Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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Involvement of a Novel Organic Cation Transporter in Paeonol Transport Across the Blood-Brain Barrier

  • Received : 2019.01.17
  • Accepted : 2019.02.20
  • Published : 2019.05.01
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Abstract

Paeonol has neuroprotective function, which could be useful for improving central nervous system disorder. The purpose of this study was to characterize the functional mechanism involved in brain transport of paeonol through blood-brain barrier (BBB). Brain transport of paeonol was characterized by internal carotid artery perfusion (ICAP), carotid artery single injection technique (brain uptake index, BUI) and intravenous (IV) injection technique in vivo. The transport mechanism of paeonol was examined using conditionally immortalized rat brain capillary endothelial cell line (TR-BBB) as an in vitro model of BBB. Brain volume of distribution (VD) of [$^3H$]paeonol in rat brain was about 6-fold higher than that of [$^{14}C$]sucrose, the vascular space marker of BBB. The uptake of [$^3H$]paeonol was concentration-dependent. Brain volume of distribution of paeonol and BUI as in vivo and inhibition of analog as in vitro studies presented significant reduction effect in the presence of unlabeled lipophilic compounds such as paeonol, imperatorin, diphenhydramine, pyrilamine, tramadol and ALC during the uptake of [$^3H$]paeonol. In addition, the uptake significantly decreased and increased at the acidic and alkaline pH in both extracellular and intracellular study, respectively. In the presence of metabolic inhibitor, the uptake reduced significantly but not affected by sodium free or membrane potential disruption. Similarly, paeonol uptake was not affected on OCTN2 or rPMAT siRNA transfection BBB cells. Interestingly. Paeonol is actively transported from the blood to brain across the BBB by a carrier mediated transporter system.

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References

  1. Abbott, N. J., Patabendige, A. A., Dolman, D. E., Yusof, S. R. and Begley, D. J. (2010) Structure and function of the blood-brain barrier. Neurobiol. Dis. 37,13-25. https://doi.org/10.1016/j.nbd.2009.07.030
  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, 1293-304. https://doi.org/10.1038/jcbfm.2009.54
  3. Bickel, U., Schumacher, O. P., Kang, Y. S. and Voigt, K. (1996) Poor permeability of morphine 3-glucuronide and morphine 6-glucuronic through the blood-brain barrier in the rat. J. Pharmacol. Exp. Ther. 278,107-113.
  4. Bostrom, E., Simonsson, U. S. and Hammarlund-Udenaes, M. (2006) In vivo blood-brain barrier transport of oxycodone in the rat: indications for active influx and implications for pharmacokinetics/pharmacodynamics. Drug Metab. Dispos. 34, 1624-1631. https://doi.org/10.1124/dmd.106.009746
  5. 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, 1-10.
  6. 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
  7. Higuchi, K., Kitamura, A., Okura, T. and Deguchi, Y. (2015) Memantine transport by a proton-coupled organic cation antiporter in hCMEC/D3 cells, an in vitro human blood-brain barrier model. Drug Metab. Pharmacokinet. 30, 182-187. https://doi.org/10.1016/j.dmpk.2014.12.006
  8. Himaya, S. W., Ryu, B., Qian, Z. J. and Kim, S. K. (2012) Paeonol from Hippocampus kudaBleeler suppressed the neuro-inflammatory responses in vitro via NF-${\kappa}$B and MAPK signaling pathways. Toxicol. In Vitro. 26, 878-887. https://doi.org/10.1016/j.tiv.2012.04.022
  9. 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
  10. Kang, Y. S., Boado, R. J. and Pardrodge, W. M. (1995) Pharmacokinetic and the organ clearance of A 3'-Biotinylaed, internally [$^{32}P$]-labeled phosphodiester oligodeoxynucleotide coupled to a neutral avidin/monoclonal antibody conjugate. Drug. Metab. Dispos. 23, 55-59.
  11. Kang, Y. S. and Park, J. H. (2000) Brain uptake and the analgesic effect oxytocin its usefulness as an analgesic agent. Arch. Pharm. Res. 23, 391-395. https://doi.org/10.1007/BF02975453
  12. 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 line (TR-BBB). Arch. Pharm. Res. 28, 443-450. https://doi.org/10.1007/BF02977674
  13. 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
  14. 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
  15. Kooijmans, S. A., Senyschyn, D., Mezhiselvam, M. M., Morizzi, J., Charman, S. A., Weksler, B., Romero, I. A., Couraud, P. O. and Nicolazzo, J. A. (2012) The involvement of a $Na^+$- and $Cl^-$-dependent transporter in the brain uptake of amantadine and rimantadine. Mol. Pharm. 9, 883-893. https://doi.org/10.1021/mp2004127
  16. Kubo, Y., Kusagawa, Y., Tachikawa, M., Akanuma, S. and Hosoya, K. (2013a) 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
  17. Kubo, Y., Shimizu, Y., Kusagawa, Y., Akanuma, S. and Hosoya, K. (2013b) Propranolol transport across the inner blood-retinal barrier: potential involvement of a novel organic cation transporter. J Pharm. Sci. 102, 3332-3342. https://doi.org/10.1002/jps.23535
  18. Lau, C. H., Chan, C. M., Chan, Y. W., Lau, K. M., Lau, T. W., Lam, F. C., Law, W. T., Che, C. T., Leung, P. C., Fung, K. P., Ho, Y. Y. and Lau, C. B. (2007) Pharmacological investigations of the antidiabetic effect of Cortex Moutan and its active component paeonol. Phytomedicine 14, 778-784. https://doi.org/10.1016/j.phymed.2007.01.007
  19. Lee, N. Y. and Kang, Y. S. (2010) The inhibitory effect of rivastigmine and galantamine on choline transport in brain capillary endothelial cells. Biomol. Ther. (Seoul) 18, 65-70. https://doi.org/10.4062/biomolther.2010.18.1.065
  20. 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
  21. Lee, N. Y., Choi, H. O. and Kang, Y. S. (2012) The acetylcholinesterase inhibitors competitively inhibited an acetyl L-carnitine transport through the blood-brain barrier. Neurochem. Res. 37, 1499-1507. https://doi.org/10.1007/s11064-012-0723-3
  22. Lee, N. Y., Lee, H. E. and Kang, Y. S. (2014a) Identification of P-Glycoprotein and transport mechanism of Paclitaxel in syncytiotrophoblast cells. Biomol. Ther. (Seoul) 22, 68-72. https://doi.org/10.4062/biomolther.2013.105
  23. Lee, N. Y., Lee, K. B. and Kang, Y. S. (2014b) Pharmacokinetic, 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., 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
  25. Li, H., Wang, S., Zhang, B., Xie, Y., Wang, J., Yang, Q., Cao, W., Hu, J. and Duan, L. (2012) Influence of co-administered danshensu on pharmacokinetic fate and tissue distribution of paeonol in rats. Planta Med. 78, 135-140. https://doi.org/10.1055/s-0031-1280269
  26. Lin, H. C., Ding, H. Y., Ko, F. N., Teng, C. M. and Wu, Y. C. (1999) Aggregation inhibitory activity of minor acetophenones from Paeonia species. Planta Med. 65, 595-599. https://doi.org/10.1055/s-1999-14030
  27. Liu, J., Feng, L., Ma, D., Zhang, M., Gu, J., Wang, S., Fu, Q., Song, Y., Lan, Z., Qu, R. and Ma, S. (2013) Neuroprotective effect of paeonol on cognition deficits of diabetic encephalopathy in streptozotocin-induced diabetic rat. Neurosci. Lett. 549, 63-68. https://doi.org/10.1016/j.neulet.2013.06.002
  28. Misra, A., Ganesh, S., Shahiwala, A. and Shah, S. P. (2003) Drug delivery to the central nervous system: a review. J. Pharm. Sci. 6, 252-273.
  29. 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
  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, 3924-38. https://doi.org/10.1002/jps.22594
  33. Okura, T., Higuchi, K., Kitamura, A. and Deguchi, Y. (2014a) Proton-coupled organic cation antiporter-mediated uptake of apomorphine enantiomers in human brain capillary endothelial cell line hCMEC/D3. Biol. Pharm. Bull. 37, 286-291. https://doi.org/10.1248/bpb.b13-00773
  34. Okura, T., Kato, S. and Deguchi, Y. (2014b) Functional expression of organic cation/carnitine transporter 2 (OCTN2/SLC22A5) in human brain capillary endothelial cell line hCMEC/D3, a human bloodbrain barrier model. Drug Metab. Pharmacokinet. 29, 69-74. https://doi.org/10.2133/dmpk.DMPK-13-RG-058
  35. Palmer, A. M. (2011) Neuroprotective therapeutics for Alzheimer's disease. Trends Pharmacol. Sci. 32, 141-147. https://doi.org/10.1016/j.tips.2010.12.007
  36. Pardridge, W. M., Kang, Y. S. and Buciak, J. L. (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
  37. Pardridge, W. M. (2005) The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2, 3-14. https://doi.org/10.1602/neurorx.2.1.3
  38. Pardridge, W. M. (2012) Drug transport across the blood-brain barrier. J. Cereb. Blood Flow Metab. 32, 1959-72. https://doi.org/10.1038/jcbfm.2012.126
  39. Pardridge, W. M. (2015) Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery. Expert. Opin. Ther. Targets 19, 1059-1072. https://doi.org/10.1517/14728222.2015.1042364
  40. Sadiq, M. W., Borgs, A., Okura, T., Shimomura, K., Kato, S., Deguchi, Y., Jansson, B., Björkman, 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
  41. Shimomura, K., Okura, T., Kato, S., Couraud, P. O., Scherrmann, 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
  42. Suzuki, T., Ohmuro, A., Miyata, M., Furuishi, T., Hidaka, S., Kugawa, F., Fukami, T. and Tomono, K. (2010) Involvement of an influx transporter in the blood brain barrier transport of naloxone. Biopharm. Drug Dispos. 31, 243-252. https://doi.org/10.1002/bdd.707
  43. 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
  44. Tega, Y., Akanuma, S., Kubo, Y. and Hosoya, K. (2015a) Involvement of the $H^+$/organic cation antiporter in nicotine transport in rat liver. Drug Metab. Dispos. 43, 89-92. https://doi.org/10.1124/dmd.114.061002
  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. Tega, Y., Kubo, Y., Yuzurihara, C., Akanuma, S. and Hosoya, K. (2015b) Carrier-mediated transport of nicotineAcross the Innerblood-retinal barrier: Involvement of a novel organic cation transporter driven by an outward $H^{(+)}$ gradient. J. Pharm. Sci. 104, 3069-3075. https://doi.org/10.1002/jps.24453
  47. Tun, T. and Kang, Y. S. (2017) Imperatorin is transported through blood-brain barrier by carrier mediated transporters. Biomol. Ther. (Seoul) 25, 441-451. https://doi.org/10.4062/biomolther.2017.082
  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. Xie, Y., Zhou, H., Wong, Y. F., Xu, H. X., Jiang, Z. H. and Liu, L. (2008) Study on the pharmacokinetics and metabolism of paeonol in rats treated with pure paeonol and an herbal preparation containing paeonol by using HPLC-DAD-MS method. J. Pharm Biomed. Anal. 46, 748-756. https://doi.org/10.1016/j.jpba.2007.11.046
  50. Xu, D., Zhou, C. and Xu, B. (2008) Protective effect of paeonol on beta-amyloid 25-35 induced toxicity in PC12 cells. Neural Regen. Res. 3, 863-866.
  51. Xu, S. P., Sun, G. P., Shen, Y. X., Wei, W., Peng, W. R. and Wang, H. (2007) Antiproliferation and apoptosis induction of paeonol in HepG2 cells. World J. Gastroenterol. 13, 250-256. https://doi.org/10.3748/wjg.v13.i2.250
  52. Zhao, Y., Fu, B., Zhang, X., Zhao, T., Chen, L., Zhang, J. and Wang, X. (2014) Paeonol pretreatment attenuates cerebral ischemic injury via upregulating expression of pAkt, Nrf2, HO-1 and ameliorating BBB permeability in mice. Brain Res. Bull. 109, 61-67. https://doi.org/10.1016/j.brainresbull.2014.09.008
  53. Zhong, S. Z., Ge, Q. H., Qu, R., Li, Q. and Ma, S. P. (2009) Paeonol attenuates neurotoxicity and ameliorates cognitive impairment induced by d-galactose in ICR mice. J. Neurol. Sci. 277, 58-64. https://doi.org/10.1016/j.jns.2008.10.008
  54. Zhou, A., Wu, H., Pan, J., Wang, X., Li, J., Wu, Z. and Hui, A. (2015) Synthesis and evaluation of paeonol derivatives as potential multifunctional agents for the treatment of Alzheimer's disease. Molecules 20, 1304-1318. https://doi.org/10.3390/molecules20011304
  55. Zhou, J., Zhou, L., Hou, D., Tang, J., Sun, J. and Bondy, S.C. (2011) Paeonol increases levels of cortical cytochrome oxidase and vascular actin and improves behavior in a rat model of Alzheimer's disease. Brain Res. 1388, 141-147. https://doi.org/10.1016/j.brainres.2011.02.064

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