Skip to main content

Advertisement

Log in

The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia

  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary.

Abnormality in cytokine signaling is implicated in the neuropathology of schizophrenia. Previously, we established an animal model for schizophrenia by administering epidermal growth factor (EGF) to neonatal rats. Here we investigated effects of the anthraquinone derivatives emodin (3-methyl-1,6,8-trihydroxyanthraquinone) and sennoside (bis-[d-glucopyranosyl-oxy]-tetrahydro-4,4′-dihydroxy-dioxo[bianthracene]-2,2′-dicarboxylic acid) on behaviors of this model and EGF signaling. Subchronic oral administration of emodin (50 mg/kg) suppressed acoustic startle responses and abolished prepulse inhibition (PPI) deficits in this rodent model. ANCOVA revealed that emodin had distinct effects on PPI and startle responses. In contrast, sennoside (50 mg/kg) had no effects. Emodin attenuated weight gain initially during treatment but had no apparent effect on weight gain and locomotor activity thereafter. Application of emodin to neocortical cultures attenuated the phosphorylation of ErbB1 and ErbB2. We conclude that emodin can both attenuate EGF receptor signaling and ameliorate behavioral deficits. Therefore, emodin might be a novel class of a pro-drug for anti-psychotic medication.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • WE Ackerman BH Rovin DA Kniss (2004) ArticleTitleEpidermal growth factor and interleukin-1beta utilize divergent signaling pathways to synergistically upregulate cyclooxygenase-2 gene expression in human amnion-derived WISH cells Biol Reprod 71 2079–2086 Occurrence Handle15329330 Occurrence Handle10.1095/biolreprod.104.030841 Occurrence Handle1:CAS:528:DC%2BD2cXhtVWgsrvM

    Article  PubMed  CAS  Google Scholar 

  • S Anttila A Illi O Kampman KM Mattila T Lehtimaki E Leinonen (2004) ArticleTitleAssociation of EGF polymorphism with schizophrenia in Finnish men Neuroreport 15 1215–1218 Occurrence Handle15129177 Occurrence Handle10.1097/00001756-200405190-00027 Occurrence Handle1:CAS:528:DC%2BD2cXjs1Ojsbo%3D

    Article  PubMed  CAS  Google Scholar 

  • KS Cadenhead MA Geyer DL Braff (1993) ArticleTitleImpaired startle prepulse inhibition and habituation in patients with schizotypal personality disorder Am J Psychiatry 150 1862–1867 Occurrence Handle8238643 Occurrence Handle1:STN:280:DyaK2c%2FlslWitQ%3D%3D

    PubMed  CAS  Google Scholar 

  • T Futamura K Toyooka S Iritani K Niizato R Nakamura K Tsuchiya T Someya A Kakita H Takahashi H Nawa (2002) ArticleTitleAbnormal expression of epidermal growth factor and its receptor in the forebrain and serum of schizophrenic patients Mol Psychiatry 7 673–682 Occurrence Handle12192610 Occurrence Handle10.1038/sj.mp.4001081 Occurrence Handle1:CAS:528:DC%2BD38XmtlSjsrs%3D

    Article  PubMed  CAS  Google Scholar 

  • T Futamura A Kakita M Tohmi H Sotoyama H Takahashi H Nawa (2003) ArticleTitleNeonatal perturbation of neurotrophic signaling results in abnormal sensorimotor gating and social interaction in adults: implication for epidermal growth factor in cognitive development Mol Psychiatry 8 19–29 Occurrence Handle12556905 Occurrence Handle10.1038/sj.mp.4001138 Occurrence Handle1:CAS:528:DC%2BD3sXntl2msw%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • JW Gu H Hasuo M Takeya T Akasu (2005) ArticleTitleEffects of emodin on synaptic transmission in rat hippocampal CA1 pyramidal neurons in vitro Neuropharmacology 49 103–111 Occurrence Handle15992585 Occurrence Handle10.1016/j.neuropharm.2005.02.003 Occurrence Handle1:CAS:528:DC%2BD2MXlvVSjsLw%3D

    Article  PubMed  CAS  Google Scholar 

  • K Hanninen H Katila S Anttila R Rontu J Maaskola M Hurme T Lehtimaki (2007) ArticleTitleEpidermal growth factor a61g polymorphism is associated with the age of onset of schizophrenia in male patients J Psychiatry Res 41 8–14 Occurrence Handle10.1016/j.jpsychires.2005.07.001

    Article  Google Scholar 

  • Q Huang G Lu HM Shen MC Chung CN Ong (2007) ArticleTitleAnti-cancer properties of anthraquinones from Rhubarb Med Res Rev 27 609–630 Occurrence Handle17022020 Occurrence Handle10.1002/med.20094 Occurrence Handle1:CAS:528:DC%2BD2sXhtFGgtL7F

    Article  PubMed  CAS  Google Scholar 

  • Y Iwakura YS Piao M Mizuno N Takei A Kakita H Takahashi H Nawa (2005) ArticleTitleInfluences of dopaminergic lesion on epidermal growth factor-ErbB signals in Parkinson’s disease and its model: neurotrophic implication in nigrostriatal neurons J Neurochem 93 974–983 Occurrence Handle15857400 Occurrence Handle10.1111/j.1471-4159.2005.03073.x Occurrence Handle1:CAS:528:DC%2BD2MXksFKgu7g%3D

    Article  PubMed  CAS  Google Scholar 

  • H Jayasuriya NM Koonchanok RL Geahlen JL McLaughlin CJ Chang (1992) ArticleTitleEmodin, a protein tyrosine kinase inhibitor from Polygonum cuspidatum J Nat Prod 55 696–698 Occurrence Handle1517743 Occurrence Handle10.1021/np50083a026 Occurrence Handle1:CAS:528:DyaK38XisVOqs70%3D

    Article  PubMed  CAS  Google Scholar 

  • GD Jahnke CJ Price MC Marr CB Myers JD George (2004) ArticleTitleDevelopmental toxicity evaluation of emodin in rats and mice Birth Defects Res B Dev Reprod Toxicol 71 89–101 Occurrence Handle15098202 Occurrence Handle10.1002/bdrb.20002 Occurrence Handle1:CAS:528:DC%2BD2cXjvFyrs7s%3D

    Article  PubMed  CAS  Google Scholar 

  • T Kaneshiro T Morioka M Inamine T Kinjo J Arakaki I Chiba N Sunagawa M Suzui N Yoshimi (2006) ArticleTitleAnthraquinone derivative emodin inhibits tumor-associated angiogenesis through inhibition of extracellular signal-regulated kinase 1/2 phosphorylation Eur J Pharmacol 553 46–53 Occurrence Handle17056031 Occurrence Handle10.1016/j.ejphar.2006.09.026 Occurrence Handle1:CAS:528:DC%2BD28Xht1Chsr7I

    Article  PubMed  CAS  Google Scholar 

  • M Kaszkin-Bettag BM Ventskovskiy A Kravchenko R Rettenberger A Richardson PW Heger M Heger (2007) ArticleTitleThe special extract ERr 731 of the roots of Rheum rhaponticum decreases anxiety and improves health state and general well-being in perimenopausal women Menopause 14 270–283 Occurrence Handle17213754 Occurrence Handle10.1097/01.gme.0000251932.48426.35

    Article  PubMed  Google Scholar 

  • A Kumar S Dhawan BB Aggarwal (1998) ArticleTitleEmodin (3-methyl-1,6,8-trihydroxyanthraquinone) inhibits TNF-induced NF-kappaB activation, IkappaB degradation, and expression of cell surface adhesion proteins in human vascular endothelial cells Oncogene 17 913–918 Occurrence Handle9780008 Occurrence Handle10.1038/sj.onc.1201998 Occurrence Handle1:CAS:528:DyaK1cXlslGgtr8%3D

    Article  PubMed  CAS  Google Scholar 

  • HZ Lee (2003) ArticleTitleEffects and mechanisms of emodin on cell death in human lung squamous cell carcinoma Br J Pharmacol 134 11–20 Occurrence Handle10.1038/sj.bjp.0704205

    Article  Google Scholar 

  • E Leng-Peschlow (1993) ArticleTitleSennoside-induced secretion is not caused by changes in mucosal permeability or Na+,K(+)-ATPase activity J Pharm Pharmacol 45 951–954 Occurrence Handle7908035 Occurrence Handle1:CAS:528:DyaK2cXpsFeksg%3D%3D

    PubMed  CAS  Google Scholar 

  • HL Li HL Chen H Li KL Zhang XY Chen XW Wang QY Kong J Liu (2005) ArticleTitleRegulatory effects of emodin on NF-kappaB activation and inflammatory cytokine expression in RAW 264.7 macrophages Int J Mol Med 16 41–47 Occurrence Handle15942676 Occurrence Handle10.1007/s00894-004-0218-5 Occurrence Handle1:CAS:528:DC%2BD2MXhtFCgu7nI

    Article  PubMed  CAS  Google Scholar 

  • MC Lu MT Hsieh CR Wu HY Cheng CC Hsieh YT Lin W Peng (2007) ArticleTitleAmeliorating effect of emodin, a constitute of Polygonatum multiflorum, on cycloheximide-induced impairment of memory consolidation in rats J Ethnopharmacol 112 552–556 Occurrence Handle17572029 Occurrence Handle10.1016/j.jep.2007.05.004 Occurrence Handle1:CAS:528:DC%2BD2sXnsFylsrs%3D

    Article  PubMed  CAS  Google Scholar 

  • M Mizuno RS Malta SuffixJr T Nagano H Nawa (2004) ArticleTitleConditioned place preference and locomotor sensitization after repeated administration of cocaine or methamphetamine in rats treated with epidermal growth factor during the neonatal period Ann NY Acad Sci 1025 612–618 Occurrence Handle15542770 Occurrence Handle10.1196/annals.1316.076 Occurrence Handle1:CAS:528:DC%2BD2MXltVSkug%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • N Muller M Riedel M Ackenheil MJ Schwarz (2000) ArticleTitleCellular and humoral immune system in schizophrenia: a conceptual re-evaluation World J Biol Psychiatry 1 173–179 Occurrence Handle12607212 Occurrence Handle1:STN:280:DC%2BD3s%2FpsVWnsQ%3D%3D Occurrence Handle10.3109/15622970009150588

    Article  PubMed  CAS  Google Scholar 

  • A Muto M Hori Y Sasaki A Saitoh I Yasuda T Maekawa T Uchida K Asakura T Nakazato T Kaneda M Kizaki Y Ikeda T Yoshida (2007) ArticleTitleEmodin has a cytotoxic activity against human multiple myeloma as a Janus-activated kinase 2 inhibitor Mol Cancer Ther 6 987–994 Occurrence Handle17363492 Occurrence Handle10.1158/1535-7163.MCT-06-0605 Occurrence Handle1:CAS:528:DC%2BD2sXivV2nurg%3D

    Article  PubMed  CAS  Google Scholar 

  • K Nakajima K Yamauchi S Kuwano (1985) ArticleTitleIsolation of a new aloe-emodin dianthrone diglucoside from senna and its potentiating effect on the purgative activity of sennoside A in mice J Pharm Pharmacol 37 703–706 Occurrence Handle2867138 Occurrence Handle1:CAS:528:DyaL28XosFelsA%3D%3D

    PubMed  CAS  Google Scholar 

  • H Nawa N Takei (2006) ArticleTitleRecent progress in animal modeling of immune inflammatory processes in schizophrenia: implication of specific cytokines Neurosci Res 56 2–13 Occurrence Handle16837094 Occurrence Handle10.1016/j.neures.2006.06.002 Occurrence Handle1:CAS:528:DC%2BD28XptFCis7g%3D

    Article  PubMed  CAS  Google Scholar 

  • Nawa H, Mizuno M (2006) Antipsychotic molecular targeting epidermal growth factor. US patent application 20060167026

  • KB Seroogy S Numan CM Gall DC Lee HI Kornblum (1994) ArticleTitleExpression of EGF receptor mRNA in rat nigrostriatal system Neuroreport 6 105–108 Occurrence Handle7703395 Occurrence Handle10.1097/00001756-199412300-00028 Occurrence Handle1:CAS:528:DyaK2MXktlansrg%3D

    Article  PubMed  CAS  Google Scholar 

  • LW Slice T Chiu E Rozengurt (2005) ArticleTitleAngiotensin II and epidermal growth factor induce cyclooxygenase-2 expression in intestinal epithelial cells through small GTPases using distinct signaling pathways J Biol Chem 280 1582–1593 Occurrence Handle15525649 Occurrence Handle10.1074/jbc.M408172200 Occurrence Handle1:CAS:528:DC%2BD2MXitFCqsg%3D%3D

    Article  PubMed  CAS  Google Scholar 

  • YT Su HL Chang SK Shyue SL Hsu (2005) ArticleTitleEmodin induces apoptosis in human lung adenocarcinoma cells through a reactive oxygen species-dependent mitochondrial signaling pathway Biochem Pharmacol 70 229–241 Occurrence Handle15941563 Occurrence Handle10.1016/j.bcp.2005.04.026 Occurrence Handle1:CAS:528:DC%2BD2MXlt1Skt7s%3D

    Article  PubMed  CAS  Google Scholar 

  • NR Swerdlow MA Geyer (1998) ArticleTitleUsing an animal model of deficient sensorimotor gating to study the pathophysiology and new treatments of schizophrenia Schizophr Bull 24 285–301 Occurrence Handle9613626 Occurrence Handle1:STN:280:DyaK1c3ntlKrsA%3D%3D

    PubMed  CAS  Google Scholar 

  • NR Swerdlow MA Geyer DL Braff (2001) ArticleTitleNeural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges Psychopharmacology (Berlin) 156 194–215 Occurrence Handle10.1007/s002130100799 Occurrence Handle1:CAS:528:DC%2BD3MXmtlCqtbs%3D

    Article  CAS  Google Scholar 

  • N Takei N Inamura M Kawamura H Namba K Hara K Yonezawa H Nawa (2004) ArticleTitleBrain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites J Neurosci 24 9760–9769 Occurrence Handle15525761 Occurrence Handle10.1523/JNEUROSCI.1427-04.2004 Occurrence Handle1:CAS:528:DC%2BD2cXhtVWhtrfO

    Article  PubMed  CAS  Google Scholar 

  • M Tohmi N Tsuda M Mizuno N Takei PW Frankland H Nawa (2005) ArticleTitleDistinct influences of neonatal epidermal growth factor challenge on adult neurobehavioral traits in four mouse strains Behav Genet 35 615–629 Occurrence Handle16184489 Occurrence Handle10.1007/s10519-005-5357-7

    Article  PubMed  Google Scholar 

  • J Wang H Huang P Liu F Tang J Qin W Huang F Chen F Guo W Liu B Yang (2006) ArticleTitleInhibition of phosphorylation of p38 MAPK involved in the protection of nephropathy by emodin in diabetic rats Eur J Pharmacol 553 297–303 Occurrence Handle17074319 Occurrence Handle10.1016/j.ejphar.2006.08.087 Occurrence Handle1:CAS:528:DC%2BD28Xht1Ciu7fF

    Article  PubMed  CAS  Google Scholar 

  • R Wang Q Wan Y Zhang F Huang K Yu D Xu Q Wang J Sun (2007) ArticleTitleEmodin suppresses interleukin-1beta induced mesangial cells proliferation and extracellular matrix production via inhibiting P38 MAPK Life Sci 80 2481–2488 Occurrence Handle17512021 Occurrence Handle10.1016/j.lfs.2007.04.010 Occurrence Handle1:CAS:528:DC%2BD2sXmtVehsbw%3D

    Article  PubMed  CAS  Google Scholar 

  • SC Wang L Zhang GN Hortobagyi MC Hung (2001) ArticleTitleTargeting HER2: recent developments and future directions for breast cancer patients Semin Oncol 6 IssueIDSuppl 18 21–29 Occurrence Handle10.1053/sonc.2001.29724

    Article  Google Scholar 

  • K Yamauchi T Yagi S Kuwano (1993) ArticleTitleSuppression of the purgative action of rhein anthrone, the active metabolite of sennosides A and B, by calcium channel blockers, calmodulin antagonists and indomethacin Pharmacology Suppl 1 22–31

    Google Scholar 

  • L Zhang YK Lau L Xi RL Hong DS Kim CF Chen GN Hortobagyi C Chang MC Hung (1998) ArticleTitleTyrosine kinase inhibitors, emodin and its derivative repress HER-2/neu-induced cellular transformation and metastasis-associated properties Oncogene 16 2855–2863 Occurrence Handle9671406 Occurrence Handle10.1038/sj.onc.1201813 Occurrence Handle1:CAS:528:DyaK1cXjvV2ktLk%3D

    Article  PubMed  CAS  Google Scholar 

  • L Zhang YK Lau W Xia GN Hortobagyi MC Hung (1999) ArticleTitleTyrosine kinase inhibitor emodin suppresses growth of HER-2/neu-overexpressing breast cancer cells in athymic mice and sensitizes these cells to the inhibitory effect of paclitaxel Clin Cancer Res 5 343–353 Occurrence Handle10037184 Occurrence Handle1:CAS:528:DyaK1MXhsVWrt7k%3D

    PubMed  CAS  Google Scholar 

  • YZ Zhu B Kang QQ Zhu (1996) ArticleTitleClinical study of shuizhi-dahuang mixture in treating schizophrenics with blood stasis syndrome Zhongguo Zhong Xi Yi Jie He Za Zhi 16 646–648 Occurrence Handle9772611 Occurrence Handle1:STN:280:DyaK1cvksFOrug%3D%3D

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H. Nawa.

Additional information

Correspondence: Hiroyuki Nawa, Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mizuno, M., Kawamura, H., Takei, N. et al. The anthraquinone derivative Emodin ameliorates neurobehavioral deficits of a rodent model for schizophrenia. J Neural Transm 115, 521–530 (2008). https://doi.org/10.1007/s00702-007-0867-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-007-0867-5

Navigation