Vol. 14, No. 1-2, 2005
Issue release date: June 2005
Neurosignals 2005;14:23–33
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Regulation of Neuroinflammation by Herbal Medicine and Its Implications for Neurodegenerative Diseases

Suk K.
Department of Pharmacology, Pain and Neural Injury Research Center, School of Medicine, Kyungpook National University, Daegu, Korea
email Corresponding Author

 goto top of outline Key Words

  • Inflammation
  • Neuroglia
  • Neurodegenerative disease
  • Flavonoid
  • Neuroprotection
  • Microglia
  • Astrocyte
  • Central nervous system

 goto top of outline Abstract

Herbal medicine has long been used to treat neural symptoms. Although the precise mechanisms of action of herbal drugs have yet to be determined, some of them have been shown to exert anti-inflammatory and/or anti-oxidant effects in a variety of peripheral systems. Now, as increasing evidence indicates that neuroglia-derived chronic inflammatory responses play a pathological role in the central nervous system, anti-inflammatory herbal medicine and its constituents are being proved to be a potent neuroprotector against various brain pathologies. Structural diversity of medicinal herbs makes them valuable source of novel lead compounds against therapeutic targets that are newly discovered by genomics, proteomics, and high-throughput screening.

Copyright © 2005 S. Karger AG, Basel

 goto top of outline References
  1. Gehrmann J, Matsumoto Y, Kreutzberg GW: Microglia: Intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995;20:269–287.
  2. Gremo F, Sogos V, Ennas MG, Meloni A, Persichini T, Colasanti M, Lauro GM: Features and functions of human microglia cells. Adv Exp Med Biol 1997;429:79–97.
  3. Stoll G, Jander S: The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 1999;58:233–247.
  4. Streit WJ, Walter SA, Pennell NA: Reactive microgliosis. Prog Neurobiol 1999;57:563–581.
  5. Kreutzberg GW: Microglia: A sensor for pathological events in the CNS. Trends Neurosci 1996;19:312–318.
  6. Minghetti L, Levi G: Microglia as effector cells in brain damage and repair: Focus on prostanoids and nitric oxide. Prog Neurobiol 1998;54:99–125.
  7. Gonzalez-Scarano F, Baltuch G: Microglia as mediators of inflammatory and degenerative diseases. Annu Rev Neurosci 1999;22:219–240.
  8. Araque A, Perea G: Glial modulation of synaptic transmission in culture. Glia 2004;47:241–248.
  9. Vesce S, Bezzi P, Volterra A: The active role of astrocytes in synaptic transmission. Cell Mol Life Sci 1999;56:991–1000.
  10. Aschner M: Astrocytes as mediators of immune and inflammatory responses in the CNS. Neurotoxicology 1998;19:269–281.
  11. Galea E, Feinstein DL, Reis DJ: Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc Natl Acad Sci USA 1992;89:10945–10949.
  12. Sawada M, Kondo N, Suzumura A, Marunouchi T: Production of tumor necrosis factor-alpha by microglia and astrocytes in culture. Brain Res 1989;491:394–397.
  13. Simmons ML, Murphy S: Induction of nitric oxide synthase in glial cells. J Neurochem 1992;59:897–905.
  14. Becher B, Prat A, Antel JP: Brain-immune connection: Immunoregulatory properties of CNS-resident cells. Glia 2000;29:293–304.
  15. Nakamura Y: Regulating factors for microglial activation. Biol Pharm Bull 2002;25:945–953.
  16. Ho LJ, Lai JH: Chinese herbs as immunomodulators and potential disease-modifying antirheumatic drugs in autoimmune disorders. Curr Drug Metab 2004;5:181–192.
  17. Li FQ, Lu XZ, Liang XB, Zhou HF, Xue B, Liu XY, Niu DB, Han JS, Wang XM: Triptolide, a Chinese herbal extract, protects dopaminergic neurons from inflammation-mediated damage through inhibition of microglial activation. J Neuroimmunol 2004;148:24–31.
  18. Ward PA, Warren JS, Johnson KJ: Oxygen radicals, inflammation, and tissue injury. Free Radic Biol Med 1988;5:403–408.
  19. Henson PM, Johnston RB Jr: Tissue injury in inflammation: Oxidants, proteinases, and cationic proteins. J Clin Invest 1987;79:669–674.
  20. Rankin JA: Biological mediators of acute inflammation. AACN Clin Issues 2004;15:3–17.
  21. Halliwell B: Oxygen radicals, nitric oxide and human inflammatory joint disease. Ann Rheum Dis 1995;54:505–510.
  22. Nakajima K, Kohsaka S: Microglia: Activation and their significance in the central nervous system. J Biochem (Tokyo) 2001;130:169–175.
  23. Liu B, Hong JS: Role of microglia in inflammation-mediated neurodegenerative diseases: Mechanisms and strategies for therapeutic intervention. J Pharmacol Exp Ther 2003;304:1–7.
  24. Chavarria A, Alcocer-Varela J: Is damage in central nervous system due to inflammation? Autoimmun Rev 2004;3:251–260.
  25. Popovich PG, Jones TB: Manipulating neuroinflammatory reactions in the injured spinal cord: Back to basics. Trends Pharmacol Sci 2003;24:13–17.
  26. von Knethen A, Lotero A, Brune B: Etoposide and cisplatin induced apoptosis in activated RAW 264.7 macrophages is attenuated by cAMP-induced gene expression. Oncogene 1998;17:387–394.
  27. Albina JE, Cui S, Mateo RB, Reichner JS: Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol 1993;150:5080–5085.
  28. Adler B, Adler H, Jungi TW, Peterhans E: Interferon-alpha primes macrophages for lipopolysaccharide-induced apoptosis. Biochem Biophys Res Commun 1995;215:921–927.
  29. Liu B, Wang K, Gao HM, Mandavilli B, Wang JY, Hong JS: Molecular consequences of activated microglia in the brain: Overactivation induces apoptosis. J Neurochem 2001;77:182–189.
  30. Lee P, Lee J, Kim S, Yagita H, Lee MS, Kim SY, Kim H, Suk K: NO as an autocrine mediator in the apoptosis of activated microglial cells: Correlation between activation and apoptosis of microglial cells. Brain Res 2001;892:380–385.
  31. Suk K, Lee J, Hur J, Kim YS, Lee MS, Cha SH, Kim SY, Kim H: Activation-induced cell death of rat astrocytes. Brain Res 2001;900:342–347.
  32. Donjerkovic D, Scott DW: Activation-induced cell death in B lymphocytes [In Process Citation]. Cell Res 2000;10:179–192.
  33. Crispe IN: Death and destruction of activated T lymphocytes. Immunol Res 1999;19:143–157.
  34. Kingham PJ, Cuzner ML, Pocock JM: Apoptotic pathways mobilized in microglia and neurones as a consequence of chromogranin A-induced microglial activation. J Neurochem 1999;73:538–547.
  35. Kingham PJ, Pocock JM: Microglial apoptosis induced by chromogranin A is mediated by mitochondrial depolarisation and the permeability transition but not by cytochrome c release. J Neurochem 2000;74:1452–1462.
  36. Yang MS, Park EJ, Sohn S, Kwon HJ, Shin WH, Pyo HK, Jin B, Choi KS, Jou I, Joe EH: Interleukin-13 and -4 induce death of activated microglia. Glia 2002;38:273–280.
  37. Takano K, Nakamura Y, Yoneda Y: Microglial cell death induced by a low concentration of polyamines. Neuroscience 2003;120:961–967.
  38. Lee J, Hur J, Lee P, Kim JY, Cho N, Lee MS, Kim SY, Kim H, Suk K: Dual role of inflammatory stimuli in activation-induced cell death of mouse microglial cells: initiation of two separate apoptotic pathways via induction of interferon regulatory factor-1 and caspase-11. J Biol Chem 2001;276:32956–32965.
  39. Lee H, Cha S, Lee MS, Cho GJ, Choi WS, Suk K: Role of antiproliferative B cell translocation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia. J Immunol 2003;171:5802–5811.
  40. Suk K, Kim SY, Kim H: Essential role of caspase-11 in activation-induced cell death of rat astrocytes. J Neurochem 2002;80:230–238.
  41. Drache B, Diehl GE, Beyreuther K, Perlmutter LS, Konig G: Bcl-xl-specific antibody labels activated microglia associated with Alzheimer’s disease and other pathological states. J Neurosci Res 1997;47:98–108.
  42. Migheli A, Cavalla P, Piva R, Giordana MT, Schiffer D: bcl-2 protein expression in aged brain and neurodegenerative diseases. Neuroreport 1994;5:1906–1908.
  43. Streit WJ: Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 2004;77:1–8.
  44. Giulian D: Ameboid microglia as effectors of inflammation in the central nervous system. J Neurosci Res 1987;18:155–171, 132–153.
  45. Giulian D, Haverkamp LJ, Li J, Karshin WL, Yu J, Tom D, Li X, Kirkpatrick JB: Senile plaques stimulate microglia to release a neurotoxin found in Alzheimer brain. Neurochem Int 1995;27:119–137.
  46. Nagata K, Takei N, Nakajima K, Saito H, Kohsaka S: Microglial conditioned medium promotes survival and development of cultured mesencephalic neurons from embryonic rat brain. J Neurosci Res 1993;34:357–363.
  47. McGeer PL, McGeer EG: The inflammatory response system of brain: Implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995;21:195–218.
  48. McGeer PL, Kawamata T, Walker DG, Akiyama H, Tooyama I, McGeer EG: Microglia in degenerative neurological disease. Glia 1993;7:84–92.
  49. Hanisch UK: Microglia as a source and target of cytokines. Glia 2002;40:140–155.
  50. Bent S, Ko R: Commonly used herbal medicines in the United States: A review. Am J Med 2004;116:478–485.
  51. De Smet PA: Herbal remedies. N Engl J Med 2002;347:2046–2056.
  52. Gong X, Sucher NJ: Stroke therapy in traditional Chinese medicine (TCM): Prospects for drug discovery and development. Trends Pharmacol Sci 1999;20:191–196.
  53. Howes MJ, Houghton PJ: Plants used in Chinese and Indian traditional medicine for improvement of memory and cognitive function. Pharmacol Biochem Behav 2003;75:513–527.
  54. Chalela JA, Merino JG, Warach S: Update on stroke. Curr Opin Neurol 2004;17:447–451.
  55. Harvey AL: Medicines from nature: Are natural products still relevant to drug discovery? Trends Pharmacol Sci 1999;20:196–198.
  56. Kim YO, Leem K, Park J, Lee P, Ahn DK, Lee BC, Park HK, Suk K, Kim SY, Kim H: Cytoprotective effect of Scutellaria baicalensis in CA1 hippocampal neurons of rats after global cerebral ischemia. J Ethnopharmacol 2001;77:183–188.
  57. Suk K, Kim SY, Leem K, Kim YO, Park SY, Hur J, Baek J, Lee KJ, Zheng HZ, Kim H: Neuroprotection by methanol extract of Uncaria rhynchophylla against global cerebral ischemia in rats. Life Sci 2002;70:2467–2480.
  58. Kubo M, Matsuda H, Tanaka M, Kimura Y, Okuda H, Higashino M, Tani T, Namba K, Arichi S: Studies on Scutellariae radix. VII. Anti-arthritic and anti-inflammatory actions of methanolic extract and flavonoid components from Scutellariae radix. Chem Pharm Bull (Tokyo) 1984;32:2724–2729.
  59. Sekiya K, Okuda H: Selective inhibition of platelet lipoxygenase by baicalein. Biochem Biophys Res Commun 1982;105:1090–1095.
  60. Wakabayashi I: Inhibitory effects of baicalein and wogonin on lipopolysaccharide-induced nitric oxide production in macrophages. Pharmacol Toxicol 1999;84:288–291.
  61. Gertz HJ, Kiefer M: Review about Ginkgo biloba special extract EGb 761 (Ginkgo). Curr Pharm Des 2004;10:261–264.
  62. Bastianetto S, Ramassamy C, Dore S, Christen Y, Poirier J, Quirion R: The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid. Eur J Neurosci 2000;12:1882–1890.
  63. Bastianetto S, Zheng WH, Quirion R: The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: Involvement of its flavonoid constituents and protein kinase C. J Neurochem 2000;74:2268–2277.
  64. Braquet P, Hosford D: Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents. J Ethnopharmacol 1991;32:135–139.
  65. Oyama Y, Chikahisa L, Ueha T, Kanemaru K, Noda K: Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide. Brain Res 1996;712:349–352.
  66. Beecher GR: Overview of dietary flavonoids: Nomenclature, occurrence and intake. J Nutr 2003;133:3248S–3254S.
  67. Middleton E, Jr., Kandaswami C, Theoharides TC: The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52:673–751.
  68. Middleton E Jr, Kandaswami C: Effects of flavonoids on immune and inflammatory cell functions. Biochem Pharmacol 1992;43:1167–1179.
  69. Kim HK, Cheon BS, Kim YH, Kim SY, Kim HP: Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW 264.7 and their structure-activity relationships. Biochem Pharmacol 1999;58:759–765.
  70. Wakabayashi I, Yasui K: Wogonin inhibits inducible prostaglandin E(2) production in macrophages [In Process Citation]. Eur J Pharmacol 2000;406:477–481.
  71. Chang YL, Shen JJ, Wung BS, Cheng JJ, Wang DL: Chinese herbal remedy wogonin inhibits monocyte chemotactic protein-1 gene expression in human endothelial cells. Mol Pharmacol 2001;60:507–513.
  72. Park BK, Heo MY, Park H, Kim HP: Inhibition of TPA-induced cyclooxygenase-2 expression and skin inflammation in mice by wogonin, a plant flavone from Scutellaria radix. Eur J Pharmacol 2001;425:153–157.
  73. Gao Z, Huang K, Yang X, Xu H: Free radical scavenging and antioxidant activities of flavonoids extracted from the radix of Scutellaria baicalensis Georgi. Biochim Biophys Acta 1999;1472:643–650.
  74. Shieh DE, Liu LT, Lin CC: Antioxidant and free radical scavenging effects of baicalein, baicalin and wogonin [In Process Citation]. Anticancer Res 2000;20:2861–2865.
  75. Kandaswami C, Middleton E Jr: Free radical scavenging and antioxidant activity of plant flavonoids. Adv Exp Med Biol 1994;366:351–376.
  76. Gao Z, Huang K, Xu H: Protective effects of flavonoids in the roots of Scutellaria baicalensis Georgi against hydrogen peroxide-induced oxidative stress in HS-SY5Y cells. Pharmacol Res 2001;43:173–178.
  77. Kim H, Kim YS, Kim SY, Suk K: The plant flavonoid wogonin suppresses death of activated C6 rat glial cells by inhibiting nitric oxide production. Neurosci Lett 2001;309:67–71.
  78. Lee H, Kim YO, Kim SY, Kim H, Noh HS, Kang SS, Cho GJ, Choi WS, Suk K: Flavonoid wogonin from medicinal herb is neuroprotective by inhibiting inflammatory activation of microglia. FASEB J 2003;17:1943–1944.
  79. Hamada H, Hiramatsu M, Edamatsu R, Mori A: Free radical scavenging action of baicalein. Arch Biochem Biophys 1993;306:261–266.
  80. Suk K, Lee H, Kang SS, Cho GJ, Choi WS: Flavonoid baicalein attenuates activation-induced cell death of brain microglia. J Pharmacol Exp Ther 2003;305:638–645.
  81. Boehm U, Klamp T, Groot M, Howard JC: Cellular responses to interferon-gamma. Annu Rev Immunol 1997;15:749–795.
  82. Zhang ZJ: Therapeutic effects of herbal extracts and constituents in animal models of psychiatric disorders. Life Sci 2004;75:1659–1699.
  83. Chopin P, Briley M: Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats. Psychopharmacology (Berl) 1992;106:26–30.
  84. Woodruff-Pak DS, Vogel RW 3rd, Wenk GL: Galantamine: Effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning. Proc Natl Acad Sci USA 2001;98:2089–2094.
  85. Sweeney JE, Bachman ES, Coyle JT: Effects of different doses of galanthamine, a long-acting acetylcholinesterase inhibitor, on memory in mice. Psychopharmacology (Berl) 1990;102:191–200.
  86. Ha JH, Shin SM, Lee SK, Kim JS, Shin US, Huh K, Kim JA, Yong CS, Lee NJ, Lee DU: In vitro effects of hydroxybenzaldehydes from Gastrodia elata and their analogues on GABAergic neurotransmission, and a structure-activity correlation. Planta Med 2001;67:877–880.
  87. Kim HJ, Moon KD, Lee DS, Lee SH: Ethyl ether fraction of Gastrodia elata Blume protects amyloid beta peptide-induced cell death. J Ethnopharmacol 2003;84:95–98.
  88. Kim HJ, Lee SR, Moon KD: Ether fraction of methanol extracts of Gastrodia elata, medicinal herb protects against neuronal cell damage after transient global ischemia in gerbils. Phytother Res 2003;17:909–912.
  89. Zangara A: The psychopharmacology of huperzine A: An alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer’s disease. Pharmacol Biochem Behav 2003;75:675–686.
  90. Wen TC, Yoshimura H, Matsuda S, Lim JH, Sakanaka M: Ginseng root prevents learning disability and neuronal loss in gerbils with 5-minute forebrain ischemia. Acta Neuropathol (Berl) 1996;91:15–22.
  91. Lim JH, Wen TC, Matsuda S, Tanaka J, Maeda N, Peng H, Aburaya J, Ishihara K, Sakanaka M: Protection of ischemic hippocampal neurons by ginsenoside Rb1, a main ingredient of ginseng root. Neurosci Res 1997;28:191–200.
  92. Kennedy DO, Scholey AB: Ginseng: Potential for the enhancement of cognitive performance and mood. Pharmacol Biochem Behav 2003;75:687–700.
  93. Fahn S, Cohen G: The oxidant stress hypothesis in Parkinson’s disease: Evidence supporting it. Ann Neurol 1992;32:804–812.
  94. Metodiewa D, Koska C: Reactive oxygen species and reactive nitrogen species: Relevance to cyto(neuro)toxic events and neurologic disorders: An overview. Neurotox Res 2000;1:197–233.
  95. Ahlemeyer B, Krieglstein J: Neuroprotective effects of Ginkgo biloba extract. Cell Mol Life Sci 2003;60:1779–1792.
  96. Rahman K: Garlic and aging: New insights into an old remedy. Ageing Res Rev 2003;2:39–56.

 goto top of outline Author Contacts

Kyoungho Suk
Department of Pharmacology, Pain and Neural Injury Research Center
Kyungpook National University School of Medicine
101 Dong-In, Joong-Gu, Daegu, 700-422 (Korea)
Tel. +82 53 420 4835, Fax +82 53 256 1566, E-Mail ksuk@knu.ac.kr

 goto top of outline Article Information

Received: July 28, 2004
Accepted after revision: September 20, 2004
Number of Print Pages : 11
Number of Figures : 4, Number of Tables : 1, Number of References : 96

 goto top of outline Publication Details


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

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

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

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