Memory/Learning, Dementia, and Kampo

  • Kinzo MatsumotoEmail author
  • Hironori Fujiwara
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


Impairment of cognitive function and learning/memory is a core symptom of patients with Alzheimer’s disease (AD), vascular dementia (VaD), and other forms of dementia. Because the number of dementia patients is increasing explosively as the world population is growing and aging, a lot of effort have been made to develop innovative drugs to overcome dementia; however, it has not succeeded yet. On the other hand, a potential usefulness of Kampo medicines for the treatment of cognitive deficits of patients with dementia has been suggested by clinical and/or preclinical studies reported during the last two decades. Those are yokukansan (YKS), chotosan, kihi-to, and kami-kihi-to (KKT), a “kihi-to”-based formula. Pharmacological and molecular biological evidence or chemical constituents, which may account for the antidementia effects of those Kampo medicines, have also been provided by lines of studies employing animal models of dementia or in vitro neurodegeneration models of dementia pathology. In this chapter, we discuss the clinical and preclinical effects of these Kampo medicines and their putative mechanisms of actions, which have been demonstrated by our own research and other laboratories.

Key words

Dementia Animal models Kampo therapy Yokukansan Chotosan Kihi-to (kami-kihi-to) Molecular mechanism 



This work was supported in part by a Grant-in-Aid for the 2012 and 2013 Cooperative Research Project I from the Institute of Natural Medicine, University of Toyama and a Grant-in-Aid for Young Scientists (B), #25860075 (to H.F.) for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan.


  1. 1.
    Wortmann M (2012) Dementia: a global health priority - highlights from an ADI and World Health Organization report. Alzheimers Res Ther 4:40PubMedPubMedCentralGoogle Scholar
  2. 2.
    Roher AE, Maarouf CL, Kokjohn TA, Whiteside CM, Kalback WM, Serrano G, Belden C, Liebsack C, Jacobson SA, Sabbagh MN, Beach TG (2014) Neuropathological and biochemical assessments of an Alzheimer’s disease patient treated with the gamma-secretase inhibitor semagacestat. Am J Neurodegener Dis 3:115–133PubMedPubMedCentralGoogle Scholar
  3. 3.
    Arrighi HM, Barakos J, Barkhof F, Tampieri D, Jack C Jr, Melancon D, Morris K, Ketter N, Liu E, Brashear HR (2016) Amyloid-related imaging abnormalities-haemosiderin (ARIA-H) in patients with Alzheimer’s disease treated with bapineuzumab: a historical, prospective secondary analysis. J Neurol Neurosurg Psychiatry 87:106–112PubMedGoogle Scholar
  4. 4.
    Bekris LM, Yu CE, Bird TD, Tsuang DW (2010) Genetics of Alzheimer disease. J Geriatr Psychiatry Neurol 23:213–227CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kivipelto M, Helkala EL, Hanninen T, Laakso MP, Hallikainen M, Alhainen K, Soininen H, Tuomilehto J, Nissinen A (2001) Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study. Neurology 56:1683–1689CrossRefPubMedGoogle Scholar
  6. 6.
    Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P (2006) Risk of dementia in diabetes mellitus: a systematic review. Lancet Neurol 5:64–74CrossRefPubMedGoogle Scholar
  7. 7.
    Crane PK, Walker R, Hubbard RA, Li G, Nathan DM, Zheng H, Haneuse S, Craft S, Montine TJ, Kahn SE, McCormick W, McCurry SM, Bowen JD, Larson EB (2013) Glucose levels and risk of dementia. N Engl J Med 369:540–548CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Larson EB, Yaffe K, Langa KM (2013) New insights into the dementia epidemic. N Engl J Med 369:2275–2277CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC (2004) Increased risk of type 2 diabetes in Alzheimer disease. Diabetes 53:474–481CrossRefPubMedGoogle Scholar
  10. 10.
    Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T (2010) Insulin resistance is associated with the pathology of Alzheimer disease: the Hisayama study. Neurology 75:764–770CrossRefPubMedGoogle Scholar
  11. 11.
    de la Torre JC (2008) Pathophysiology of neuronal energy crisis in Alzheimer’s disease. Neurodegener Dis 5:126–132CrossRefPubMedGoogle Scholar
  12. 12.
    Humpel C (2011) Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol 46:225–232CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV (2002) Efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease: a randomised trial. Lancet 359:1283–1290CrossRefPubMedGoogle Scholar
  14. 14.
    Wilkinson D, Doody R, Helme R, Taubman K, Mintzer J, Kertesz A, Pratt RD, Donepezil 308 Study G (2003) Donepezil in vascular dementia: a randomized, placebo-controlled study. Neurology 61:479–486CrossRefPubMedGoogle Scholar
  15. 15.
    Roman GC, Salloway S, Black SE, Royall DR, Decarli C, Weiner MW, Moline M, Kumar D, Schindler R, Posner H (2010) Randomized, placebo-controlled, clinical trial of donepezil in vascular dementia: differential effects by hippocampal size. Stroke 41:1213–1221CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Matsuda Y, Kishi T, Shibayama H, Iwata N (2013) Yokukansan in the treatment of behavioral and psychological symptoms of dementia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol 28:80–86CrossRefPubMedGoogle Scholar
  17. 17.
    Matsumoto K, Zhao Q, Niu Y, Fujiwara H, Tanaka K, Sasaki-Hamada S, Oka J (2013) Kampo formulations, chotosan, and yokukansan, for dementia therapy: existing clinical and preclinical evidence. J Pharmacol Sci 122:257–269CrossRefPubMedGoogle Scholar
  18. 18.
    Tabuchi M, Yamaguchi T, Iizuka S, Imamura S, Ikarashi Y, Kase Y (2009) Ameliorative effects of yokukansan, a traditional Japanese medicine, on learning and non-cognitive disturbances in the Tg2576 mouse model of Alzheimer’s disease. J Ethnopharmacol 122:157–162CrossRefPubMedGoogle Scholar
  19. 19.
    Fujiwara H, Takayama S, Iwasaki K, Tabuchi M, Yamaguchi T, Sekiguchi K, Ikarashi Y, Kudo Y, Kase Y, Arai H, Yaegashi N (2011) Yokukansan, a traditional Japanese medicine, ameliorates memory disturbance and abnormal social interaction with anti-aggregation effect of cerebral amyloid β proteins in amyloid precursor protein transgenic mice. Neuroscience 180:305–313CrossRefPubMedGoogle Scholar
  20. 20.
    Sekiguchi K, Imamura S, Yamaguchi T, Tabuchi M, Kanno H, Terawaki K, Kase Y, Ikarashi Y (2011) Effects of yokukansan and donepezil on learning disturbance and aggressiveness induced by intracerebroventricular injection of amyloid beta protein in mice. Phytother Res 25:501–507CrossRefPubMedGoogle Scholar
  21. 21.
    Ikarashi Y, Iizuka S, Imamura S, Yamaguchi T, Sekiguchi K, Kanno H, Kawakami Z, Yuzurihara M, Kase Y, Takeda S (2009) Effects of yokukansan, a traditional Japanese medicine, on memory disturbance and behavioral and psychological symptoms of dementia in thiamine-deficient rats. Biol Pharm Bull 32:1701–1709CrossRefPubMedGoogle Scholar
  22. 22.
    Yamada M, Hayashida M, Zhao Q, Shibahara N, Tanaka K, Miyata T, Matsumoto K (2011) Ameliorative effects of yokukansan on learning and memory deficits in olfactory bulbectomized mice. J Ethnopharmacol 135:737–746CrossRefPubMedGoogle Scholar
  23. 23.
    Calingasan NY, Gandy SE, Baker H, Sheu KF, Kim KS, Wisniewski HM, Gibson GE (1995) Accumulation of amyloid precursor protein-like immunoreactivity in rat brain in response to thiamine deficiency. Brain Res 677:50–60CrossRefPubMedGoogle Scholar
  24. 24.
    Hozumi S, Nakagawasai O, Tan-No K, Niijima F, Yamadera F, Murata A, Arai Y, Yasuhara H, Tadano T (2003) Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy. Behav Brain Res 138:9–15CrossRefPubMedGoogle Scholar
  25. 25.
    Aleksandrova IY, Kuvichkin VV, Kashparov IA, Medvinskaya NI, Nesterova IV, Lunin SM, Samokhin AN, Bobkova NV (2004) Increased level of beta-amyloid in the brain of bulbectomized mice. Biochemistry (Mosc) 69:176–180CrossRefGoogle Scholar
  26. 26.
    Cryan JF, Mombereau C (2004) In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. Mol Psychiatry 9:326–357CrossRefPubMedGoogle Scholar
  27. 27.
    Mizuki D, Matsumoto K, Tanaka K, Le Thi X, Fujiwara H, Ishikawa T, Higuchi Y (2014) Antidepressant-like effect of Butea superba in mice exposed to chronic mild stress and its possible mechanism of action. J Ethnopharmacol 156:16–25CrossRefPubMedGoogle Scholar
  28. 28.
    Fujiwara H, Iwasaki K, Furukawa K, Seki T, He M, Maruyama M, Tomita N, Kudo Y, Higuchi M, Saido TC, Maeda S, Takashima A, Hara M, Ohizumi Y, Arai H (2006) Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer’s β-amyloid proteins. J Neurosci Res 84:427–433CrossRefPubMedGoogle Scholar
  29. 29.
    Kanno H, Kawakami Z, Iizuka S, Tabuchi M, Mizoguchi K, Ikarashi Y, Kase Y (2013) Glycyrrhiza and Uncaria Hook contribute to protective effect of traditional Japanese medicine yokukansan against amyloid beta oligomer-induced neuronal death. J Ethnopharmacol 149:360–370CrossRefPubMedGoogle Scholar
  30. 30.
    Kawakami Z, Kanno H, Ueki T, Terawaki K, Tabuchi M, Ikarashi Y, Kase Y (2009) Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells. Neuroscience 159:1397–1407CrossRefPubMedGoogle Scholar
  31. 31.
    Kanno H, Kawakami Z, Mizoguchi K, Ikarashi Y, Kase Y (2014) Yokukansan, a kampo medicine, protects PC12 cells from glutamate-induced death by augmenting gene expression of cystine/glutamate antiporter system Xc. PLoS One 9:e116275CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kang TH, Murakami Y, Matsumoto K, Takayama H, Kitajima M, Aimi N, Watanabe H (2002) Rhynchophylline and isorhynchophylline inhibit NMDA receptors expressed in Xenopus oocytes. Eur J Pharmacol 455:27–34CrossRefPubMedGoogle Scholar
  33. 33.
    Kang TH, Murakami Y, Takayama H, Kitajima M, Aimi N, Watanabe H, Matsumoto K (2004) Protective effect of rhynchophylline and isorhynchophylline on in vitro ischemia-induced neuronal damage in the hippocampus: putative neurotransmitter receptors involved in their action. Life Sci 76:331–343CrossRefPubMedGoogle Scholar
  34. 34.
    Zhao Q, Murakami Y, Tohda M, Watanabe H, Matsumoto K (2005) Preventive effect of chotosan, a Kampo medicine, on transient ischemia-induced learning deficit is mediated by stimulation of muscarinic M1 but not nicotinic receptor. Biol Pharm Bull 28:1873–1878CrossRefPubMedGoogle Scholar
  35. 35.
    Murakami Y, Zhao Q, Harada K, Tohda M, Watanabe H, Matsumoto K (2005) Choto-san, a Kampo formula, improves chronic cerebral hypoperfusion-induced spatial learning deficit via stimulation of muscarinic M1 receptor. Pharmacol Biochem Behav 81:616–625CrossRefPubMedGoogle Scholar
  36. 36.
    Terasawa K, Shimada Y, Kita T, Yamamoto T, Tosa H, Tanaka N, Saito E, Kanaki E, Goto S, Mizushima N, Fujioka M, Takase S, Seki H, Kimura I, Ogata T, Nakamura S, Araki G, Maruyama I, Maruyama Y, Takaori S (1997) Choto-san in the treatment of vascular dementia: a double-blind, placebo-controlled study. Phytomedicine 4:15–22CrossRefPubMedGoogle Scholar
  37. 37.
    Yamaguchi S, Matsubara M, Kobayashi S (2004) Event-related brain potential changes after Choto-san administration in stroke patients with mild cognitive impairments. Psychopharmacology (Berl) 171:241–249CrossRefGoogle Scholar
  38. 38.
    Suzuki T, Futami S, Igari Y, Matsumura N, Watanabe K, Nakano H, Oba K, Murata Y, Koibuchi H, Kigawa Y (2005) A Chinese herbal medicine, choto-san, improves cognitive function and activities of daily living of patients with dementia: a double-blind, randomized, placebo-controlled study. J Am Geriatr Soc 53:2238–2240CrossRefPubMedGoogle Scholar
  39. 39.
    Yuzurihara M, Goto K, Sugimoto A, Ishige A, Komatsu Y, Shimada Y, Terasawa K (1999) Effect of Choto-san, a kampo medicine, on impairment of passive avoidance performance in mice. Phytother Res 13:233–235CrossRefPubMedGoogle Scholar
  40. 40.
    Morley JE, Farr SA, Kumar VB, Armbrecht HJ (2012) The SAMP8 mouse: a model to develop therapeutic interventions for Alzheimer’s disease. Curr Pharm Des 18:1123–1130CrossRefPubMedGoogle Scholar
  41. 41.
    Zhao WQ, Townsend M (1792) Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer’s disease. Biochim Biophys Acta 2009:482–496Google Scholar
  42. 42.
    Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV (2009) Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 301:1565–1572CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Zhao Q, Yokozawa T, Tsuneyama K, Tanaka K, Miyata T, Shibahara N, Matsumoto K (2011) Chotosan (Diaoteng San)-induced improvement of cognitive deficits in senescence-accelerated mouse (SAMP8) involves the amelioration of angiogenic/neurotrophic factors and neuroplasticity systems in the brain. Chin Med 6:33CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Zhao Q, Niu Y, Matsumoto K, Tsuneyama K, Tanaka K, Miyata T, Yokozawa T (2012) Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: possible involvement of cholinergic and VEGF/PDGF mechanisms in the brain. BMC Complement Altern Med 12:188CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Sasaki-Hamada S, Tamaki K, Otsuka H, Ueno T, Sacai H, Niu Y, Matsumoto K, Oka J (2014) Chotosan, a Kampo formula, ameliorates hippocampal LTD and cognitive deficits in juvenile-onset diabetes rats. J Pharmacol Sci 124:192–200CrossRefPubMedGoogle Scholar
  46. 46.
    Zhao Q, Murakami Y, Tohda M, Obi R, Shimada Y, Matsumoto K (2007) Chotosan, a kampo formula, ameliorates chronic cerebral hypoperfusion-induced deficits in object recognition behaviors and central cholinergic systems in mice. J Pharmacol Sci 103:360–373CrossRefPubMedGoogle Scholar
  47. 47.
    Sherin A, Peeyush KT, Naijil G, Nandhu MS, Jayanarayanan S, Jes P, Paulose CS (2011) The effects of abnormalities of glucose homeostasis on the expression and binding of muscarinic receptors in cerebral cortex of rats. Eur J Pharmacol 651:128–136CrossRefPubMedGoogle Scholar
  48. 48.
    Zhao Q, Yokozawa T, Yamabe N, Tsuneyama K, Li X, Matsumoto K (2010) Kangen-karyu improves memory deficit caused by aging through normalization of neuro-plasticity-related signaling system and VEGF system in the brain. J Ethnopharmacol 131:377–385CrossRefPubMedGoogle Scholar
  49. 49.
    Rocco ML, Pristera A, Pistillo L, Aloe L, Canu N, Manni L (2013) Brain cholinergic markers and Tau phosphorylation are altered in experimental type 1 diabetes: normalization by electroacupuncture. J Alzheimers Dis 33:767–773PubMedGoogle Scholar
  50. 50.
    Zhao Q, Matsumoto K, Tsuneyama K, Tanaka K, Li F, Shibahara N, Miyata T, Yokozawa T (2011) Diabetes-induced central cholinergic neuronal loss and cognitive deficit are attenuated by tacrine and a Chinese herbal prescription, kangen-karyu: elucidation in type 2 diabetes db/db mice. J Pharmacol Sci 117:230–242CrossRefPubMedGoogle Scholar
  51. 51.
    Lau GC, Saha S, Faris R, Russek SJ (2004) Up-regulation of NMDAR1 subunit gene expression in cortical neurons via a PKA-dependent pathway. J Neurochem 88:564–575CrossRefPubMedGoogle Scholar
  52. 52.
    Zhao H-F, Li Q, Zhang Z-F, Pei X-R, Wang J, Li Y (2009) Long-term ginsenoside consumption prevents memory loss in aged SAMP8 mice by decreasing oxidative stress and up-regulating the plasticity-related proteins in hippocampus. Brain Res 1256:111–122CrossRefPubMedGoogle Scholar
  53. 53.
    Vaynman S, Ying Z, Pinilla FG (2007) The select action of hippocampal calcium calmodulin protein kinase II in mediating exercise-enhanced cognitive function. Neuroscience 144:825–833CrossRefPubMedGoogle Scholar
  54. 54.
    Lamprecht R (1999) CREB: a message to remember. Cell Mol Life Sci 55:554–563CrossRefPubMedGoogle Scholar
  55. 55.
    Lay I-S, Ciu J-H, Shiao M-S, Lui W-Y, Wu C-W (2003) Crude extract of Salvia miltiorrhiza and salvianolic acid B enhance in vitro angiogenesis in murine SVR endothelial cell line. Planta Med 69:26–32CrossRefPubMedGoogle Scholar
  56. 56.
    Gong Y, Liu L, Xie B, Liao Y-C, Yang E, Sun Z (2008) Ameliorative effects of lotus seedpod proanthocyanidins on cognitive deficits and oxidative damage in senescence-accelerated mice. Behav Brain Res 194:100–107CrossRefPubMedGoogle Scholar
  57. 57.
    Wada T, Haigh JJ, Ema M, Hitoshi S, Chaddah R, Rossant J, Nagy A, van der Kooy D (2006) Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival. J Neurosci 26:6803–6812CrossRefPubMedGoogle Scholar
  58. 58.
    Udo H, Yoshida Y, Kino T, Ohnuki K, Mizunoya W, Mukuda T, Sugiyama H (2008) Enhanced adult neurogenesis and angiogenesis and altered affective behaviors in mice overexpressing vascular endothelial growth factor 120. J Neurosci 28:14522–14536CrossRefPubMedGoogle Scholar
  59. 59.
    Kim BW, Choi M, Kim YS, Park H, Lee HR, Yun CO, Kim EJ, Choi JS, Kim S, Rhim H, Kaang BK, Son H (2008) Vascular endothelial growth factor (VEGF) signaling regulates hippocampal neurons by elevation of intracellular calcium and activation of calcium/calmodulin protein kinase II and mammalian target of rapamycin. Cell Signal 20:714–725CrossRefPubMedGoogle Scholar
  60. 60.
    Wu KW, Yang P, Li SS, Liu CW, Sun FY (2015) VEGF attenuated increase of outward delayed-rectifier potassium currents in hippocampal neurons induced by focal ischemia via PI3-K pathway. Neuroscience 298:94–101CrossRefPubMedGoogle Scholar
  61. 61.
    Matsui T, Sano K, Tsukamoto T, Ito M, Takaishi T, Nakata H, Nakamura H, Chihara K (1993) Human neuroblastoma cells express α and β platelet-derived growth factor receptors coupling with neurotrophic and chemotactic signaling. J Clin Invest 92:1153–1160CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Zheng L, Ishii Y, Tokunaga A, Hamashima T, Shen J, Zhao Q-L, Ishizawa S, Fujimori T, Nabeshima Y-I, Mori H, Kondo T, Sasahara M (2010) Neuroprotective effects of PDGF against oxidative stress and the signaling pathway involved. J Neurosci Res 88:1273–1284CrossRefPubMedGoogle Scholar
  63. 63.
    Inada C, Niu Y, Matsumoto K, Le XT, Fujiwara H (2014) Possible involvement of VEGF signaling system in rescuing effect of endogenous acetylcholine on NMDA-induced long-lasting hippocampal cell damage in organotypic hippocampal slice cultures. Neurochem Int 75:39–47CrossRefPubMedGoogle Scholar
  64. 64.
    Inada C, Le Thi X, Tsuneyama K, Fujiwara H, Miyata T, Matsumoto K (2013) Endogenous acetylcholine rescues NMDA-induced long-lasting hippocampal cell damage via stimulation of muscarinic M(1) receptors: Elucidation using organic hippocampal slice cultures. Eur J Pharmacol 699:150–159CrossRefPubMedGoogle Scholar
  65. 65.
    Niu Y, Li F, Inada C, Tanaka K, Watanabe S, Fujiwara H, Sasaki-Hamada S, Oka J, Matsumoto K (2015) Chemical profiling with HPLC-FTMS of exogenous and endogenous chemicals susceptible to the administration of chotosan in an animal model of type 2 diabetes-induced dementia. J Pharm Biomed Anal 104:21–30CrossRefPubMedGoogle Scholar
  66. 66.
    Onozuka H, Nakajima A, Matsuzaki K, Shin RW, Ogino K, Saigusa D, Tetsu N, Yokosuka A, Sashida Y, Mimaki Y, Yamakuni T, Ohizumi Y (2008) Nobiletin, a citrus flavonoid, improves memory impairment and Abeta pathology in a transgenic mouse model of Alzheimer’s disease. J Pharmacol Exp Ther 326:739–744CrossRefPubMedGoogle Scholar
  67. 67.
    Nakajima A, Yamakuni T, Matsuzaki K, Nakata N, Onozuka H, Yokosuka A, Sashida Y, Mimaki Y, Ohizumi Y (2007) Nobiletin, a citrus flavonoid, reverses learning impairment associated with N-methyl-D-aspartate receptor antagonism by activation of extracellular signal-regulated kinase signaling. J Pharmacol Exp Ther 321:784–790CrossRefPubMedGoogle Scholar
  68. 68.
    Kawahata I, Yoshida M, Sun W, Nakajima A, Lai Y, Osaka N, Matsuzaki K, Yokosuka A, Mimaki Y, Naganuma A, Tomioka Y, Yamakuni T (2013) Potent activity of nobiletin-rich citrus reticulata peel extract to facilitate cAMP/PKA/ERK/CREB signaling associated with learning and memory in cultured hippocampal neurons: identification of the substances responsible for the pharmacological action. J Neural Transm 120:1397–1409CrossRefPubMedGoogle Scholar
  69. 69.
    Nishizawa K, Saito H, Nishiyama N (1990) Effects of Kamikihi-To, a traditional Chinese medicine, on passive and conditioned avoidance performance impairment in senescence accelerated mouse (SAM). Jpn J Pharmacol 54:375–382CrossRefPubMedGoogle Scholar
  70. 70.
    Egashira N, Manome N, Kurauchi K, Matsumoto Y, Iwasaki K, Mishima K, Shoyama Y, Fujiwara M (2007) Kamikihi-to, a Kampo medicine, ameliorates impairment of spatial memory in rats. Phytother Res 21:126–129CrossRefPubMedGoogle Scholar
  71. 71.
    Egashira N, Sudo S, Murayama F, Kohno S, Kudo Y, Goto S, Takayama F, Yamanaka Y (1991) Effects of kamikihi-to, a Chinese traditional medicine, on various cholinergic biochemical markers in the brains of aged rats. Folia Pharmacol Japon 98:273–281CrossRefGoogle Scholar
  72. 72.
    Tohda C, Naito R, Joyashiki E (2008) Kihi-to, a herbal traditional medicine, improves Abeta(25–35)-induced memory impairment and losses of neurites and synapses. BMC Complement Altern Med 8:49CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Tohda C, Nakada R, Urano T, Okonogi A, Kuboyama T (2011) Kamikihi-to (KKT) rescues axonal and synaptic degeneration associated with memory impairment in a mouse model of Alzheimer’s disease, 5XFAD. Int J Neurosci 121:641–648CrossRefPubMedGoogle Scholar
  74. 74.
    Watari H, Shimada Y, Tohda C (2014) New treatment for Alzheimer’s disease, Kamikihito reverses amyloid-beta-induced progression of tau phosphorylation and axonal atrophy. Evid Based Complement Alternat Med 2014:706487CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Welt T, Kulic L, Hoey SE, McAfoose J, Spani C, Chadha AS, Fisher A, Nitsch RM (2015) Acute effects of muscarinic M1 receptor modulation on AβPP metabolism and amyloid-β levels in vivo: a microdialysis study. J Alzheimers Dis 46:971–982. doi: 10.3233/JAD-150152 CrossRefPubMedGoogle Scholar
  76. 76.
    Del Pino J, Zeballos G, Anadon MJ, Moyano P, Diaz MJ, Garcia JM, Frejo MT (2016) Cadmium-induced cell death of basal forebrain cholinergic neurons mediated by muscarinic M1 receptor blockade, increase in GSK-3β enzyme, β-amyloid and tau protein levels. Arch Toxicol 90:1081–1092. doi: 10.1007/s00204-015-1540-7 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Division of Medicinal Pharmacology, Department of Bioscience, Institute of Natural MedicineUniversity of ToyamaToyamaJapan

Personalised recommendations