Bio-effectiveness of the main flavonoids of Achillea millefolium in the pathophysiology of neurodegenerative disorders- a review

Document Type: Review Article


1 Physiology-Pharmacology Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

2 Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

3 Geriatric Care Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

4 Department of Neurology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

5 Pistachio Safety Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran

6 Non-communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran


The Achillea millefolium L. (Yarrow) is a common herb which is widely being used, worldwide. Achillea is being used for treatment of many disorders since centuries. It is considered safe for supplemental use and flavonoids such as kaempferol, luteolin and apigenin are of main constituents present in Achillea. Most of both antioxidant and anti-inflammatory properties of this herb have been attributed to its flavonoid content. Oxidative and inflammatory processes play important roles in pathogenesis of neurodegenerative diseases. Present review was aimed to review the latest literature evidences regarding application of Achillea and/or its three main flavonoid constituents on epilepsy, Alzheimer's disease, multiple sclerosis, Parkinson's disease and stroke.


1. Applequist WL, Moerman DE. Yarrow (Achillea millefolium L.): a neglected panacea? A review of ethnobotany, bioactivity, and biomedical research. Econ Bot  2011; 65: 209-225.

2. Kowal T, Pic S. Produktywność gatunku Achillea millefolium L, w warunkach naturalnych [Productivity of the species Achillea millejolium L. in natural habitats]. Acta Agrobot 2015; 32:91-100.

3. Stojanović G, Radulović N, Hashimoto T, Palić R. In vitro antimicrobial activity of extracts of four Achillea species: The composition of Achillea clavennae L.(Asteraceae) extract. J Ethnopharmacol 2005; 101:185-190.

4. Benedek B, Kopp B, Melzig MF. Achillea millefolium L. sl–Is the anti-inflammatory activity mediated by protease inhibition? J Ethnopharmacol 2007; 113:312-317.

5. Mahady GB, Pendland SL, Stoia A, Hamill FA, Fabricant D, Dietz BM, et al. In vitro susceptibility of Helicobacter pylori to botanical extracts used traditionally for the treatment of gastrointestinal disorders. Phytother Res 2005; 19:988-991.

6. Lemmens-Gruber R, Marchart E, Rawnduzi P, Engel N, Benedek B, Kopp B. Investigation of the spasmolytic activity of the flavonoid fraction of Achillea millefolium sl on isolated guinea-pig ilea. Arzneimittelforschung 2005; 56:582-588.

7. Ivanov Ch, L. Y. Composition of Achillea millefolium. III. Composition of the acidic, water-insoluble part of the alcoholic extract. God Vissh Khimikotekhnol Inst Sofia 1967; 14:61-72.

8. Ivanov Ch, L. Y. Composition of Achillea millefolium. V. Composition and structure of the components of neutral fraction insoluble in the aqueous part of the alcoholic extract. God Vissh Khimikotekhnol Inst Sofia 1967; 14: 73-101.

9. Chandler R, Hooper S, Harvey MJ. Ethnobotany and phytochemistry of yarrow, Achillea millefolium, Compositae. Econ Bot 1982; 36:203-223.

10. Falk A, Smolenski S, Bauer L, Bell C. Isolation and identification of three new flavones from Achillea millefolium L. J Pharm Sci 1975; 64:1838-1842.

11. Vazirinejad R, Ayoobi F, Arababadi MK, Eftekharian MM, Darekordi A, Goudarzvand M, et al. Effect of aqueous extract of Achillea millefolium on the development of experimental autoimmune encephalomyelitis in C57BL/6 mice. Indian J Pharm 2014; 46:303.

12. Ginwala R, McTish E, Raman C, Singh N, Nagarkatti M, Nagarkatti P, et al. Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions. J Neuroimmune Pharmacol 2016; 11:36-47.

13. Hendriks JJ, Alblas J, van der Pol SM, van Tol EA, Dijkstra CD, de Vries HE. Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis. J Exp Med 2004; 200:1667-1672.

14. Barbierato M, Facci L, Marinelli C, Zusso M, Argentini C, Skaper SD, et al. Co-ultramicronized Palmitoylethanolamide/Luteolin Promotes the Maturation of Oligodendrocyte Precursor Cells. Sci Rep 2015; 5:16676.

15. Verbeek R, van Tol EA, van Noort JM. Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice. Biochem Pharmacol 2005; 70:220-228.

16. Elsisi NS, Darling-Reed S, Lee EY, Oriaku ET, Soliman KF. Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia. Neurosci Lett 2005; 375:91-96.

17. Rezai-Zadeh K, Ehrhart J, Bai Y, Sanberg PR, Bickford P, Tan J, et al. Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflamm 2008; 5:41.

18. Zhao L, Wang JL, Wang YR, Fa XZ. Apigenin attenuates copper-mediated beta-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model. Brain Res 2013; 1492:33-45.

19. Zhao L, Wang JL, Liu R, Li XX, Li JF, Zhang L. Neuroprotective, anti-amyloidogenic and neurotrophic effects of apigenin in an Alzheimer's disease mouse model. Molecules 2013; 18:9949-9965.

20. Choi SM, Kim BC, Cho YH, Choi KH, Chang J, Park MS, et al. Effects of Flavonoid Compounds on beta-amyloid-peptide-induced Neuronal Death in Cultured Mouse Cortical Neurons. Chonnam Med J 2014; 50:45-51.

21. Paterniti I, Cordaro M, Campolo M, Siracusa R, Cornelius C, Navarra M, et al. Neuroprotection by association of palmitoylethanolamide with luteolin in experimental Alzheimer's disease models: the control of neuroinflammation. CNS Neurol Disord Drug Targets 2014; 13:1530-1541.

22. Yu TX, Zhang P, Guan Y, Wang M, Zhen MQ. Protective effects of luteolin against cognitive impairment induced by infusion of Abeta peptide in rats. Int J Clin Exp Pathol 2015; 8:6740-6747.

23. Wang H, Wang H, Cheng H, Che Z. Ameliorating effect of luteolin on memory impairment in an Alzheimer's disease model. Mol Med Rep 2016; 13:4215-4220.

24. Sawmiller D, Li S, Shahaduzzaman M, Smith AJ, Obregon D, Giunta B, et al. Luteolin reduces Alzheimer’s disease pathologies induced by traumatic brain injury. Int J Mol Sci 2014; 15:895-904.

25. Sharoar MG, Thapa A, Shahnawaz M, Ramasamy VS, Woo ER, Shin SY, et al. Keampferol-3-O-rhamnoside abrogates amyloid beta toxicity by modulating monomers and remodeling oligomers and fibrils to non-toxic aggregates. J Biomed Sci 2012; 19:104.

26. Yang EJ, Kim GS, Jun M, Song KS. Kaempferol attenuates the glutamate-induced oxidative stress in mouse-derived hippocampal neuronal HT22 cells. Food Funct 2014; 5:1395-1402.

27. Roth A, Schaffner W, Hertel C. Phytoestrogen kaempferol (3,4',5,7-tetrahydroxyflavone) protects PC12 and T47D cells from beta-amyloid-induced toxicity. J Neurosci Res 1999; 57:399-404.

28. Kim JK, Choi SJ, Cho HY, Hwang HJ, Kim YJ, Lim ST, et al. Protective effects of kaempferol (3,4',5,7-tetrahydroxyflavone) against amyloid beta peptide (Abeta)-induced neurotoxicity in ICR mice. Biosci Biotechnol Biochem 2010; 74:397-401.

29. Akramian Fard M, Moghadam Ahmadi A, Ayoobi F, Nakisa H, Hadadian Z, Shabani M, et al. Effects of Achillea millefolium aqueous extract in a Parkinsons diaease model induced by intra-cerebralventricular injection of 6-hydroxydopamine in male rats. Quarterly J Sabzevar Univ Med Sci 2015; 22.

30. Caruana M, Neuner J, Hogen T, Schmidt F, Kamp F, Scerri C, et al. Polyphenolic compounds are novel protective agents against lipid membrane damage by alpha-synuclein aggregates in vitro. Biochim Biophys Acta 2012; 1818:2502-2510.

31. Patil SP, Jain PD, Sancheti JS, Ghumatkar PJ, Tambe R, Sathaye S. Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice. Neuropharmacology 2014; 86:192-202.

32. Wruck CJ, Claussen M, Fuhrmann G, Romer L, Schulz A, Pufe T, et al. Luteolin protects rat PC12 and C6 cells against MPP+ induced toxicity via an ERK dependent Keap1-Nrf2-ARE pathway. J Neural Transm Suppl 2007; 72:57-67.

33. Lin YP, Chen TY, Tseng HW, Lee MH, Chen ST. Chemical and biological evaluation of nephrocizin in protecting nerve growth factor-differentiated PC12 cells by 6-hydroxydopamine-induced neurotoxicity. Phytochemistry 2012; 84:102-115.

34. Qu W, Fan L, Kim YC, Ishikawa S, Iguchi-Ariga SM, Pu XP, et al. Kaempferol derivatives prevent oxidative stress-induced cell death in a DJ-1-dependent manner. J Pharmacol Sci 2009; 110:191-200.

35. Li S, Pu XP. Neuroprotective effect of kaempferol against a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson's disease. Biol Pharm Bull 2011; 34:1291-1296.

36. Imani E, Esmaili A, Alimohammadi R, Ehsani V, Shamsizadeh A, Mobini M, et al. Effects of Achillea.millefolium on the Consequences of Stroke in Ovarectomized Rats. J Shahid Sadoughi Univ Med Sci 2015; 22:1725-1736.

37. Ha SK, Lee P, Park JA, Oh HR, Lee SY, Park JH, et al. Apigenin inhibits the production of NO and PGE2 in microglia and inhibits neuronal cell death in a middle cerebral artery occlusion-induced focal ischemia mice model. Neurochem Int 2008; 52:878-886.

38. Guo H, Kong S, Chen W, Dai Z, Lin T, Su J, et al. Apigenin mediated protection of OGD-evoked neuron-like injury in differentiated PC12 cells. Neurochem Res 2014; 39:2197-2210.

39. Marniemi J, Alanen E, Impivaara O, Seppanen R, Hakala P, Rajala T, et al. Dietary and serum vitamins and minerals as predictors of myocardial infarction and stroke in elderly subjects. Nutr Metab Cardiovasc Dis 2005; 15:188-197.

40. Holt EM, Steffen LM, Moran A, Basu S, Steinberger J, Ross JA, et al. Fruit and vegetable consumption and its relation to markers of inflammation and oxidative stress in adolescents. J Am Diet Assoc 2009; 109:414-421.

41. Zhao G, Zang S-Y, Jiang Z-H, Chen Y-Y, Ji X-H, Lu B-F, et al. Postischemic administration of liposome-encapsulated luteolin prevents against ischemia-reperfusion injury in a rat middle cerebral artery occlusion model. J Nutr Biochem 2011; 22:929-936.

42. Qiao H, Dong L, Zhang X, Zhu C, Zhang X, Wang L, et al. Protective effect of luteolin in experimental ischemic stroke: upregulated SOD1, CAT, Bcl-2 and claudin-5, down-regulated MDA and Bax expression. Neurochem Res 2012; 37:2014-2024.

43. Qiao H, Zhang X, Zhu C, Dong L, Wang L, Zhang X, et al. Luteolin downregulates TLR4, TLR5, NF-κB and p-p38MAPK expression, upregulates the p-ERK expression, and protects rat brains against focal ischemia. Brain Res 2012; 1448:71-81.

44. Caltagirone C, Cisari C, Schievano C, Di Paola R, Cordaro M, Bruschetta G, et al. Co-ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: from Rodent to Man. Transl Stroke Res 2016; 7:54-69.

45. Lopez-Sanchez C, Martin-Romero FJ, Sun F, Luis L, Samhan-Arias AK, Garcia-Martinez V, et al. Blood micromolar concentrations of kaempferol afford protection against ischemia/reperfusion-induced damage in rat brain. Brain Res 2007; 1182:123-137.

46. Yu L, Chen C, Wang LF, Kuang X, Liu K, Zhang H,  et al. Neuroprotective effect of kaempferol glycosides against brain injury and neuroinflammation by inhibiting the activation of NF-kappaB and STAT3 in transient focal stroke. PLoS One 2013; 8:e55839.

47. Hosseini M, Harandizadeh F, Niazamand S, Soukhtanloo M, Mahmoudabady M. Antioxidant effect of Achillea wilhelmsii extract on pentylenetetrazole (seizure model)-induced oxidative brain damage in Wistar rats. Indian J Physiol Pharmacol 2013; 57:418-424.

48. Avallone R, Zanoli P, Puia G, Kleinschnitz M, Schreier P, Baraldi M. Pharmacological profile of apigenin, a flavonoid isolated from Matricaria chamomilla. Biochem Pharm 2000; 59:1387-1394.

49. Han J-Y, Ahn S-Y, Kim C-S, Yoo S-K, Kim S-K, Kim H-C, et al. Protection of apigenin against kainate-induced excitotoxicity by anti-oxidative effects. Biol Pharm Bull 2012; 35:1440-1446.

50. Zhen J-L, Chang Y-N, Qu Z-Z, Fu T, Liu J-Q, Wang W-P. Luteolin rescues pentylenetetrazole-induced cognitive impairment in epileptic rats by reducing oxidative stress and activating PKA/CREB/BDNF signaling. Epilepsy  Behav 2016; 57:177-184.

51. Song J, Parker L, Hormozi L, Tanouye MA. DNA topoisomerase I inhibitors ameliorate seizure-like behaviors and paralysis in a Drosophila model of epilepsy. Neuroscience 2008; 156:722-728.

52. Nugroho A, Kim MH, Choi J, Choi JS, Jung WT, Lee KT, et al. Phytochemical studies of the phenolic substances in Aster glehni extract and its sedative and anticonvulsant activity. Arch Pharm Res 2012; 35:423-430.

53. Khorramdelazad H, Bagheri V, Hassanshahi G, Zeinali M, Vakilian A. New insights into the role of stromal cell-derived factor 1 (SDF-1/CXCL12) in the pathophysiology of multiple sclerosis. J Neuroimmunol 2016; 290:70-75.

54. Noroozi Karimabad M, Khanamani Falahati-Pour S, Hassanshahi G. Significant Role(s) of CXCL12 and the SDF-1 3'A Genetic Variant in the Pathogenesis of Multiple Sclerosis. Neuroimmunomodulation 2016; 23:197-208.

55. Vazirinejad R, Ahmadi Z, Kazemi Arababadi M, Hassanshahi G, Kennedy D. The biological functions, structure and sources of CXCL10 and its outstanding part in the pathophysiology of multiple sclerosis. Neuroimmunomodulation 2014; 21:322-330.

56. Fatemi I, Shamsizadeh A, Ayoobi F, Taghipour Z, Sanati MH, Roohbakhsh A, et al. Role of orexin-A in experimental autoimmune encephalomyelitis. J Neuroimmunol 2016; 291:101-109.

57. Fatemi I, Shamsizadeh A, Roohbakhsh A, Ayoobi F, Sanati MH, Motevalian M. Increased mRNA Level of Orexin1 and 2 Receptors Following Induction of Experimental Autoimmune Encephalomyelitis in Mice. Iran J Allergy Asthma Immunol 2016; 15:20.

58. Hollinger KR, Alt J, Riehm AM, Slusher BS, Kaplin AI. Dose-dependent inhibition of GCPII to prevent and treat cognitive impairment in the EAE model of multiple sclerosis. Brain Res 2016; 1635:105-112.

59. Ayoobi F, Fatemi I, Roohbakhsh A, Shamsizadeh A. Tactile learning within the early phase of experimental autoimmune encephalomyelitis in mice. Neurophysiology 2013; 45:306-311.

60. Jafarzadeh A, Mohammadi-Kordkhayli M, Ahangar-Parvin R, Azizi V, Khoramdel-Azad H, Shamsizadeh A, et al. Ginger extracts influence the expression of IL-27 and IL-33 in the central nervous system in experimental autoimmune encephalomye-litis and ameliorates the clinical symptoms of disease. J Neuroimmunology 2014; 276:80-88.

61. Jafarzadeh A, Ahangar-Parvin R, Azizi S, Ayobi F, Taghipour Z, Shamsizadeh A, et al. Evaluation of the Effect of Vitamin D3 and Ginger Extract on the Clinical Symptoms and the Severity of Inflammation in EAE. J Rafsanjan Univ Med Sci 2015; 13:683-694.

62. Jafarzadeh A, Azizi S-V, Nemati M, Khoramdel-Azad H, Shamsizadeh A, Ayoobi F, et al. Ginger Extract Reduces the Expression of IL-17 and IL-23 in the Seraand Central Nervous System of EAEMice. Iran J Immunol 2015; 12:288.

63. Association AP. Diagnostic and Statistical Manual of Mental Disorders:: DSM-5: ManMag; 2003.

64. Rezaie Ali, Changhiz. A. Study of sedation, pre-anesthetic and anti-anxiety effects of polar, semi-polar and non-polar fractions of yarrow (Achillea millefolium) extract compared with Diazepam in rats. Life Sci J 2013; 10.

65. Irinéia Paulina Barettaa, Regiane Américo Felizardoa, Vanessa Fávero Bimbatoa, Gonc¸ M, alves Jorge dos Santosa, Candida Aparecida Leite Kassuyab c, et al. Anxiolytic-like effects of acute and chronic treatment with Achillea millefolium L. extract. J Ethnopharmacol 2012:46– 54.

66. Molina-Hernandez M, Tellez-Alcantara NP, Diaz MA, Perez Garcia J, Olivera Lopez JI, Jaramillo MT. Anticonflict actions of aqueous extracts of flowers of A. millefolium L. vary according to the estrous cycle phases in Wistar rats. Phytother Res  2004; 18:915-920.

67. Herrera-Ruiz M, Román-Ramos R, Zamilpa A, Tortoriello J, Jiménez-Ferrer JE. Flavonoids from Tilia americana with anxiolytic activity in plus-maze test. J Ethnopharmacol 2008; 118:312-317.

68. Grundmann O, Nakajima J-I, Kamata K, Seo S, Butterweck V. Kaempferol from the leaves of Apocynum venetum possesses anxiolytic activities in the elevated plus maze test in mice. Phytomedicine 2009; 16:295-302.

69. Coleta M, Campos MG, Cotrim MD, de Lima TCM, da Cunha AP. Assessment of luteolin (3′, 4′, 5, 7-tetrahydroxyflavone) neuropharmacological activity. Behav Brain Res 2008; 189:75-82.

70. Crupi R, Paterniti I, Ahmad A, Campolo M, Esposito E, Cuzzocrea S. Effects of palmitoylethanol-amide and luteolin in an animal model of anxiety/depression. CNS Neurol Disord Drug Targets 2013; 12:989-1001.

71. Glenner GG. Reprint of “Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein”. Biochem Biophys Res Commun 2012; 425:534-539.

72. Ono K, Yoshiike Y, Takashima A, Hasegawa K, Naiki H, Yamada M. Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease. J Neurochem 2003; 87:172-181.

73. NCCfC. C. Parkinson's disease: National clinical guideline for diagnosis and management in primary and secondary care. Royal College of Physicians 2006.

74. Guo DJ, Li F, Yu PH, Chan SW. Neuroprotective effects of luteolin against apoptosis induced by 6-hydroxydopamine on rat pheochromocytoma PC12 cells. Pharm Biol 2013; 51:190-196.

75. Hu LW, Yen JH, Shen YT, Wu KY, Wu MJ. Luteolin modulates 6-hydroxydopamine-induced transcrip-tional changes of stress response pathways in PC12 cells. PLoS One 2014; 9:e97880.

76. Siracusa R, Paterniti I, Impellizzeri D, Cordaro M, Crupi R, Navarra M, et al. The Association of Palmitoylethanolamide with Luteolin Decreases Neuroinflammation and Stimulates Autophagy in Parkinson's Disease Model. CNS Neurol Disord Drug Targets 2015; 14:1350-1365.

77. Caruana M, Hogen T, Levin J, Hillmer A, Giese A, Vassallo N. Inhibition and disaggregation of alpha-synuclein oligomers by natural polyphenolic compounds. FEBS Lett 2011; 585:1113-1120.

78. Lee VM, Trojanowski JQ. Mechanisms of Parkinson's disease linked to pathological alpha-synuclein: new targets for drug discovery. Neuron 2006; 52:33-38.

79. Filomeni G, Graziani I, De Zio D, Dini L, Centonze D, Rotilio G, et al. Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson's disease. Neurobiol Aging 2012; 33:767-785.

80. Ariga H, Takahashi-Niki K, Kato I, Maita H, Niki T, Iguchi-Ariga SM. Neuroprotective function of DJ-1 in Parkinson's disease. Oxid Med Cell Longev 2013; 2013:683920.

81. Yamagata K, Kitazawa T, Shinoda M, Tagawa C, Chino M, Matsufuji H. Stroke status evoked adhesion molecule genetic alterations in astrocytes isolated from stroke-prone spontaneously hypertensive rats and the apigenin inhibition of their expression. Stroke Res Treat 2010; 2010.

82. Dirscherl K, Karlstetter M, Ebert S, Kraus D, Hlawatsch J, Walczak Y, et al. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. J Neuroinflammation 2010; 7:1742-2094.

83. Shaikh MF, Tan KN, Borges K. Anticonvulsant screening of luteolin in four mouse seizure models. Neurosci Lett 2013; 550:195-199.

84. Campbell EL, Chebib M, Johnston GA. The dietary flavonoids apigenin and (−)-epigallocatechin gallate enhance the positive modulation by diazepam of the activation by GABA of recombinant GABA A receptors. Biochemical pharmacology 2004; 68:1631-1638.

85. Jager AK, Saaby L. Flavonoids and the CNS. Molecules 2011; 16:1471-1485.

86. Ayoobi Fatemeh, Roohbakhsh Ali, Allahtavakoli Mohammad, Vazirinejad Reza, Rajabi Soodeh, Ali. S. Achillea millefolium Aqueous Extract Does not Impair Recognition Memory in Mice. Trop J Pharm Res 2013; 12.

87. Salaria E, Shamsizadeh A, Noorbakhsh SM, Ayoobi F, Sheibani V, Oryan S. Effects of Achillea millefolium Aqueous Extract on Electrophysiological Properties of Rat Barrel Cortex Neurons.  2016; 10:56-59.