 2005-2013. https://doi.org/10.1124/dmd.108.022087
  32. Okura, T., Kato, S., Takano, Y., Sato, T., Yamashita, A., Morimoto, R., Ohtsuki, S., Terasaki, T. and Deguchi, Y. (2011) Functional characterization of rat plasma membrane monoamine transporter in the blood-brain and blood-cerebrospinal fluid barriers. J. Pharm. Sci. 100, 3924-3938. https://doi.org/10.1002/jps.22594
  33. Pardridge, W. M., Kang, Y. S. and Buciak, J. (1994) Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood-brain barrier in vivo using vector-mediated peptide drug delivery. Pharm. Res. 11, 738-746. https://doi.org/10.1023/A:1018940732550
  34. Roth, M., Obaidat, A. and Hagenbuch, B. (2012) OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br. J. Pharmacol. 165, 1260-1287. https://doi.org/10.1111/j.1476-5381.2011.01724.x
  35. Sadiq, M. W., Borgs, A., Okura, T., Shimomura, K., Kato, S., Deguchi, Y., Jansson, B., Bjorkman, S., Terasaki, T. and Hammarlund-Udenaes, M. (2011) Diphenhydramine active uptake at the blood-brain barrier and its interaction with oxycodone in vitro and in vivo. J. Pharm. Sci. 100, 3912-3923. https://doi.org/10.1002/jps.22567
  36. Sai, Y., Kaneko, Y., Ito, S., Mitsuoka, K., Kato, Y., Tamai, I., Artursson, P. and Tsuji, A. (2006) Predominant contribution of organic anion transporting polypeptide OATP-B (OATP2B1) to apical uptake of estrone-3-sulfate by human intestinal Caco-2 cells. Drug Metab. Dispos. 34, 1423-1431. https://doi.org/10.1124/dmd.106.009530
  37. Sancho, R., Marquez, N., Gomez-Gonzalo, M., Calzado, M. A., Bettoni, G., Coiras, M. T., Alcami, J., Lopez-Cabrera, M., Appendino, G. and Munoz, E. (2004) Imperatorin inhibits HIV-1 replication through an Sp1-dependent pathway. J. Biol. Chem. 279, 37349-37359. https://doi.org/10.1074/jbc.M401993200
  38. Senol, F. S., Wozniak, K. S., Khan, M. T. H., Orhan, I. E., Sener, B. and Glowniak, K. (2011) An in vitro and in silico approach to cholinesterase inhibitory and antioxidant effects of the methanol extract, furanocoumarin fraction, and major coumarins of Angelica officinalis L. fruits. Phytochem. Lett. 4, 462-467. https://doi.org/10.1016/j.phytol.2011.08.016
  39. Shimomura, K., Okura, T., Kato, S., Couraud, P. O., Schermann, J. M., Terasaki, T. and Deguchi, Y. (2013) Functional expression of a proton-coupled organic cation (H+/OC) antiporter in human brain capillary endothelial cell line hCMEC/D3, a human blood-brain barrier model. Fluids Barriers CNS 10, 8. https://doi.org/10.1186/2045-8118-10-8
  40. Sigurdsson, S. and Gudbjarnason, S. (2007) Inhibition of acetylcholinesterase by extracts and constituents from Angelica archangelica and Geranium sylvaticum. Z. Naturforsch., C, J. Biosci. 62, 689-693.
  41. Stavri, M. and Gibbons, S. (2005) The antimycobacterial constituents of dill (Anethum graveolens). Phytother. Res. 19, 938-941. https://doi.org/10.1002/ptr.1758
  42. Suzuki, T., Moriki, Y., Goto, H., Tomono, K., Hanano, M. and Watanabe, J. (2002) Investigation on the influx transport mechanism of pentazocine at the blood-brain barrier in rats using the carotid injection technique. Biol. Pharm. Bull. 25, 1351-1355. https://doi.org/10.1248/bpb.25.1351
  43. Takasato, Y., Rapoport, S. I. and Smith, Q. R. (1984) An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am. J. Physiol. 247, H484-H493.
  44. Tamai, I., Nakanishi, T., Kobayashi, D., China, K., Kosugi, Y., Nezu, J., Sai, Y. and Tsuji, A. (2004) Involvement of OCTN1 (SLC22A4) in pH-dependent transport of organic cations. Mol. Pharm. 1, 57-66. https://doi.org/10.1021/mp0340082
  45. Tega, Y., Akanuma, S., Kubo, Y., Terasaki, T. and Hosoya, K. (2013) Blood-to-brain influx transport of nicotine at the rat blood-brain barrier: involvement of a pyrilamine-sensitive organic cation transport process. Neurochem. Int. 62, 173-181. https://doi.org/10.1016/j.neuint.2012.11.014
  46. Terada, T. and Inui, K. (2008) Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem. Pharmacol. 75, 1689-1696. https://doi.org/10.1016/j.bcp.2007.12.008
  47. Terasaki, T. and Hosoya, K. (2001) Conditionally immortalized cell lines as a new in vitro model for the study of barrier functions. Biol. Pharm. Bull. 24, 111-118. https://doi.org/10.1248/bpb.24.111
  48. Wu, D., Kang, Y. S., Bickel, U. and Pardridge, W. M. (1997) Bloodbrain barrier permeability to morphine-6-glucuronide is markedly reduced compared with morphine. Drug Metab. Dispos. 25, 768-771.
  49. Wu, D. and Pardridge, W. M. (1999) Blood-brain barrier transport of reduced folic acid. Pharm. Res. 16, 415-419. https://doi.org/10.1023/A:1018829920158
  50. Zhang, X., Xie, Y., Cao, W., Qian, Y., Shan, M. and Siwang, W. (2011) Brain distribution study of imperatorin in rats after oral administration assessed by HPLC. Chromatographia 74, 259-265. https://doi.org/10.1007/s10337-011-2073-8

Cited by

  1. Involvement of a Novel Organic Cation Transporter in Paeonol Transport Across the Blood-Brain Barrier vol.27, pp.3, 2017, https://doi.org/10.4062/biomolther.2019.007
  2. How do psychostimulants enter the human brain? Analysis of the role of the proton-organic cation antiporter vol.192, pp.None, 2021, https://doi.org/10.1016/j.bcp.2021.114751