Biomolecules & Therapeutics

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

DOI QR Code

The Scutellaria Flavone, Oroxylin A, Improves Attention-Deficit/Hyperactivity Disorder Related Behaviors in Spontaneously Hypertensive Rats

  • Yoon, Seo-Young (Department of Pharmacy, Sahmyook University) ;
  • Chun, Mi-Sook (Department of Pharmacy, Sahmyook University) ;
  • Lee, Yong-Soo (Department of Pharmacology College of Pharmacy, Duksung Women's University) ;
  • Park, Hae-Il (College of Pharmacy, Kangwon National University) ;
  • Shin, Chan-Young (Department of Pharmacology College of Medicine, Konkuk University) ;
  • Ryu, Jong-Hoon (Department of Oriental Pharmaceutical Science College of Pharmacy, KyungHee University) ;
  • Cheong, Jae-Hoon (Uimyung Institute for Neuroscience, Sahmyook University)
  • Published : 2008.12.31
Download PDF
⟨ Previous Next ⟩

Abstract

Oroxylin A is a flavonoid isolated from Scutellaria baicalensis, which is one of the most important medicinal herbs in traditional Korean medicine. In this study, we investigated the psychopharmacological activities of oroxylin A using the open field, rota-rod, balanced wire and plus-maze tests in Spontaneously Hypertensive Rats (SHR) and Wistar Kyoto Rats (WKY). Oroxylin A reduced hyperactivity in SHR (ADHD animal model) although it tended to increase locomotor activity in WKY. Methylphenidate did not reduce hyperactivity. Oroxylin A alleviated impulsive behaviors such as rearing, the percentage of moving time to the central area and the tendency to move into an unstable condition (open area in elevated plus-maze). Methylphenidate also reduced the percentage of staying time in the central area and the tendency to move into an unstable condition. Both oroxylin A and methylphenidate enhanced motor attention in SHR and WKY. Oroxylin A antagonized the muscimol ($GABA_A$ receptor agonist)-induced $Cl^-$current and its action was similar to that of bicuculline ($GABA_A$ receptor antagonist). The effects of oroxylin A may be caused by the antagonism at the $GABA_A$ receptor. Thus, oroxylin A may be a candidate of drug for treatment of ADHD.

Keywords

References

  1. Basar, E. and Guntekin, B. (2008). A review of brain oscillations in cognitive disorders and the role of neurotransmitters. Brain Res. 1235, 172-193 https://doi.org/10.1016/j.brainres.2008.06.103
  2. Brambilla, P., Perez, J., Barale, F., Schettini, G. and Soares, J. C. (2003). GABAergic dysfunction in mood disorders. Mol. Psychiatry 8, 721–737 https://doi.org/10.1038/sj.mp.4001362
  3. Brummelte, S., Grund, T., Moll, G. H., Teuchert-Noodt, G. and Dawirs, R. R. (2008). Environmental enrichment has no effect on the development of dopaminergic and GABAergic fibers during methylphenidate treatment of early traumatized gerbils. J. Negat. Results Biomed. 7, 2 https://doi.org/10.1186/1477-5751-7-2
  4. Dekermendjian, K., Kahnberg, P., Witt, M. R., Sterner, O., Nielsen, M., and Liljefors, T. (1999). Structure-activity relationships and molecular modeling analysis of flavonoids binding to the benzodiazepine site of the rat brain GABA(A) receptor complex. J. Med. Chem. 42, 4343–4350 https://doi.org/10.1021/jm991010h
  5. Elia, J., Ambrosini, P. J. and Rapoport, J. L. (1999). Treatment of attention-deficit- hyperactivity disorder. N. Engl. J. Med. 340, 780–788 https://doi.org/10.1056/NEJM199903113401007
  6. Farkas, S., Berzsenyi, P., Karpati, E., Kocsis, P. and Tarnawa, I. (2005). Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs. J. Pharmacol. Toxicol. Methods 52, 264-273 https://doi.org/10.1016/j.vascn.2004.11.005
  7. Ferguson, S. A., Gray, E. P. and Cada, A. M. (2003). Early Behavioral Development in the Spontaneously Hypertensive Rat: A Comparison With the Wistar–Kyoto and Sprague–Dawley Strains. Behav. Neurosci. 117, 263-270 https://doi.org/10.1037/0735-7044.117.2.263
  8. Fone, K. C. and Nutt, D. J. (2005) Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder. Curr. Opin. Pharmacol. 5, 87-93 https://doi.org/10.1016/j.coph.2004.10.001
  9. Fone, K. C. and Nutt, D. J. (2005) Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder. Curr. Opin. Pharmacol. 5, 87-93 https://doi.org/10.1016/j.coph.2004.10.001
  10. Gardner, C. R., Tully, W. R. and Hedgecock, C. J. R. (1993). The rapidly expanding range of neuronal benzodiazepine receptor ligands. Prog. Neurobiol. 40, 1-61 https://doi.org/10.1016/0301-0082(93)90047-V
  11. Hui, K. M., Michael, S. Y., Huen, H. Y. W., Zheng, H., Sigel, E., Baur, R., Ren, H., Li, Z. W., Wong, J. T. F. and Xue, H. (2002). Anxiolytic effect of wogonin, a benzodiazepine receptor ligand isolated from Scutellaria baicalensis Georgi. Biochem. Pharmacol. 64, 1415-1424 https://doi.org/10.1016/S0006-2952(02)01347-3
  12. Hui, K. M., Wang, X. H. and Xue, H. (2000). Interaction of flavones from the roots of Scutellaria baicalensis with the benzodiazepine site. Planta Med. 66, 91-93
  13. Jeong, J. O., An, N. Y., Park, S. H., Oh, J. G., Oh, H. L., Lee, B. G., Om, A. S., Kim, B. S., Kim, D. H., Ryu, J. H. (2004). The Anxiolytic-like Effects of Scutellaria baicalensis Using Elevated Plus-Maze in Rats. Kor. J. Pharmacogn. 35, 22-27 https://doi.org/10.1016/j.pbb.2006.10.025
  14. Kim, D. H., Jeon, S. J., Son, K. H., Jung, J. W., Lee, S., Yoon, B. H., Choi, J. W. Cheong, J. H., Ko, K. H. and Ryu, J. H. (2006). Effect of the flavonoid, oroxylin A, on transient cerebral hypoperfusion-induced memory impairment in mice, Pharmacol. Biochem. Behav. 85, 658–668 https://doi.org/10.1016/j.pbb.2006.10.025
  15. Kim, D. H., Jeon, S. J., Son, K. H., Jung, J. W., Lee, S., Yoon, B. H., Lee, J. J., Cho, Y. W., Cheong, J. H., Ko, K. H. and Ryu, J. H. (2007). The ameliorating effect of oroxylin A on scopolamine-induced memory impairment in mice, Neurobiol. Learning & Memory 87, 536–546 https://doi.org/10.1016/j.nlm.2006.11.005
  16. Kim, D. H., Kim, S., Jeon, S. J., Son, K. H., Lee, S., Yoon, B. H., Cheong, J. H., Ko, K. H. and Ryu, J. H. (2008). The effects of acute and repeated oroxylin A treatments on Abeta(25-35)-induced memory impairment in mice. Neuropharmacol. 55, 639-647 https://doi.org/10.1016/j.neuropharm.2008.05.019
  17. Kim, M. K., Yu, G. Y., Tan-Lee, B. S., Oh, H. J., Dong, K. W., Jeong, S. H., Han, S. W. and Cheong, J. H. (2003). Antistress effect of Pyroligneous liquid in SD rats and ICR mice. J. Appl. Pharmacol. 11, 249-256 https://doi.org/10.1016/S0091-3057(01)00464-6
  18. Kollins, S. H. MacDonald, E. K. and Rush, C. R. (2001). Assessing the abuse potential of methylphenidate in nonhuman and human subjects-a review. Pharmacol. Biochem. Behav. 68, 611–627 https://doi.org/10.1016/S0091-3057(01)00464-6
  19. Krause, K. H., Dresel, S. H., Krause, J., Fougere, C. and Ackenheil, M. (2003). The dopamine transporter and neuroimaging in attention deficit hyperactivity disorder. Neurosci. Biobehav. Rev. 27, 605–613 https://doi.org/10.1016/j.neubiorev.2003.08.012
  20. Lee, G. S. Choi, J. Y., Ko, H. S., Tan-Lee, B. S., Yu, G. Y., Park, H. G. Kim, M. K., Ryu, J. H., Jung, I. K. and Cheong, J. H. (2006). Stress-reducing Effects of Brown Rice Koji. Food Sci. Biotech. 15, 63-69 https://doi.org/10.1142/S0192415X96000050
  21. Lin, C. and Shieh, D. E. (1996). The anti-inflammatory activity of Scutellaria rivularis extracts and its active components, baicalin, baicalein and wogonin. Am. J. Chin. Med. 24, 31-36 https://doi.org/10.1142/S0192415X96000050
  22. Michael S. Y. H., Justin W. C. L., Wah, Ng., Lui, W. S., Michelle, N. S. C., Wong, J. T. and Xue, H. (2003). 5,7-Dihydroxy-6-methoxyflavone, a benzodiazepine site ligand isolated from Scutellaria baicalensis Georgi, with selective antagonistic properties. Biochem. Pharmacol. 66, 125-132 https://doi.org/10.1016/S0006-2952(03)00233-8
  23. Miyazaki, M., Ito, H., Saijo, T., Mori, K., Kagami, S. and Kuroda, Y. (2006). Favorable response of ADHD with giant SEP to extended-release valproate. Brain Develop. 28, 470-472 https://doi.org/10.1016/j.braindev.2006.01.005
  24. Montgomery, K. S., Mackey, J., Thuett, K., Ginestra, S., Bizon, J. L. and Abbott, L. C. (2008). Chronic, low-dose prenatal exposure to methylmercury impairs motor and mnemonic function in adult C57/B6 mice. Behav. Brain Res. 191, 55-61 https://doi.org/10.1016/j.bbr.2008.03.008
  25. Noldus, L. P. J. J., Spink, A. J. and Tegelenbosch, A. J. (2001). EthoVision: A versatile video tracking system for automation of behavioral experiments. Psychonomic Society 33, 398-414 https://doi.org/10.1211/0022357991772790
  26. Paladini, A. C., Marder, M., Viola, H., Wolfman, C., Wasowski, C. and Medina, J. H. (1999). Flavonoids and central nervous system: from forgotten factors to potent anxiolytic compounds. J. Pharm. Pharmacol. 51, 519-526 https://doi.org/10.1211/0022357991772790
  27. Pandolfo, P., Pamplona, F. A., Prediger, R. D. S. and Taka-hashi, R. N. (2007). Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2. European J. Pharmacol. 563, 141-148 https://doi.org/10.1016/j.ejphar.2007.02.013
  28. Park, H. G., Choi, J. Y., Lee, G. S., Choi, J. H., Son, K. H., Ko, H. S., Ko, K. H., Ryu, J. H. and Cheong, J. H. (2006). Different effects of flavonoids in Scutellaria baicalensis on anxious and sedative behaviors. J. Appl. Pharmacol. 14, 83-89 https://doi.org/10.1016/j.ejphar.2007.07.011
  29. Park, H. G., Yoon, S. Y., Choi, J. Y., Lee, G. S., Shin, C. Y., Son, K. H., Lee, Y. S., Kim, W. K., Ryu, J. H., Ko, K. H. and Cheong J. H. (2007). Anticonvulsant effect of wogonin isolated from Scutellaria baicalensis. European J. Pharmacol. 574, 112-119 https://doi.org/10.1016/j.ejphar.2007.07.011
  30. Prediger, R. D., Pamplona, F. A., Fernandes, D. and Takahashi, R. N. (2005). Caffeine improves spatial learning deficits in an animal model of attention deficit hyperactivity disorder-the spontaneously hypertensive rat. Int. J. Neuropsychopharmacol. 8, 583-594 https://doi.org/10.1017/S1461145705005341
  31. Ramos, A., Kangerski, A.L. Basso, P.F., Da Silva, G.E. Santos, J.E., Assreuy, J., Vendruscolo, L.F. and Takahashi, R.N. (2002). Evaluation of Lewis and SHR rat strains as a genetic model for the study of anxiety and pain, Behav. Brain Res. 129, 113-123 https://doi.org/10.1016/S0166-4328(01)00337-0
  32. Sagvolden, T. (2000). Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attentiondeficit/hyperactivity disorder (AD/HD). Neurosci. Biobehav. Rev. 24, 31-39 https://doi.org/10.1016/S0149-7634(99)00058-5
  33. Sagvolden, T., Russell, V. A., Aase, H., Johansen, E. B. and Farshbaf, M. (2005). Rodent models of attention-deficit/hyperactivity disorder. Biol. Psychiatry 57, 1239–1247 https://doi.org/10.1016/j.biopsych.2005.02.002
  34. Salgueiro, J. B., Ardenghi, P., Dias, M., Ferreira, M. B. C., Izquierdo, I. and Medina, J. H. (1997). Anxiolytic natural and synthetic flavonoid ligands of the central benzodiazepine receptor have no effect on memory tasks in rat. Pharmacol. Biochem. Behav. 58, 887-891 https://doi.org/10.1016/S0091-3057(97)00054-3
  35. Shumaker, H., Amlal, H., Frizzell, R., Ulrich, C. D. Jr and Soleimani, M. (1999). CFTR drives $Na^+-nHCO3^-$ cotransport in pancreatic duct cells: a basis for defective HCO3- secretion in CF. AM. J. Physiol. 276, C16-25 https://doi.org/10.1016/S0166-4328(01)00431-4
  36. Solanto, M. V. (2002). Dopamine dysfunction in AD/HD: integrating clinical and basic neuroscience research. Behav. Brain Res. 130, 65-71 https://doi.org/10.1016/S0166-4328(01)00431-4
  37. Tomimori, T., Miyaichi, Y. and Kizu, H. (1982). On the flavonoid constituents from the roots of Scutellaria baicalensis Georgi. Yakugaku Zasshi 102, 388-391 https://doi.org/10.1016/0003-2697(89)90652-0
  38. Verkman, A. S., Sellers, M. C., Chao, A. C., Leung, T. and Ketcham, R. (1989). Synthesis and characterization of improved chloride-sensitive flurorescent indicators for biological applications. Anal. Biochem. 178, 355-361 https://doi.org/10.1016/0003-2697(89)90652-0
  39. Wang, Q., Han, Y. and Xue, H. (1999). Ligands of GABAA receptor benzodiazepine binding site. CNS Drug Rev. 5, 125-144 https://doi.org/10.1517/14728214.12.3.423
  40. Weisler, R. H. (2007). Emerging drugs for attention-deficit/hyperactivity disorder. Expert. Opin. Emerg. Drugs 12, 423-34 https://doi.org/10.1517/14728214.12.3.423
  41. West, M. R. and Molloy, C. R. (1996). A microplate assay measuring chloride ion channel activity. Anal. Biochem. 241, 51-58 https://doi.org/10.1006/abio.1996.0377

Cited by

  1. Oroxylin A improves attention deficit hyperactivity disorder-like behaviors in the spontaneously hypertensive rat and inhibits reuptake of dopamine in vitro vol.36, pp.1, 2013, https://doi.org/10.1007/s12272-013-0009-6
  2. Oroxylin A analogs exhibited strong inhibitory activities against iNOS-mediated nitric oxide (NO) production vol.22, pp.7, 2012, https://doi.org/10.1016/j.bmcl.2012.01.135
  3. 5,7-Dihydroxy-6-methoxy-4'-phenoxyflavone, a derivative of oroxylin A improves attention-deficit/hyperactivity disorder (ADHD)-like behaviors in spontaneously hypertensive rats vol.715, pp.1-3, 2013, https://doi.org/10.1016/j.ejphar.2013.05.002
  4. Channel Activation vol.14, pp.11, 2011, https://doi.org/10.1089/jmf.2010.1529
  5. An unambiguous and practical synthesis of Oroxylin A: a commonly misidentified flavone vol.35, pp.9, 2008, https://doi.org/10.1080/14786419.2019.1650359