Address of Corresponding Author

Neurosignals 2005;14:34-45 (DOI: 10.1159/000085384)

  Key Words

• Neuritic atrophy
• Synaptic loss
• Dendrite
• Axon
• Alzheimer's disease
• Amyloid-beta
• Ginseng
• Withania somnifera
• Ashwagandha
• Coffee bean

  Abstract

The reconstruction of neuronal networks in the damaged brain is necessary for the therapeutic treatment of neurodegenerative diseases. We have screened the neurite outgrowth activity of herbal drugs, and identified several active constituents. In each compound, neurite outgrowth activity was investigated under amyloid--induced neuritic atrophy. Most of the compounds with neurite regenerative activity also demonstrated memory improvement activity in Alzheimer's disease-model mice. Protopanaxadiol-type saponins in Ginseng drugs and their metabolite, M1 (20-O--D-glucopyranosyl-(20S)-protopanaxadiol), showed potent regeneration activity for axons and synapses, and amelioration of memory impairment. Withanolide derivatives (withanolide A, withanoside IV, and withanoside VI) isolated from the Indian herbal drug Ashwagandha, also showed neurite extension in normal and damaged cortical neurons. Trigonelline, a constituent of coffee beans, demonstrated the regeneration of dendrites and axons, in addition to memory improvement.

Copyright © 2005 S. Karger AG, Basel

  References

1.

Ogura H, Kosasa T, Kuriya Y, Yamanishi Y: Donepezil, a centrally acting acetylcholinesterase inhibitor, alleviates learning deficits in hypocholinergic models in rats. Methods and Findings in Exp Clin Pharmacol 2000;22:89-95.

2.

DeKosky S, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity. Ann Neurol 1990;27:457-464.

3.

Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, et al: Physical basis of cognitive alterations in Alzheimer's disease: Synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991;30:572-580.

4.

Dickson TC, Vickers JC: The morphological phenotype of -amyloid plaques and associated neuritic changes in Alzheimer's disease. Neuroscience 2001;105:99-107.

5.

Jackson M, Gentleman S, Lennox L, Ward L, Gray T, Randall K, et al: The cortical neuritic pathology by Huntington's disease. Neuropathol Appl Neurobiol 1995;21:18-26.

6.

Mattila PM, Rinne JO, Helenius H, Roytta M: Neuritic degeneration in the hippocampus and amygdala in Parkinson's disease in relation to Alzheimer pathology. Acta Neuropathol 1999;98:157-164.

7.

Liberski PP, Budka H: Neuroaxonal pathology in Creutzfeldt-Jakob disease. Acta Neuropathol 1999;97:329-334.

8.

Zhao R, MaDaniel WF: Ginseng improves strategic learning by normal and brain-damaged rats. NeuroReport 1998;9:1618-1624.

9.

Zhong YM, Nishijo H, Uwano T, Tamura R, Kawanishi K, Ono T: Red Ginseng ameliorated place navigation deficits in young rats with hippocampal lesions and aged rats. Physiol Behav 2000;69:511-525.

10.

Mook-Jung I, Hong HS, Boo JH, Lee KH, Yun SH, Cheong MY, Joo I, Huh K, Jung MW: Ginsenoside Rb₁ and Rg₁ improve spatial learning and increase hippocampal synaptophysin level in mice. J Neurosci Res 2001;63:509-515.

11.

Sugaya A, Yuzurihara M, Tsuda T, Yasuda K, Kajiwara K, Sugaya E: Proliferative effect of Ginseng saponin on neurite extension of primary cultured neurons of the rat cerebral cortex. J Ethnopharmacol 1988;22:173-181.

12.

Saito H, Suda K, Schwab M, Thoenen H: Potentiation of the NGF-mediated nerve fiber outgrowth by ginsenoside Rb₁ in organ cultures of chicken dorsal root ganglia. Jpn J Pharmacol 1977;27:445-451.

13.

Nishiyama N, Cho SI, Kitagawa I, Saito H: Malonylginsenoside Rb₁ potentiated nerve growth factor (NGF)-induced neurite outgrowth of cultured chick embryonic dorsal root ganglia. Biol Pharm Bull 1994;17:509-513.

14.

Tohda C, Matsumoto N, Zou K, Meselhy RM, Komatsu K: Axonal and dendritic extension by protopanaxadiol-type saponins from Ginseng drugs in SK-N-SH cells. Jpn J Pharmacol 2002;90:254-262.

15.

Zou K, Zhu S, Tohda C, Cai SQ, Komatsu K: Dammarane-type triterpene saponins from Panax japonicus. J Natural Products 2002;65:346-351.

16.

Zou K, Zhu S, Meselhy RM, Tohda C, Cai SQ, Komatsu K: Dammarane-type saponins from Panax japonicus and their neurite outgrowth activity in SK-N-SH cells. J Natural Products 2002;65:1288-1292.

17.

Zou K, Zhu S, Cai SQ, Komatsu K: In Ye San Qi, Kou Zi Qi: Constituents from the underground part of Panax plants. Abstract 121th Ann Meet Pharmaceutical Soc Japan, 2001, p 110.

18.

Zhu S, Zou K, Fushimi H, Cai SQ, Komatsu K: Comparative study on triterpene saponins of Ginseng drugs. Planta Medica 2004;70:666-677.

19.

Odani T, Tanizawa H, Takino Y: Studies on the absorption, distribution, excretion and metabolism of Ginseng saponins. III. The absorption, distribution and excretion of ginsenoside Rb₁ in the rat. Chem Pharm Bull 1983;31:1059-1066.

20.

Tawab MA, Bahr U, Karas M, Wurglics M, Schubert-Zsilavecz M: Degeneration of ginsenosides in humans after oral administration. Drug Metab Dispos 2003;31:1065-1071.

21.

Tohda C, Matsumoto N, Zou K, Meselhy RM, Komatsu K: A(25-35)-induced memory impairment, axonal atrophy, and synaptic loss are ameliorated by M1, a metabolite of protopanaxadiol-type saponins. Neuropsychopharmacology 2004;29:860-868.

22.

DeKosky ST, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer's disease: Correlation with cognitive severity. Ann Neurol 1990;27:457-464.

23.

Heinonen O, Soininen H, Sorvari H, Kosunen O, Paljarvi L, Koivisto E, Riekkinen PJ Sr: Loss of synaptophysin-like immunoreactivity in the hippocampal formation is an early phenomenon in Alzheimer's disease. Neuroscience 1995;64:375-384.

24.

Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F, Guido T, Hagopian S, Johnson-Wood K, Khan K, Lee M, Leibowitz P, Lieberburg I, Little S, Masliah E, McConlogue L, Montoya-Zavala M, Mucke L, Paganini L, Penniman E, Power M, Schenk D, Seubert P, Snyder B, Soriano F, Tan H, Vitale J, Wadsworth S, Wolozin B, Zhao J: Alzheimer-type neuropathology in transgenic mice overexpressing V717F-amyloid precursor protein. Nature 1995;373:523-527.

25.

Karikura M, Miyase T, Tanizawa H, Taniyama T, Takino Y: Studies on absorption, excretion and metabolism of Ginseng saponons. VII. Comparison of the decomposition of ginsenoside-Rb₁ and -Rb₂ in the digestive tract of rats. Chem Pharm Bull 1991;39:2357-2361.

26.

Hasegawa H, Sung J-H, Benno Y: Role of human intestinal Prevotella oris in hydrolyzing Ginseng saponins. Planta Medica 1997;63:436-440.

27.

Postuma RB. He W, Nunan J, Beyreuther K, Masters CL, Barrow CJ, Small DH: Substrate-bound beta-amyloid peptides inhibit cell adhesion and neurite outgrowth in primary neuronal cultures. J Neurochem 2000;74:1122-1130.

28.

Grace EA, Rabiner CA, Busciglio: Characterization of neuronal dystrophy induced by fibrillar amyloid beta: Implications for Alzheimer's disease. J Neurosci 2002;114:265-273.

29.

Grace EA, Busciglio J: Aberrant activation of focal adhesion proteins mediates fibrillar amyloid -induced neuronal dystrophy. J Neurosci 2003;23:493-502.

30.

Lin H, Bhatia R, Lal R: Amyloid protein forms ion channels: implications for Alzheimer's disease pathophysiology. FASEB J 2001;15:2433-2444.

31.

Xie Z, Wei M, Morgan TE, Fabrizio P, Han D, Finch CE, Longo VD: Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia. J Neurosci 2002;22:3484-3492.

32.

Casley CS, Land JM, Sharpe MA, Clark JB, Duchen MR, Canevari L: -Amyloid fragment 25-35 causes mitochondrial dysfunction in primary cortical neurons. Neurobiol Dis 2002;10:258-267.

33.

Dhuley JN: Nootropic-like effect of Ashwagandha (Withania somnifera L.) in mice. Phytother Res 2001;15:524-528.

34.

Tohda C, Kuboyama T, Komatsu K: Dendrite extension by methanol extract of Ashwagandha (roots of Withania somnifera) in SK-N-SH cells. NeuroReport 2000;11:1981-1985.

35.

Zhao J, Nakamura N, Hattori M, Kuboyama T, Tohda C, Komatsu K: Withanolide derivatives from the roots of Withania somnifera and their neurite outgrowth activities. Chem Pharm Bull 2002;50:760-765.

36.

Kuboyama T, Tohda C, Zhao J, Nakamura N, Hattori M, Komatsu K: Axon- or dendrite-predominant outgrowth induced by constituents from Ashwagandha. NeuroReport 2002;13:1715-1720.

37.

Kuboyama T, Tohda C, Komatsu K: Neuritic regeneration and synaptic reconstruction induced by withanolide A. Br J Pharmacol 2005;144:961-971.

38.

Czok G: Coffee and health (abstract in English). Z Ernährungswiss 1977;16:248-255.

39.

Riedel W, Hogervorst E, Leboux R, Verhey F, van Praag H, Jolles J: Caffeine attenuates scopolamine-induced memory impairment in humans. Psychopharmacology 1995;122:158-168.

40.

Liu YM, Shawuti Y: Pharmacography of Uighur. Wulumuqi, Xinjiang People's Publishing House, 1985, p 267.

41.

Tohda C, Nakamura N, Komatsu K, Hattori M: Trigonelline-induced neurite outgrowth in human neuroblastoma SK-N-SH cells. Biol Pharm Bull 1999;22:679-682.

42.

Taguchi H: Biosynthesis and metabolism of trigonelline, and physiological action of the compound (abstract in English). Vitamins 1988;62:549-557.

43.

Fukuyama Y, Nakade K, Minoshima Y, Yokoyama R, Zhai H, Mitsumoto Y: Neurotrophic activity of honokiol on the cultures of fetal rat cortical neurons. Bioorg Med Chem Lett 2002;12:1163-1166.

44.

Hur JY, Lee P, Kim H, Kang I, Lee KR, Kim SY: (-)-3,5-Dicaffeoyl-muco-quinic acid isolated from Aster scaber contributes to the differentiation of PC12 cells: Through tyrosine kinase cascade signaling. Biochem Biophys Res Commun 2004;313:948-953.

45.

Yamazaki M, Chiba K, Mohri T: Neuritogenesis effect of natural iridoid compounds on PC12h cells and its possible relation to signaling protein kinases. Biol Pharm Bull 1996;19:791-795.

46.

Li P, Matsunaga K, Yamakuni T, Ohizumi Y: Potentiation of nerve growth factor-action by picrosides I and II, natural iridoids, in PC12D cells. Eur J Pharmacol 2000;406:203-208.

47.

Li P, Matsunaga K, Yamamoto K, Yoshikawa R, Kawashima K, Ohizumi Y: Nardosinone, a novel enhancer of nerve growth factor in neurite outgrowth from PC12D cells. Neurosci Lett 1999;273:53-56.

  Author Contacts

Katsuko Komatsu, PhD
Research Center for Ethnomedicines, Institute of Natural Medicine
Toyama Medical and Pharmaceutical University, 2630 Sugitani
Toyama 930-0194 (Japan)
Tel. +81 76 434 7645, Fax +81 76 434 5064, E-Mail katsukok@ms.toyama-mpu.ac.jp

  Article Information

Received: October 11, 2004
Accepted after revision: November 16, 2004
Number of Print Pages : 12
Number of Figures : 7, Number of Tables : 1, Number of References : 47

  Publication Details

Neurosignals

Vol. 14, No. 1-2, Year 2005 (Cover Date: Released June 2005)

Journal Editor: N.Y. Ip, Hong Kong
ISSN: 1424-862X (print), 1424-8638 (Online)

For additional information: http://www.karger.com/nsg

  Drug Dosage / Copyright

Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.