Neuropharmacological efficacy of the traditional Japanese Kampo medicine yokukansan and its active ingredients

Pharmacology and Therapeutics

Volumn 166, Issue , 2016, Pages 84-95

  Ikarashi, Yasushi ^a   Mizoguchi, Kazushige ^a  

^a TSUMURA AND CO   (Japan)

Author keywords

18 Glycyrrhetinic acid; Behavioral and psychological symptoms of dementia; Dementia; Geissoschizine methyl ether; Neuropharmacology; Yokukansan

Indexed keywords

1 METHYL 4 PHENYLPYRIDINIUM; CENTRAL NERVOUS SYSTEM AGENTS; KAMPO; UNCLASSIFIED DRUG; YOKUKANSAN; 18ALPHA-GLYCYRRHETINIC ACID; 4 AMINOBUTYRIC ACID; AMYLOID BETA PROTEIN; CATECHOLAMINE; GEISSOSCHIZINE METHYLETHER; GLUTAMIC ACID; GLYCYRRHETINIC ACID; HERBACEOUS AGENT; INDOLE ALKALOID; SEROTONIN RECEPTOR; YI-GAN SAN;

ADRENERGIC TRANSMISSION; AGGRESSION; ANXIETY; AUTORADIOGRAPHY; CELL DIFFERENTIATION; CELL PROLIFERATION; CHOLINERGIC TRANSMISSION; DRUG EFFICACY; GLYCYRRHIZA; HUMAN; NERVE CELL PLASTICITY; NERVOUS SYSTEM DEVELOPMENT; NEUROBLASTOMA CELL; NEUROPHARMACOLOGY; NEUROPROTECTION; NEUROTOXICITY; NEUROTRANSMISSION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SEROTONINERGIC SYSTEM; SOCIAL BEHAVIOR; ANALOGS AND DERIVATIVES; ANIMAL; BLOOD BRAIN BARRIER; CHINESE MEDICINE; DEMENTIA; DRUG EFFECTS; ENDOPLASMIC RETICULUM; INFLAMMATION; METABOLISM; PATHOLOGY; RAT; UNCARIA;

AMYLOID BETA-PEPTIDES; ANIMALS; BLOOD-BRAIN BARRIER; CATECHOLAMINES; DEMENTIA; DRUGS, CHINESE HERBAL; ENDOPLASMIC RETICULUM; GAMMA-AMINOBUTYRIC ACID; GLUTAMIC ACID; GLYCYRRHETINIC ACID; HUMANS; INDOLE ALKALOIDS; INFLAMMATION; MEDICINE, KAMPO; RATS; RECEPTORS, SEROTONIN; UNCARIA;

EID: 84979562082     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2016.06.018     Document Type: Review

References (144)

1. Akao, T., Hayashi, T., Kobashi, K., Kanaoka, M., Kato, H., Kobayashi, M., et al. Intestinal bacterial hydrolysis is indispensable to absorption of 18β-glycyrrhetic acid after oral administration of glycyrrhizin in rats. J Pharm Pharmacol 46 (1994), 135–137.
2. Anisman, H., Zacharko, R.M., Multiple neurochemical and behavioral consequences of stressors: Implications for depression. Pharmacol Ther 46 (1990), 119–136.
3. Arai, Y.C., Kawanishi, J., Sakakima, Y., Sueoka, S., Ito, A., Tawada, Y., et al. The effect of the Kampo medicine yokukansan on preoperative anxiety and sedation levels. Evid Based Complement Alternat Med, 2014, 2014, 965045.
4. Cantelli-Forti, G., Maffei, F., Hrelia, P., Bugamelli, F., Bernardi, M., D'Intino, P., et al. Interaction of licorice on glycyrrhizin pharmacokinetics. Environ Health Perspect 102 (1994), 65–68.
5. Carrasco, G.A., Van de Kar, L.D., Jia, C., Xu, H., Chen, Z., Chadda, R., et al. Single exposure to a serotonin 1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, produces a prolonged heterologous desensitization of serotonin 2A receptors in neuroendocrine neurons in vivo. J Pharmacol Exp Ther 320 (2007), 1078–1086.
6. Carthew, R.W., Gene regulation by microRNAs. Curr Opin Genet Dev 16 (2006), 203–208.
7. Cerejeira, J., Lagarto, L., Mukaetova-Ladinska, E.B., Behavioral and psychological symptoms of dementia. Front Neurol, 3, 2012, 73.
8. Chen, J.Y., Lin, J.R., Cimprich, K.A., Meyer, T., A two-dimensional ERK-AKT signaling code for an NGF-triggered cell-fate decision. Mol Cell 45 (2012), 196–209.
9. Cheng, C.Y., Ho, T.Y., Lee, E.J., Su, S.Y., Tang, N.Y., Hsieh, C.L., Ferulic acid reduces cerebral infarct through its antioxidative and anti-inflammatory effects following transient focal cerebral ischemia in rats. Am J Chin Med 36 (2008), 1105–1119.
10. Cheung, N.S., Pacoe, C.J., Giardina, S.F., John, C.A., Beart, P.M., Micromolar L-glutamate induces extensive apoptosis in an apoptotic–necrotic continuum of insult-dependent, excitotoxic injury in cultured cortical neurones. Neuropharmacology 37 (1998), 1419–1429.
11. Choi, D.W., Glutamate neurotoxicity and diseases of the nervous system. Neuron 1 (1988), 623–634.
12. −: cystine supplier and beyond. Amino Acids 42 (2012), 231–246.
13. Conradt, M., Stoffel, W., Inhibition of the high-affinity brain glutamate transporter GLAST-1 via direct phosphorylation. J Neurochem 68 (1997), 1244–1251.
14. Cooper, J.R., Bloom, F.E., Roth, R.H., (eds.) Amino acid transmitters: The biochemical basis of neuropharmacology, 1991, Oxford University Press, 133–189.
15. +/MPTP-induced cytotoxicity in vitro and in vivo. J Ethnopharmacol 131 (2010), 433–442.
16. Edwards, M.A., Loxley, R.A., Williams, A.J., Connor, M., Phillips, J.K., Lack of functional expression of NMDA receptors in PC12 cells. Neurotoxicology 28 (2007), 876–885.
17. Egashira, N., Iwasaki, K., Ishibashi, A., Hayakawa, K., Okuno, R., Abe, M., et al. Repeated administration of yokukansan inhibits DOI-induced head-twitch response and decreases expression of 5-hydroxytryptamine (5-HT)2A receptors in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 32 (2008), 1516–1520.
18. A-benzodiazepine receptor complex. J Pharmacol Sci 116 (2011), 316–320.
19. FDA, FDA public health advisory: Deaths with antipsychotics in elderly patients with behavioral disturbances. http://www.fda.gov/cder/drug/advisory/antipsychotics.htm, 2005.
20. FDA, Information for healthcare professionals: Conventional antipsychotics. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124830.htm, 2008.
21. Froissard, P., Duval, D., Cytotoxic effects of glutamic acid on PC12 cells. Neurochem Int 24 (1994), 485–493.
22. Fujiwara, H., Iwasaki, K., Furukawa, K., Seki, T., He, M., Maruyama, M., et al. Uncaria rhynchophylla, a Chinese medicinal herb, has potent antiaggregation effects on Alzheimer's beta-amyloid proteins. J Neurosci Res 84 (2006), 427–433.
23. Fujiwara, H., Takayama, S., Iwasaki, K., Tabuchi, M., Yamaguchi, T., Sekiguchi, K., et al. 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 (2011), 305–313.
24. Furuya, M., Miyaoka, T., Tsumori, T., Liaury, K., Hashioka, S., Wake, R., et al. Yokukansan promotes hippocampal neurogenesis associated with the suppression of activated microglia in Gunn rat. J Neuroinflammation, 10, 2013, 145.
25. Gonzalez, M.I., Lopez-Colom, A.M., Ortega, A., Sodium-dependent glutamate transporter in Muller glial cells: regulation by phorbol esters. Brain Res 831 (1999), 140–145.
26. Hayashi, Y., Ishida, Y., Inoue, T., Udagawa, M., Takeuchi, K., Yoshimuta, H., et al. Treatment of behavioral and psychological symptoms of Alzheimer-type dementia with Yokukansan in clinical practice. Prog Neuropsychopharmacol Biol Psychiatry 34 (2010), 541–545.
27. Hazell, A.S., Pannunzio, P., Rama Rao, K.V., Pow, D.V., Rambaldi, A., Thiamine deficiency results in downregulation of the GLAST glutamate transporter in cultured astrocytes. Glia 43 (2003), 175–184.
28. Hiratsuka, T., Matsuzaki, S., Miyata, S., Kinoshita, M., Kakehi, K., Nishida, S., et al. Yokukansan inhibits neuronal death during ER stress by regulating the unfolded protein response. PLoS One, 5, 2010, e13280.
29. Hisada, T., Maki, A., Katori, Y., Motoki, K., Adverse drug reaction frequency investigation of Tsumura yokukansan extract granules for ethical use. Diagn Treat 102 (2014), 1577–1589.
30. Iizuka, S., Kawakami, Z., Imamura, S., Yamaguchi, T., Sekiguchi, K., Kanno, H., et al. Electron-microscopic examination of effects of yokukansan, a traditional Japanese medicine, on degeneration of cerebral cells in thiamine-deficient rats. Neuropathology 30 (2010), 524–536.
31. Ikarashi, Y., Iizuka, S., Imamura, S., Yamaguchi, T., Sekiguchi, K., Kanno, H., et al. 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 (2009), 1701–1709.
32. Imamura, S., Tabuchi, M., Kushida, H., Nishi, A., Kanno, H., Yamaguchi, T., et al. The blood–brain barrier permeability of geissoschizine methyl ether in Uncaria hook, a galenical constituent of the traditional Japanese medicine yokukansan. Cell Mol Neurobiol 31 (2011), 787–793.
33. Irie, A., Fukui, T., Negishi, M., Nagata, N., Ichikawa, A., Glycyrrhetinic acid bound to 11 beta-hydroxysteroid dehydrogenase in rat liver microsomes. Biochim Biophys Acta 1160 (1992), 229–234.
34. Ishida, Y., Ebihara, K., Tabuchi, M., Imamura, S., Sekiguchi, K., Mizoguchi, K., et al. Yokukansan, a traditional Japanese medicine, enhances the L-DOPA induced rotational response in 6-hydroxydopamine-lesioned rats: possible inhibition of COMT. Biol Pharm Bull 39 (2016), 104–113.
35. Iwasaki, K., Kosaka, K., Mori, H., Okitsu, R., Furukawa, K., Manabe, Y., et al. Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration of yokukansan, a traditional Japanese medicine. Psychogeriatrics 12 (2012), 235–241.
36. Iwasaki, K., Satoh-Nakagawa, T., Maruyama, M., Monma, M.N., Nemoto, M., Tomita, N., et al. A randomized, observer-blind, controlled trial of the traditional Chinese medicine Yi-Gan San for improvement of behavioral and psychological symptoms and activities of daily living in dementia patients. J Clin Psychiatry 66 (2005), 248–252.
37. Kamei, J., Miyata, S., Ohsawa, M., Involvement of the benzodiazepine system in the anxiolytic-like effect of yokukansan (Yi-gan san). Prog Neuropsychopharmacol Biol Psychiatry 33 (2009), 1431–1437.
38. Kanno, H., Kawakami, Z., Iizuka, S., Tabuchi, M., Mizoguchi, K., Ikarashi, Y., et al. Glycyrrhiza and Uncaria hook contribute to protective effect of traditional Japanese medicine yokukansan against amyloid β oligomer-induced neuronal death. J Ethnopharmacol 149 (2013), 360–370.
39. −. PLoS One, 2014, 2014, e116275.
40. Kanno, H., Kawakami, Z., Tabuchi, M., Mizoguchi, K., Ikarashi, Y., Kase, Y., Protective effects of glycycoumarin and procyanidin B1, active components of traditional Japanese medicine yokukansan, on amyloid β oligomer-induced neuronal death. J Ethnopharmacol 159 (2015), 122–128.
41. Kanno, H., Sekiguchi, K., Yamaguchi, T., Terawaki, K., Yuzurihara, M., Kase, Y., et al. Effect of yokukansan, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected rats. J Pharm Pharmacol 61 (2009), 1249–1256.
42. Kato, S., Kato, T.A., Nishie, H., Nishima, S., Iwanaga, T., Monji, A., et al. Successful treatment of chronic urticaria with a Japanese herbal medicine, yokukansan. J Dermatol 37 (2010), 1066–1067.
43. Kawakami, Z., Ikarashi, Y., Kase, Y., Isoliquiritigenin is a novel NMDA receptor antagonist in Kampo medicine yokukansan. Cell Mol Neurobiol 31 (2011), 1203–1212.
44. Kawakami, Z., Kanno, H., Ikarashi, Y., Kase, Y., Yokukansan, a kampo medicine, protects against glutamate cytotoxicity due to oxidative stress in PC12 cells. J Ethnopharmacol 134 (2011), 74–81.
45. Kawakami, Z., Ikarashi, Y., Kase, Y., Glycyrrhizin and its metabolite 18β- glycyrrhetinic acid in Glycyrrhiza, a constituent herb of yokukansan, ameliorate thiamine deficiency-induced dysfunction of glutamate transport in cultured rat cortical astrocytes. Eur J Pharmacol 626 (2010), 154–158.
46. Kawakami, Z., Kanno, H., Ueki, T., Terawaki, K., Tabuchi, M., Ikarashi, Y., et al. Neuroprotective effects of yokukansan, a traditional Japanese medicine, on glutamate-mediated excitotoxicity in cultured cells. Neuroscience 159 (2009), 1397–1407.
47. Khaksa, G., Zolfaghari, M.E., Dehpour, A.R., Samadian, T., Anti-inflammatory and anti-nociceptive activity of disodium glycyrrhetinic acid hemiphthalate. Planta Med 62 (1996), 326–328.
48. Kim, Y.W., Zhao, R.J., Park, S.J., Lee, J.R., Cho, I.J., Yang, C.H., et al. Antiinflammatory effects of liquiritigenin as a consequence of the inhibition of NF-kappaB-dependent iNOS and proinflammatory cytokines production. Br J Pharmacol 154 (2008), 165–173.
49. Kitagawa, H., Munekage, M., Ichikawa, K., Fukudome, I., Munekage, E., Takezaki, Y., et al. Pharmacokinetics of active components of yokukansan, a traditional Japanese herbal medicine after a single oral administration to healthy Japanese volunteers: A cross-over, randomized study. PLoS One, 10, 2015, e0131165.
50. Kitano, H., A robustness-based approach to systems-oriented drug design. Nat Rev Drug Discov 6 (2007), 202–210.
51. Kozutsumi, Y., Segal, M., Normington, K., Gething, M.J., Sambrook, J.F., The presence of malfolded proteins in the endoplasmic reticulum signals the induction of glucose-regulated proteins. Nature 332 (1988), 462–464.
52. Kubota, K., Sano, K., Shiraishi, A., Beppu, N., Nogami, A., Uchida, N., et al. Yokukansan, a traditional Japanese herbal medicine, promotes neurite outgrowth in PC12 cells through the activation of extracellular signal regulated kinase 1/2 and phosphatidylinositol 3-kinase/Akt. J Trad Med 30 (2013), 102–113.
53. Kushida, H., Fukutake, M., Tabuchi, M., Katsuhara, T., Nishimura, H., Ikarashi, Y., et al. Simultaneous quantitative analyses of indole and oxindole alkaloids of Uncaria hook in rat plasema and brain after oral administration of the traditional Japanese medicine yokukansan using high-performance liquid chromatography with tandem mass spectrometry. Biomed Chromatogr 27 (2013), 2647–2656.
54. Kushida, H., Matsumoto, T., Igarashi, Y., Nishimura, H., Watanabe, J., Maemura, K., et al. Metabolic profiling of the Uncaria hook alkaloid geissoschizine methyl ether in rat and human liver microsomes using high-performance liquid chromatography with tandem mass spectrometry. Molecules 20 (2015), 2100–2114.
55. Lawlor, B.A., Behavioral and psychological symptoms in dementia: The role of atypical antipsychotics. J Clin Psychiatry 65:Suppl. 11 (2004), 5–10.
56. − in health and disease: from molecular mechanisms to novel therapeutic opportunities. Antioxid Redox Signal 18 (2013), 522–555.
57. − function in neuronal cells. Amino Acids 42 (2012), 171–179.
58. Liao, J.F., Jan, Y.M., Huang, S.Y., Wang, H.H., Yu, L.L., Chen, C.F., Evaluation with receptor binding assay on the water extracts of ten CNS-active Chinese herbal drugs. Proc Natl Sci Counc Repub China B 19 (1995), 151–158.
59. − cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases. J Cell Physiol 215 (2008), 593–602.
60. Liu, Y., Nakamura, T., Toyoshima, T., Lu, F., Sumitani, K., Shinomiya, A. et al., Ameliorative effects of yokukansan on behavioral deficits in a gerbil model of global cerebral ischemia. Brain Res 1543 (2014), 300–307.
61. Lu, C.N., Yuan, Z.G., Zhang, X.L., Yan, R., Zhao, Y.Q., Liao, M., et al. Saikosaponin a and its epimer saikosaponin d exhibit anti-inflammatory activity by suppressing activation of NF-kappaB signaling pathway. Int Immunopharmacol 14 (2012), 121–126.
62. Lysko, P.G., Cox, J.A., Vigano, M.A., Henneberry, R.C., Excitatory amino acid neurotoxicity at the N-methyl-D-aspartate receptor in cultured neurons: Pharmacological characterization. Brain Res 499 (1989), 258–266.
63. Makinodan, M., Yamauchi, T., Tatsumi, K., Okuda, H., Noriyama, Y., Sadamatsu, M., et al. Yi-Gan San restores behavioral alterations and a decrease of brain glutathione level in a mouse model of schizophrenia. J Brain Dis 1 (2009), 1–6.
64. Matsuda, Y., Kishi, T., Shibayama, H., Iwata, N., Yokukansan in the treatment of behavioral and psychological symptoms of dementia: A systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol 28 (2013), 80–86.
65. Matsumoto, T., Kushida, H., Maruyama, T., Nishimura, H., Watanabe, J., Maemura, K., et al. In vitro identification of human cytochrome P450 isoforms involved in the metabolism of Geissoschizine methyl ether, an active component of the traditional Japanese medicine yokukansan. Xenobiotica 46 (2016), 325–334.
66. Matsumoto, K., Uzunova, V., Pinna, G., Taki, K., Uzunov, D.P., Watanabe, H., et al. Permissive role of brain allopregnanolone content in the regulation of pentobarbital-induced righting reflex loss. Neuropharmacology 38 (1999), 955–963.
67. Mazure, C.M., Does stress cause psychiatric illness?. Spiegel, D., (eds.) Progress in psychiatry, 1995, American Psychiatric, Washington, DC, 270–298.
68. Miyaoka, T., Furuya, M., Yasusda, H., Hayashida, M., Inagaki, T., Horiguchi, J., Yi-gan san for the treatment of borderline personality disorder: An open-label study. Prog Neuropsychopharmacol Biol Psychiatry 32 (2008), 150–164.
69. Miyaoka, T., Furuya, M., Yasusda, H., Hayashida, M., Nishida, A., Inagaki, T., et al. Yi-gan san for the treatment of neuroleptic-induced tardive dyskinesia: An open-label study. Prog Neuropsychopharmacol Biol Psychiatry 32 (2008), 761–764.
70. Miyaoka, T., Furuya, M., Yasusda, H., Hayashida, M., Nishida, A., Inagaki, T., et al. Yi-gan san as adjunctive therapy for treatment-resistant schizophrenia: An open-label study. Clin Neuropharmacol 32 (2009), 6–9.
71. Miyaoka, T., Wake, R., Furuya, M., Liaury, K., Ieda, M., Kawakami, K., et al. Yokukansan (TJ-54) for treatment of pervasive developmental disorder not otherwise specified and Asperger's disorder: A 12-week prospective, open-label study. BMC Psychiatry, 12, 2012, 215.
72. Mizoguchi, K., Kanno, H., Ikarashi, Y., Kase, Y., Specific binding and characteristics of 18β-glycyrrhetinic acid in rat brain. PLoS One, 9, 2014, e95760.
73. Mizoguchi, K., Kushida, H., Kanno, H., Igarashi, Y., Nishimura, H., Ikarashi, Y., et al. Specific binding and characteristics of Geissoschizine methy ether, an indole alkaloid of Uncaria hook, in rat brain. J Ethnopharmacol 158 (2014), 264–270.
74. Mizoguchi, K., Shoji, H., Tanaka, Y., Tabira, T., Ameliorative effect of traditional Japanese medicine yokukansan on age-related impairments of working memory and reversal learning in rats. Neuroscience 177 (2011), 127–137.
75. Mizoguchi, K., Tanaka, Y., Tabira, T., Anxiolytic effect of a herbal medicine, yokukansan, in aged rats: involvement of serotonergic and dopaminergic transmission in the prefrontal cortex. J Ethnopharmacol 127 (2010), 70–76.
76. Mizoguchi, K., Yuzurihara, M., Ishige, A., Sasaki, H., Chui, D.H., Tabira, T., Chronic stress induces impairment of spatial working memory because of prefrontal dopaminergic dysfunction. J Neurosci 20 (2000), 1568–1574.
77. Mizukami, K., Asada, T., Kinoshita, T., Tanaka, K., Sonohara, K., Nakai, R., et al. A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of the behavioural and psychological symptoms of dementia. Int J Neuropsychopharmacol 12 (2009), 191–199.
78. Monji, A., Takita, M., Samejima, T., Takaishi, T., Hashimoto, K., Matsunaga, H., et al. Effect of yokukansan on the behavioral and psychological symptoms of dementia in elderly patients with Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 33 (2009), 308–311.
79. Morita, S., Tatsumi, K., Makinodan, M., Okuda, H., Kishimoto, T., Wanaka, A., Geissoschizine methyl ether, an alkaloid from the Uncaria hook, improves remyelination after cuprizone-induced demyelination in medial prefrontal cortex of adult mice. Neurochem Res 39 (2014), 59–67.
80. Murphy, T.H., Schnaar, R.L., Coyle, J.T., Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake. FASEB J 4 (1990), 1624–1633.
81. Nagaratnam, N., Lewis-Jones, M., Scott, D., Palazzi, L., Behavioral and psychiatric manifestations in dementia patients in a community: Caregiver burden and outcome. Alzheimer Dis Assoc Disord 12 (1998), 330–334.
82. Nagata, K., Yokoyama, E., Yamazaki, T., Takano, D., Maeda, T., Takahashi, S., et al. Effects of yokukansan on behavioral and psychological symptoms of vascular dementia: An open-label trial. Phytomedicine 19 (2012), 524–528.
83. Nakagawa, T., Nagayasu, K., Nishitani, N., Shirakawa, H., Sekiguchi, K., Ikarashi, Y., et al. Yokukansan inhibits morphine tolerance and physical dependence in mice: The role of α2A-adrenoceptor. Neuroscience 227 (2012), 336–349.
84. Nakamura, Y., Tajima, K., Kanai, M., Mitsuhata, H., Efficacy of traditional herbal medicine, yokukansan on patients with neuropathic pain. Masui 10 (2009), 1248–1255.
85. Nakatani, Y., Tsuji, M., Amano, T., Miyagawa, K., Miyagishi, H., Saito, A., et al. Neuroprotective effect of yokukansan against cytotoxicity induced by corticosterone on mouse hippocampal neurons. Phytomedicine 21 (2014), 1458–1465.
86. Nichols, D.E., Hallucinogens. Pharmacol Ther 101 (2004), 131–181.
87. Nishi, A., Yamaguchi, T., Sekiguchi, K., Imamura, S., Tabuchi, M., Kanno, H., et al. Geissoschizine methyl ether, an alkaloid in Uncaria hook, is a potent serotonin1A receptor agonist and candidate for amelioration of aggressiveness and sociality by yokukansan. Neuroscience 207 (2012), 124–136.
88. Nogami, A., Takasaki, K., Kubota, K., Yamaguchi, K., Kawasaki, C., Nakamura, K., et al. Effect of yokukansan on memory disturbance in an animal model of cerebrovascular dementia. J Trad Med 30 (2013), 164–175.
89. Nukaya, H., Yamashiro, H., Fukazawa, H., Ishida, H., Tsuji, K., Isolation of inhibitors of TPA-induced mouse ear edema from Hoelen, Poria cocos. Chem Pharm Bull(Tokyo) 44 (1996), 847–849.
90. Obara, Y., Aoki, T., Kusano, M., Ohizumi, Y., β-Eudesmol induces neurite outgrowth in rat pheochromocytoma cells accompanied by an activation of mitogen-activated protein kinase. J Pharmacol Exp Ther 301 (2002), 803–811.
91. Okahara, K., Ishida, Y., Hayashi, Y., Inoue, T., Tsuruta, K., Takeuchi, K., et al. Effects of yokukansan on behavioral and psychological symptoms of dementia in regular treatment for Alzheimer's disease. Prog Neuropsychopharmacol Biol Psychiatry 34 (2010), 532–536.
92. Or, T.C., Yang, C.L., Law, A.H., Li, J.C., Lau, A.S., Isolation and identification of anti-inflammatory constituents from Ligusticum chuanxiong and their underlying mechanisms of action on microglia. Neuropharmacology 60 (2011), 823–831.
93. Oyadomari, S., Mori, M., Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11 (2004), 381–389.
94. Oyadomari, S., Araki, E., Mori, M., Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 7 (2002), 335–345.
95. Penugonda, S., Mare, S., Goldstein, G., Banks, W.A., Ercal, N., Effects of N-acetylcysteine amide (NACA), a novel thiol antioxidant against glutamate-induced cytotoxicity in neuronal cell line PC12. Brain Res 1056 (2005), 132–138.
96. 2 + homeostasis. Neurosci Res 37 (2000), 227–236.
97. Ploeger, B., Mensinga, T., Sips, A., Seinen, W., Meulenbelt, J., DeJongh, J., The pharmacokinetics of glycyrrhizic acid evaluated by physiologically based pharmacokinetic modeling. Drug Metab Rev 33 (2001), 125–147.
98. Porter, N., Herman, J.P., Landfield, P.W., Mechanisms of glucocorticoid actions in stress and brain aging. McEwen, B.S., (eds.) Handbook of physiology: Coping with the environment, 2001, Oxford University Press, Oxford, 293–309.
99. Saito, S., Kobayashi, T., Osawa, T., Kato, S., Effectiveness of Japanese herbal medicine yokukansan for alleviating psychiatric symptoms after traumatic brain injury. Psychogeriatrics 10 (2010), 45–48.
100. Sapolsky, R.M., Krey, L.C., McEwen, B.S., The neuroendocrinology of stress and aging: The glucocorticoid cascade hypothesis. Endocr Rev 7 (1986), 284–301.
101. Schubert, D., Kimura, H., Maher, P., Growth factors and vitamin E modify neuronal glutamate toxicity. Proc Natl Acad Sci U S A 89 (1992), 8264–8267.
102. Sekiguchi, K., Imamura, S., Yamaguchi, T., Tabuchi, M., Kanno, H., Terawaki, K., et al. Effects of yokukansan and donepezil on learning disturbance and aggressiveness induced by intracerebroventricular injection of amyloid β protein in mice. Phytother Res 25 (2011), 501–507.
103. Sekiguchi, K., Kanno, H., Yamaguchi, T., Ikarashi, Y., Kase, Y., Ameliorative effect of yokukansan on vacuous chewing movement in haloperidol-induced rat tardive dyskinesia model and involvement of glutamatergic system. Brain Res Bull 89 (2012), 151–158.
104. Sekiguchi, K., Yamaguchi, T., Tabuchi, M., Ikarashi, Y., Kase, Y., Effects of yokukansan, a traditional Japanese medicine, on aggressiveness induced by intracerebro-ventricular injection of amyloid β protein into mice. Phytother Res 23 (2009), 1175–1181.
105. Seo, M.J., Kim, S.J., Kang, T.H., Rim, H.K., Jeong, H.J., Um, J.Y., et al. The regulatory mechanism of beta-eudesmol is through the suppression of caspase-1 activation in mast cell-mediated inflammatory response. Immunopharmacol Immunotoxicol 33 (2011), 178–185.
106. Shimizu, S., Tanaka, T., Takeda, T., Tohyama, M., Miyata, S., The kampo medicine yokukansan decreases microRNA-18 expression and recovers glucocorticoid receptors protein expression in the hypothalamus of stressed mice. Biomed Res Int, 2015, 2015, 797280.
107. Shimizu, S., Tanaka, T., Tohyama, M., Miyata, S., Yokukansan normalizes glucocorticoid receptor protein expression in oligodendrocytes of the corpus callosum by regulating microRNA-124a expression after stress exposure. Brain Res Bull 114 (2015), 49–55.
108. Shoji, H., Mizoguchi, K., Brain region-specific reduction in c-Fos expression associated with an anxiolytic effect of yokukansan in rats. J Ethnopharmacol 149 (2013), 93–102.
109. Sidrauski, C., Chapman, R., Walter, P., The unfolded protein response: An intracellular signaling pathway with many surprising features. Trends Cell Biol 8 (1998), 245–249.
110. Song, Y., Qu, R., Zhu, S., Zhang, R., Ma, S., Rhynchophylline attenuates LPS-induced pro-inflammatory responses through down-regulation of MAPK/NF-kappaB signaling pathways in primary microglia. Phytother Res 26 (2012), 1528–1533.
111. Sun, J., Ren, X., Med, W.Q., Yuan, D., Simpkins, J.W., Geissoschizine methyl ether protects oxidative stress-mediated cytotoxicity in neurons through the ‘neuronal Warburg effect’. J Ethnopharmacol 187 (2016), 249–258.
112. Suzuki, Y., Mitsuhata, H., Yuzurihara, M., Kase, Y., Antiallodynic effect of herbal medicine yokukansan on peripheral neuropathy in rats with chronic constriction injury. Evid Based Complement Alternat Med, 2012, 2012, 953459.
113. Tabuchi, M., Imamura, S., Kawakami, Z., Ikarashi, Y., Kase, Y., The blood–brain barrier permeability of 18β-glycyrrhetinic acid, a major metabolite of glycyrrhizin in Glycyrrhiza root, a constitutent of the traditional Japanese medicine yokukansan. Cell Mol Neurobiol 32 (2012), 1139–1146.
114. Tabuchi, M., Yamaguchi, T., Iizuka, S., Imamura, S., Ikarashi, Y., Kase, Y., 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 (2009), 157–162.
115. Takeda, S., Ishihara, K., Wakui, Y., Amagaya, S., Maruno, M., Akao, T., et al. Bioavailability study of glycyrrhetic acid after oral administration of glycyrrhizin in rats; relevance to the intestinal bacterial hydrolysis. J Pharm Pharmacol 48 (1996), 902–905.
116. Takeda, A., Itoh, H., Tamano, H., Yuzurihara, M., Oku, N., Suppressive effect of yokukansan on excessive release of glutamate and aspartate in the hippocampus of zinc-deficient rats. Nutr Neurosci 11 (2008), 41–46.
117. Takeda, A., Iwaki, H., Ide, K., Tamano, H., Oku, N., Therapeutic effect of yokukansan on social isolation-induced aggressive behavior of zinc-deficient and pair-fed mice. Brain Res Bull 87 (2012), 551–555.
118. Takeda, A., Tamano, H., Itoh, H., Oku, N., Attenuation of abnormal glutamate release in zinc deficiency by zinc and yokukansan. Neurochem Int 53 (2008), 230–235.
119. Tamano, H., Kan, F., Oku, N., Takeda, A., Ameliorative effect of yokukansan on social isolation-induced aggressive behavior of zinc-deficient young mice. Brain Res Bull 83 (2010), 351–355.
120. Tamano, H., Yusuke, E., Ide, K., Takeda, A., Influences of Yokukansankachimpihange on aggressive behavior of zinc-deficient mice and actions of the ingredients on excessive neural exocytosis in the hippocampus of zinc-deficient rats. Exp Anim, 2016 (in press).
121. Tanaka, Y., Mizoguchi, K., Influence of aging on chondroitin sulfate proteoglycan expression and neural stem/progenitor cells in rat brain and improving effects of a herbal medicine, yokukansan. Neuroscience 164 (2009), 1224–1234.
122. Tanji, H., Ootsuki, M., Matsui, T., Maruyama, M., Nemoto, M., Tomita, N., et al. Dementia caregiver's burdens and use of public services. Geriatr Gerontol Int 5 (2005), 94–98.
123. Tateno, M., Ukai, W., Ono, T., Saito, S., Hashimoto, E., Saito, T., Neuroprotective effects of Yi-Gan San against beta amyloid-induced cytotoxicity on rat cortical neurons. Prog Neuropsychopharmacol Biol Psychiatry 32 (2008), 1704–1707.
124. Terawaki, K., Ikarashi, Y., Sekiguchi, K., Nakai, Y., Kase, Y., Partial agonistic effect of yokukansan on human recombinant serotonin 1A receptors expressed in the membranes of Chinese hamster ovary cells. J Ethnopharmacol 127 (2010), 306–312.
125. Tirasophon, W., Welihinda, A.A., Kaufman, R.J., A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev 12 (1998), 1812–1824.
126. Tsuji, M., Inanami, O., Kuwabara, M., Induction of neurite outgrowth in PC12 cells by alpha-phenyl-N-tert-butylnitron through activation of protein kinase C and the Ras-extracellular signal-regulated kinase pathway. J Biol Chem 276 (2001), 32779–32785.
127. Tsuji, M., Takeuchi, T., Miyagawa, K., Ishii, D., Imai, T., Takeda, K., et al. Yokukansan, a traditional Japanese herbal medicine, alleviates the emotional abnormality induced by maladaptation to stress in mice. Phytomedicine 21 (2014), 363–371.
128. Uchida, N., Takasaki, K., Sakata, Y., Nogami, A., Oishi, H., Watanabe, T., et al. Cholinergic involvement and synaptic dynamin 1 expression in yokukansan-mediated improvement of spatial memory in a rat model of early Alzheimer's disease. Phytother Res 27 (2013), 966–972.
129. Ueda, T., Ugawa, S., Ishida, Y., Shimada, S., Geissoschizine methyl ester has third-generation antipsychotic-like actions at the dopamine and serotonin receptors. Eur J Pharmacol 671 (2011), 79–86.
130. Ueki, T., Ikarashi, Y., Kawakami, Z., Mizoguchi, K., Kase, Y., Promotive effects of yokukansan, a traditional Japanese medicine, on proliferation and differentiation of cultured mouse cortical oligodendrocytes. Pharmacol Pharm 5 (2014), 670–680.
131. 1A receptor agonist-induced behavioral responses in socially isolated mice. Evid Based Complement Alternat Med, 2015, 2015, 726471.
132. 2A receptors in the prefrontal cortex of isolation-stressed mice. J Ethnopharmacol 166 (2015), 23–30.
133. Ueki, T., Nishi, A., Imamura, S., Kanno, H., Mizoguchi, K., Sekiguchi, K., et al. Effects of geissoschizine methyl ether, an indole alkaloid in Uncaria hook, a constituent of yokukansan, on human recombinant serotonin 7 receptor. Cell Mol Neurobiol 33 (2013), 129–135.
134. Vaudry, D., Stork, P.J., Lazarovici, P., Eiden, L.E., Signaling pathways for PC12 cell differentiation: making the right connections. Science 296 (2002), 1648–1649.
135. Vazhappilly, R., Wee, K.S., Sucher, N.J., Low, C.M., A non-muscle myosin II motor links NR1 to retrograde trafficking and proteasomal degradation in PC12 cells. Neurochem Int 56 (2010), 569–576.
136. Vreugdenhil, E., Verissimo, C.S., Mariman, R., Kamphorst, J.T., Barbosa, J.S., Zweers, T., et al. MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. Endocrinology 150 (2009), 2220–2228.
137. Wang, Z., Kurosaki, Y., Nakayama, T., Kimura, T., Mechanism of gastrointestinal absorption of glycyrrhizin in rats. Biol Pharm Bull 17 (1994), 1399–1403.
138. Wang, P.S., Schneeweiss, S., Avorn, J., Fischer, M.A., Mogun, H., Solomon, D.H., et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med 353 (2005), 2335–2341.
139. Wang, Y., Stricker, H.M., Gou, D., Liu, L., MicroRNA: past and present. Front Biosci 12 (2007), 2316–2329.
140. Wieland, S., Fischette, C.T., Lucki, I., Effect of chronic treatments with tandospirone and imipramine on serotonin-mediated behavioral responses and monoamine receptors. Neuropharmacology 32 (1993), 561–573.
141. Yamaguchi, T., Tsujimatsu, A., Kumamoto, H., Izumi, T., Ohmura, Y., Yoshida, T., et al. (2012). Anxiolytic effects of yokukansan, a traditional Japanese medicine, via serotonin 5-HT1A receptors on anxiety-related behaviors in rats experienced aversive stress. J Ethnopharmacol 143, 533–539 (2012).
142. Yuan, R., Lin, Y., Traditional Chinese medicine: An approach to scientific proof and clinical validation. Pharmacol Ther 86 (2000), 191–198.
143. Yuan, D., Ma, B., Yang, J.Y., Xie, Y.Y., Wang, L., Zhang, L.J., et al. Anti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanism. Int Immunopharmacol 9 (2009), 1549–1554.
144. Zhu, M.Y., Piletz, J.E., Halaris, A., Regunathan, S., Effect of agmatine against cell death induced by NMDA and glutamate in neurons and PC12 cells. Cell Mol Neurobiol 23 (2003), 865–872.