Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
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A Proposal of Dietary Supplement from Choto-san, a Kampo Medicine

  • Watanabe, Hiroshi (Institute of National Medicine, Yoyama Medical and Pharmaceutical University)
  • Published : 2004.09.01
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Abstract

Therapeutic effect of a Kampo medicine, Choto-san, in patients with vascular dementia was demonstrated by a double-blind and placebo-controlled clinical trial. To clarify the therapeutic efficacy of Choto-san, anti-ischemic effect in mice, hypotensive effect in spontaneously hypertensive rats (SHR), anti-oxidative effects in vitro, and N-methyl-D-aspartate (NMDA) receptor-blocking activity using Xenopus oocytes were studied. (1) Pretreatment with Choto-san (0.75-6.O g/kg, P.O.) or a component herb Chotoko (Uncaria genus: 75 - 600 mg/kg, P.O.) prevented ischemia-induced impairment of spatial learning behaviour in mice. Indole alkaloids- and phenolic fractions extracted from Chotoko also improved significantly the learning deficit. (2) Subchronic administration of Choto-san (0.5 g/kg, p.o.) caused a significant hypotensive effects in SHR. (3) Choto-san, Chotoko, and the phenolic constituent, (-) epicatechin, significantly protected the NG108-15 cell injury induced by $H_20_2$ exposure in vitro and also inhibited lipid peroxidation in the brain homogenate. (4) Indole alkaloids, rhynchophylline and isorhynchophylline (1-100 uM), reversibly reduced NMDA-induced current in the receptor-expressed Xenopus oocytes. These results suggest that anti-vascular dementia effects of Choto-san are mainly due to the effect of Chotoko. From these results, it is possible to make a novel dietary supplement through several extraction steps from Chotoko.

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References

  1. Aisawa K, Hattori Y, Kihara T, Ishihara T, Endo K, Hikino H. (1985). Hypotensive action of 3-alpha-dihydrocadambine, an indole alkaloid glycoside of Uncaria hooks. Planta Med. 51,424-7 https://doi.org/10.1055/s-2007-969538
  2. Bliss TVP, Collingridge GL. (1993). A synaptic model of memory: long-term potentiation in thehippocampus. Nature 361, 31-9 https://doi.org/10.1038/361031a0
  3. Block F. (1999). Global ischemia and behavioral deficits. Prog. Neurobiol. 58, 279-95
  4. Cotman CW, Bridges RT, Taube JS, Clark AS, Geddes JW, Monaghan DT (1989). The role of NMDA receptor in the central nervous system plasticity and pathology. J. NIH Res. 11,65-74
  5. del Zoppo GJ., Wagner S, Tagaya M. (Trends and future developments in the pharmacological treatment of acute ischemic stroke. Drugs 54, 9-38 https://doi.org/10.2165/00003495-199754010-00002
  6. Esterbauer H, Schau RJ, Zollner H. (1997) Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic. BioI. Med. 11,81-128.
  7. Gluck MR, Moy LY, Jayatilleke E, Hogan KA, Manzino L, Sonsalla PK. (2001). Parallel increases in lipid and protein oxidative markers in several mouse brain regions after methamphetamine treatment. J. Neurochem. 79, 152-60. https://doi.org/10.1046/j.1471-4159.2001.00549.x
  8. Goto H, Tanigawa K, Sekiya N, Kusano Y, Shimada Y, Tenisawa K. (1998). Effect of Uncariae Ramulus on the endothelium in spontaneously hypertensive rats (in Japanese). J. Trad. Med. 15,410-1.
  9. Horie S, Yano S, Aimi N, Sakai S, Watanabe K. (1992). Effects of hirsutine, an antihypertensive indole alkaloid from Uncaria rhynchophylla, on intracellular calcium in rat thoracic aorta. Life. Sci. 50, 491-8 https://doi.org/10.1016/0024-3205(92)90388-6
  10. Ishige K, Schubert D, Sagara Y. (2001). Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic. BioI. Med. 30, 433-446 https://doi.org/10.1016/S0891-5849(00)00498-6
  11. Ishii K, Kano T, Ando J. (1987). Pharmacological effect of Diao-Teng-San, a blended traditional Chinese herb medicine, in spontaneously hypertensive (SHR) and normotensive WistarKyoto (WKY) rats (Abstract in English). J. Med. Pharmaceut. Soc. WAKAN-YAKU 4,107-15
  12. Leewanich P, Tohda M, Matsumoto K, Subhadhirasakul S, Takayama H, Kitajima M, Aimi N, Watanabe H. (1998). A possible mechanism underlying corymine inhibition of glycineinduced chloride current in Xenopus oocytes. Eur. J. Pharmacol. 348, 271-7. https://doi.org/10.1016/S0014-2999(98)00147-2
  13. Liu J, Mori A. (1992). Antioxidant and free radical scavenging activities of Gastrodia elata Bl. and Uncaria rhynchophylla (Miq.) Jacks. Neuropharmacol. 31, 1287-98 https://doi.org/10.1016/0028-3908(92)90058-W
  14. Muller WE, Mutschler E, Riederer P. (1995). Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimers dementia. Pharmacopsychiatry 28, 113-124 https://doi.org/10.1055/s-2007-979603
  15. Ozaki Y. (1989). Pharmacological studies of indole alkaloids obtained from domestic plants, Uncaria rhychophylla MIQ. and Amsonia elliptica ROEM (Abstract in English). Folia Pharmacol. Japon 94, 17-26 https://doi.org/10.1254/fpj.94.17
  16. Ozaki Y. (1990). Vasodilative effects of indole alkaloids obtained from domestic plants, Uncaria rhynchophylla MIQ. and Amsonia elliptica ROEM (Abstract in English). Folia Pharmacol. Japon 95, 47-54
  17. Parsons CG, Danysz W, Quack G. (1998). Glutamate in CNS disorders as a target for drug development - an update. Drug News Perspect 11, 523-569 https://doi.org/10.1358/dnp.1998.11.9.863689
  18. Sakakibara I, Terabayashi S, Kubo M, Higuchi M, Sasako H, Okada M. (1999). Evaluation of Gou-teng (hooks and stems of Uncariae plants) III. Hypotensive principle fromUncaria rhychophylla and alteration of its content during extraction process (in Japanese). Natural Medicine 53, 308-312
  19. Shimada, Y., Goto, H., Itoh, T., Sakakibara, I., Kubo, M., Sasaki, H., and Terasawa, K. (1999). Evaluation of the protective effects of alkaloids isolated from the hooks and stems of Uncaria sinensis on glutamate-induced neuronal death in cultured cerebellar granule cells from rats. J. Pharm. Pharmacol. 51, 715-722 https://doi.org/10.1211/0022357991772853
  20. Suk K, Kim SY, Leein K, Kim YO, Park SY, Hur J, Baek J, Lee KJ, Zheng HZ, Kim H. (2002). Neuroprotection by methanol extract of Uncaria rhynchophylla against global cerebral ischemia in rats. Life Sci. 70, 2467-80 https://doi.org/10.1016/S0024-3205(02)01534-5
  21. Tanaka K, Fujita N, Yoshioka M, Ogawa N. (2001). Immunosuppressive and non-imrnuno-suppressive imrnunophilin ligands improve H202-induced dell damage by increasing glutathione levels in NG108-15 cell. Brain Res. 889, 225-8 https://doi.org/10.1016/S0006-8993(00)02851-1
  22. Terasawa K. (1993). Kampo; Insights from clinical cases (in Japanese). K. K. Standard McIntyre Pub., Tokyo
  23. Terasawa K, Shimada Y, Kita T, Yamamoto T, Tosa H, Tanaka N, Saito Y, Kanaki E, Goto S, Mizushima N, Fujioka M, Takase S, Seki H, Kimura I, Ogawa T, Nakamura S, Araki G, Maruyama I, Maruyama Y, Takaori S. (1997). Choto-san in the treatment of vascular dementia: a double-blind, placebocontrolled study. Phytomedicine 4, 15-22 https://doi.org/10.1016/S0944-7113(97)80022-0
  24. Watanabe K, Hirokawa Y, Shibata A, Wakabayashi H, Shimada K. (1987). Effects of Daisaiko-to, Choto-san and Sairei-to in spontaneously hyperetnsive rats (in Japanese). J. Med. Pharmaceut. Soc. WAKAN-YAKU 4,356-7.
  25. Watanabe K, Yano S, Horie S, Yamamoto LT, Takayama H, Aimi N, Sakai S, Ponglux D, Tongroach P, Shan J, Pang, PKT. (1999). Pharmacological properties of some structurally related indole alkaloids contained in the Asian herbal medicines, hirsutine and mitragynine, with special reference to their $Ca^2^+$ antagonistic and opioid-like effects. In: Watanabe H and Shibuya T, editors. Pharmacological research on traditional herbal medicines. Amsterdam: Harwood Academic Publishers; p.163-77
  26. Yamahara J, Miki S, Matsuda H, Kobayashi G, Fujimura H. (1987). Screening test for calcium antagonist in natural products. The active principles of Uncaria Ramulus et Uncus (Abstract in English). Folia Pharmacol. Japon 90, 133-9. https://doi.org/10.1254/fpj.90.133
  27. Yano S, Horiuchi H, Horie S, Aimi N, Sakai S, Watanabe K. (1991). $Ca^2^+$ channel blocking effects of hirsutine, an indole alkaloid from Uncaria Genus, in the isolated rat aorta. Planta Med. 57, 399-510 https://doi.org/10.1055/s-2006-960133
  28. Yokose T, Okubo H, Sakurai Y, Yoshizawa T, Oka T, Akamine Y, Kurida K, Hino T, Kamimatsuse K. (2000). Effects of Choto-san on hemodynamics, the sympathetic nervous system and the renin-angiotensin system in spontaneously hypertensive rats (Abstract in English). Jpn. J. Clin. Physiol. 30, 125-31.