Planta Med 2017; 83(01/02): 51-56
DOI: 10.1055/s-0042-107471
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Arctigenin Attenuates Learning and Memory Deficits through PI3k/Akt/GSK-3β Pathway Reducing Tau Hyperphosphorylation in Aβ-Induced AD Mice

Yue Qi
1   Department of Pharmacology, The Second Hospital Affiliated to Liaoning Chinese Medical University, Shenyang, P. R. China
De-Qiang Dou
2   College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shenyang, P. R. China
Hong Jiang
1   Department of Pharmacology, The Second Hospital Affiliated to Liaoning Chinese Medical University, Shenyang, P. R. China
Bing-Bing Zhang
2   College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shenyang, P. R. China
Wen-Yan Qin
1   Department of Pharmacology, The Second Hospital Affiliated to Liaoning Chinese Medical University, Shenyang, P. R. China
Kai Kang
2   College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shenyang, P. R. China
Na Zhang
2   College of Pharmacy, Liaoning University of Traditional Chinese Medicine, Shenyang, P. R. China
Dong Jia
1   Department of Pharmacology, The Second Hospital Affiliated to Liaoning Chinese Medical University, Shenyang, P. R. China
› Author Affiliations
Further Information

Publication History

received 09 December 2015
revised 14 April 2016

accepted 15 April 2016

Publication Date:
25 May 2016 (online)


Arctigenin is a phenylpropanoid dibenzylbutyrolactone lignan compound possessing antitumor, anti-inflammatory, anti-influenza, antioxidant, antibacterial, and hypoglycaemic activities. Our previous study demonstrated that arctigenin exerts neuroprotective effects both in vitro and in vivo in a Parkinsonʼs disease model. However, the exact mechanism through which arctigenin improves amyloid beta-induced memory impairment by inhibiting the production of the hyperphosphorylated tau protein is unknown. Amyloid β 1–42 was slowly administered via the intracerebroventricular route in a volume of 3 µL (≈ 410 pmmol/mouse) to mice. The mice were administered arctigenin (10, 40, or 150 mg/kg) or vehicle starting from the second day after amyloid β 1–42 injection to the end of the experiment. Behavioural tests were performed from days 9 to 15. On day 16 after the intracerebroventricular administration of amyloid β 1–42, the mice were sacrificed for biochemical analysis. Arctigenin (10–150 mg/kg) significantly attenuated the impairment of spontaneous alternation behaviours in the Y-maze task, decreased the escape latency in the Morris water maze test, and increased the swimming times and swimming distances to the platform located in the probe test. Arctigenin attenuated the level of phosphorylated tau at the Thr-181, Thr-231, and Ser-404 sites in the hippocampus, and increased the phosphorylation levels of phosphatidylinositol-3-kinase, threonine/serine protein kinase B, and glycogen synthase kinase-3β. Arctigenin effectively provides protection against learning and memory deficits and in inhibits hyperphosphorylated tau protein expression in the hippocampus. The possible mechanism may occur via the phosphatidylinositol-3-kinase/protein kinase B-dependent glycogen synthase kinase-3β signalling pathway.

  • References

  • 1 Qi Y, Zou LB, Wang LH, Jin G, Pan JJ, Chi TY, Ji XF. Xanthoceraside inhibits pro-inflammatory cytokine expression in Aβ 25–35/IFN-γ-stimulated microglia through the TLR2 receptor, MyD88, nuclear factor-κB, and mitogen-activated protein kinase signaling pathways. J Pharmacol Sci 2013; 122: 305-317
  • 2 Krause DL, Müller N. Neuroinflammation, microglia and implications for anti-inflammatory treatment in Alzheimerʼs disease. Int J Alzheimers Dis 2010; 2010: 732806
  • 3 Zumkehr J, Rodriguez-Ortiz CJ, Cheng D, Kieu Z, Wai T, Hawkins C, Kilian J, Lim SL, Medeiros R, Kitazaw M. Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial glutamate transporter in a mouse model of Alzheimerʼs disease. Neurobiol Aging 2015; 36: 2260-2271
  • 4 Reddy PH. Abnormal tau, mitochondrial dysfunction, impaired axonal transport of mitochondria, and synaptic deprivation in Alzheimerʼs disease. Brain Res 2011; 1415: 136-148
  • 5 Dugger BN, Tu M, Murray ME, Dickson DW. Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimerʼs disease and progressive supranuclear palsy. Neurosci Lett 2011; 491: 122-126
  • 6 Tang Z, Ioja E, Bereczki E, Hultenby K, Li C, Guan Z, Winblad B, Pei JJ. mTor mediates tau localization and secretion: Implication for Alzheimerʼs disease. Biochim Biophys Acta 2015; 1853: 1646-1657
  • 7 Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol 2008; 85: 148-175
  • 8 Wei W, Wang X, Kusiak JW. Signaling events in amyloid beta-peptide-induced neuronal death and insulin-like growth factor I protection. J Biol Chem 2002; 277: 17649-17656
  • 9 Stein TD, Johnson JA. Lack of neurodegeneration in transgenic mice overexpressing mutant amyloid precursor protein is associated with increased levels of transthyretin and the activation of cell survival pathways. J Neurosci 2002; 22: 7380-7388
  • 10 Hoppe JB, Coradini K, Frozza R, Oliveira CM, Meneghetti AB, Bernardi A, Pires ES, Beck RCR, Salbego CG. Free and nanoencapsulated curcumin suppress β-amyloid-induced cognitive impairments in rats: involvement of BDNF and Akt/GSK-3β signaling pathway. Neurobiol Learn Mem 2013; 106: 134-144
  • 11 Koh SH, Kim SH, Kwon H, Park Y, Kim KS, Song CW, Kim J, Kim MH, Yu HJ, Henkel JS, Jung HK. Epigallocatechin gallate protects nerve growth factor differentiated PC12 cells from oxidative-radical-stress-induced apoptosis through its effect on phosphoinositide 3-kinase/Akt and glycogen synthase kinase-3. Brain Res Mol Brain Res 2003; 118: 72-81
  • 12 Wang W, Pan Q, Han XY, Wang J, Tan RQ, He F, Dou DQ, Kang TG. Simultaneous determination of arctiin and its metabolites in rat urine and feces by HPLC. Fitoterapia 2013; 86: 6-12
  • 13 Swarup V, Ghosh J, Mishra M, Basu A. Novel strategy for treatment of Japanese encephalitis using arctigenin, a plant lignan. J Antimicrob Chemother 2008; 3: 679-688
  • 14 Zhao F, Wang L, Liu K. In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway. J Ethnopharmacol 2009; 122: 457-462
  • 15 Kang HS, Lee JY, Kim CJ. Anti-inflammatory activity of arctigenin from Forsythiae Fructus. J Ethnopharmacol 2008; 116: 305-312
  • 16 Li DW, Liu QP, Jia D, Dou DQ, Wang XF, Kang TG. Protective effect of arctigenin against MPP+ and MPTP-induced neurotoxicity. Planta Med 2014; 80: 48-55
  • 17 Avila J. Tau phosphorylation and aggregation in Alzheimerʼs disease pathology. FEBS Lett 2006; 580: 2922-2927
  • 18 Zhu ZY, Yan JM, Jiang W, Yao XG, Chen J, Chen LL, Li CJ, Hu LH, Jiang HL, Shen X. Arctigenin effectively ameliorates memory impairment in Alzheimerʼs disease model mice targeting both β-amyloid production and clearance. J Neurosci 2013; 33: 13138-13149
  • 19 Martin L, Page G, Terro F. Tau phosphorylation and neuronal apoptosis induced by the blockade of PP2A, preferentially involve GSK3β . Neurochem Int 2011; 59: 235-250
  • 20 Fujimura M, Usuki F, Sawada M, Takashima A. Methylmercury induces neuropathological changes with tau hyperphosphorylation mainly through the activation of the c-jun-N-terminal kinase pathway in the cerebral cortex, but not in the hippocampus of the mouse brain. Neurotoxicology 2009; 30: 1000-1007
  • 21 Peng CX, Hu J, Liu D, Hong XP, Wu YY, Zhu LQ, Wang JZ. Disease-modified glycogen synthase kinase-3β intervention by melatonin arrests the pathology and memory deficits in an Alzheimerʼs animal model. Neurobiol Aging 2013; 34: 1555-1563
  • 22 Jin G, Wang LH, Ji XF, Chi TY, Qi Y, Jiao Q, Xu Q, Zhou XY, Zhang R, Zou LB. Xanthoceraside rescues learning and memory deficits through attenuating beta-amyloid deposition and tau hyperphosphorylation in APP mice. Neurosci Lett 2014; 573: 58-63
  • 23 Xiong YS, Wang DL, Tan L, Wang X, Chen LM, Gong CX, Wang JZ, Zhu LQ. Inhibition of glycogen synthase kinase-3 reverses tau hyperphosphorylation induced by Pin1 down-regulation. CNS Neurol Disord Drug Targets 2013; 12: 436-443
  • 24 Dewachter I, Ris L, Jaworski T, Seymour CM, Kremer A, Borghgraef P, Vijver HD, Godaux E, Van Leuven F. GSK3β, a centre-staged kinase in neuropsychiatric disorders, modulates long term memory by inhibitory phosphorylation at serine-9. Neurobiol Dis 2009; 35: 193-200
  • 25 Noh MY, Chun K, Kang BY, Kim H, Park JS, Lee HC, Kim YH, Ku S, Kim SH. Newly developed glycogen synthase kinase-3 (GSK-3) inhibitors protect neuronal cells death in amyloid-beta induced cell model and in a transgenic mouse model of Alzheimerʼs disease. Biochem Biophys Res Commun 2013; 435: 274-281
  • 26 Liu P, Zou LB, Wang LH, Jiao Q, Chi TY, Ji XF, Jin G. Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats. Psychopharmacology (Berl) 2014; 231: 345-356
  • 27 Maqbool M, Mobashir M, Hoda N. Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimerʼs disease. Eur J Med Chem 2016; 107: 63-81
  • 28 Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 2014; 26: 2694-2701
  • 29 Lou HY, Fan PH, Perez RG. Neuroprotective effects of linarin through activation of the PI3K/Akt pathway in amyloid-β-induced neuronal cell death. Bioorg Med Chem 2011; 19: 4021-4027
  • 30 Hou Q, He F, Dou DQ, Kang TG, Li HF. [New preparation method of arctigenin from Fructus Arctii]. Chin J New Drugs 2011; 20: 871-873
  • 31 Jana M, Palencia CA, Pahan K. Fibrillar amyloid-β peptides activate microglia via TLR2: implications for Alzheimerʼs disease. J Immunol 2008; 181: 7254-7262
  • 32 Chi TY, Wang LH, Ji XF, Li W, Wang Y, Xia M, Zou LB. [Protective effects of xanthoceraside on learning and memory impairment induced by intracerebroventricular injections of Aβ 1–42 in mice]. J Shenyang Pharm Univ 2010; 27: 314-320
  • 33 Laursen SE, Belknap JK. Intranerebroventricular injections in mice. Some methodological refinements. J Pharmacol Methods 1986; 16: 335-357