Abstract
Behavioral and psychological symptoms of dementia (BPSD) are commonly seen in patients with dementia. Current pharmacological approaches to treatment are inadequate, despite the availability of serotonergic agents to ameliorate anxiety, one of the symptoms of BPSD. The herbal medicine yokukansan has been demonstrated to improve BPSD in a randomized, single-blinded, placebo-controlled study. However, the mechanisms of the anxiolytic effect of yokukansan have not been clarified. There are also no reports on the anxiolytic effect of yokukansan in cerebrovascular ischemia models. In this study, we examined whether rats subjected to repeated cerebral ischemia exhibited anxiety-like behavior in a plus-maze task, a light/dark box test and an open-field task. We then investigated the effect of yokukansan on anxiety-like behavior in ischemic rats. Repeated ischemia was induced by the four-vessel occlusion method in which a 10-min ischemic episode was repeated once after 60 min. Yokukansan was orally administered once a day for 14 days from 7 days before ischemia induction. The last administration was performed 1 h before the behavioral experiments. The ischemic rats showed anxiety-like behavior in all three tasks, suggesting that this rat may be a good model for anxiety in cerebrovascular dementia. Yokukansan exhibited anxiolytic effects on the anxiety-like behavior in rats subjected to repeated cerebral ischemia, and exerted antagonistic effects on the wet-dog shakes induced by 1-(2,5-dimethoxy-4-indophenyl)-2-amino propane, a serotonin receptor (5-HT2A) agonist. This study revealed that yokukansan shows anxiolytic effects not only in normal animals but also in cerebrovascular model rats.
Similar content being viewed by others
References
Seignourel PJ, Kunik ME, Snow L, Wilson N, Stanley M (2008) Anxiety in dementia: a critical review. Clin Psychol Rev 28:1071–1082
Sato S, Mizukami K, Asada T (2007) A preliminary open-label study of 5-HT1A partial agonist tandospirone for behavioural and psychological symptoms associated with dementia. Int J Neuropsychopharmacol 10:281–283
Iwasaki K, Satoh-Nakagawa T, Maruyama M, Monma Y, Nemoto M, Tomita N, Tanji H, Fujiwara H, Seki T, Fujii M, Arai H, Sasaki H (2005) 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 66:248–252
Mizoguchi K, Tanaka Y, Tabira T (2010) Anxiolytic effect of a herbal medicine, yokukansan, in aged rats: involvement of serotonergic and dopaminergic transmissions in the prefrontal cortex. J Ethnopharmacol 127:70–76
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 32:1701–1709
Kamei J, Miyata S, Ohsawa M (2009) Involvement of the benzodiazepine system in the anxiolytic-like effect of yokukansan (Yi-gan san). Prog Neuropsychopharmacol Biol Psychiatry 33:1431–1437
Chung E, Iwasaki K, Mishima K, Egashira N, Fujiwara M (2002) Repeated cerebral ischemia induced hippocampal cell death and impairments of spatial cognition in the rat. Life Sci 72:609–619
Iwasaki K, Chung EH, Egashira N, Hatip-Al-Khatib I, Mishima K, Egawa T, Irie K, Fujiwara M (2004) Non-NMDA mechanism in the inhibition of cellular apoptosis and memory impairment induced by repeated ischemia in rats. Brain Res 995:131–139
Iwasaki K, Kitamura Y, Ohgami Y, Mishima K, Fujiwara M (1996) The impairment of spatial cognition and changes in brain amino acid, monoamine and acetylcholine in rats with transient cerebral ischemia. Brain Res 709:163–172
Misslin R, Belzung C, Vogel E (1988) Interaction of RO 15-4513 and ethanol on the behaviour of mice: antagonistic or additive effects? Psychopharmacology (Berl) 94:392–396
Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14:149–167
al-Khatib IM, Dokmeci I, Fujiwara M (1995) Differential role of nucleus accumbens and caudate-putamen in mediating the effect of nomifensine and methamphetamine on ambulation and rearing of rats in the open-field test. Jpn J Pharmacol 67:69–77
Choleris E, Thomas AW, Kavaliers M, Prato FS (2001) A detailed ethological analysis of the mouse open field test: effects of diazepam, chlordiazepoxide and an extremely low frequency pulsed magnetic field. Neurosci Biobehav Rev 25:235–260
Egashira N, Iwasaki K, Ishibashi A, Hayakawa K, Okuno R, Abe M, Uchida N, Mishima K, Takasaki K, Nishimura R, Oishi R, Fujiwara M (2008) 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 32:1516–1520
Weisstaub NV, Zhou M, Lira A, Lambe E, Gonzalez-Maeso J, Hornung JP, Sibille E, Underwood M, Itohara S, Dauer WT, Ansorge MS, Morelli E, Mann JJ, Toth M, Aghajanian G, Sealfon SC, Hen R, Gingrich JA (2006) Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science 313:536–540
Jung JW, Ahn NY, Oh HR, Lee BK, Lee KJ, Kim SY, Cheong JH, Ryu JH (2006) Anxiolytic effects of the aqueous extract of Uncaria rhynchophylla. J Ethnopharmacol 108:193–197
Liao JF, Jan YM, Huang SY, Wang HH, Yu LL, Chen CF (1995) Evaluation with receptor binding assay on the water extracts of ten CNS-active Chinese herbal drugs. Proc Natl Sci Counc Repub China B 19:151–158
Iwasaki K, Mishima K, Egashira N, Al-Khatib IH, Ishibashi D, Irie K, Kobayashi H, Egawa T, Fujiwara M (2003) Effect of nilvadipine on the cerebral ischemia-induced impairment of spatial memory and hippocampal apoptosis in rats. J Pharmacol Sci 93:188–196
Mishima K, Pu F, Kaneko T, Egashira N, Iwasaki K, Fujiwara M (2003) Post-ischemic administration but not pre-ischemic administration of N G-nitro-l-arginine prevents spatial memory impairments and apoptosis by an inhibition of a delayed increase in NO − x in the hippocampus following repeated cerebral ischemia. Neuropharmacology 44:533–540
Pu F, Mishima K, Egashira N, Iwasaki K, Kaneko T, Uchida T, Irie K, Ishibashi D, Fujii H, Kosuna K, Fujiwara M (2004) Protective effect of buckwheat polyphenols against long-lasting impairment of spatial memory associated with hippocampal neuronal damage in rats subjected to repeated cerebral ischemia. J Pharmacol Sci 94:393–402
Spencer SJ, Mouihate A, Pittman QJ (2007) Peripheral inflammation exacerbates damage after global ischemia independently of temperature and acute brain inflammation. Stroke 38:1570–1577
Spencer SJ, Galic MA, Tsutsui M, Pittman QJ, Mouihate A (2008) Effects of global cerebral ischemia in the pregnant rat. Stroke 39:975–982
Bantsiele GB, Bentue-Ferrer D, Saikali S, Laviolle B, Bourin M, Reymann JM (2009) Behavioral effects of four antidepressants on an ischemic rat model of emotional disturbances. Behav Brain Res 201:265–271
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 159:1397–1407
Acknowledgments
This study was partially supported by a research grant from Tsumura & Co. We thank Tsumura & Co. for providing the yokukansan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nogami, A., Sakata, Y., Uchida, N. et al. Effects of yokukansan on anxiety-like behavior in a rat model of cerebrovascular dementia. J Nat Med 65, 275–281 (2011). https://doi.org/10.1007/s11418-010-0487-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11418-010-0487-5