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Licensed Unlicensed Requires Authentication Published by De Gruyter October 12, 2018

Ethanolic extract of Erythrina velutina Willd ameliorate schizophrenia-like behavior induced by ketamine in mice

  • Naiara Coelho Ximenes , Manuel Alves Dos Santos Júnior , Germana Silva Vasconcelos , Kátia Cilene Ferreira Dias , Mércia Marques Jucá , Aline Holanda Silva , Luzia Kalyne Almeida Moreira Leal , Glauce Socorro Barros Viana , Francisca Cléa Florenço de Sousa and Silvânia Maria Mendes Vasconcelos EMAIL logo



Schizophrenia is a chronic mental disorder, characterized by positive, negative and cognitive symptoms. In general, several plants have shown activity in diseases related to the central nervous system (e.g., Erythrina velutina (EEEV), also known as “mulungu”). For this reason, we aimed to investigate the effects of standardized ethanol extract obtained from the stem bark of EEEV on the schizophrenia-like behaviors induced by ketamine (KET) administration.


Swiss mice were treated with KET (20 mg/kg, i.p.) or saline for 14 days. In addition, from 8th to 14th days, saline, EEEV (200 or 400 mg/kg, p.o.) or olanzapine (OLAN 2 mg/kg, p.o.) were associated to the protocol. On the 14th day of treatment, schizophrenia-like symptoms were evaluated by the prepulse inhibition of the startle reflex (PPI), locomotor activity evaluated by the open field test (OFT), spatial recognition memory evaluated by the Y-maze task and social interaction test (SIT).


KET has caused deficits in PPI, and it has also has caused hyperlocomotion in OFT and deficits in SIT as compared to control. EEEV in both doses used, reversed behavioral changes induced by KET, likewise results obtained with the administration of OLAN.


Taken together, the results demonstrate that the standard extract of EEEV was able to revert schizophrenia-like symptoms, due to the administration in repeated doses of ketamine. Thus, our findings lead to a new perspective for the use of EEEV an interesting alternative for drug discovery in schizophrenia.


We thank the support by University Federal of Ceará, Funcap, CAPES, and CNPq.

  1. Conflict of interest: None declared.

  2. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  3. Research funding: Funcap, CAPES and CNPq.

  4. Employment or leadership: None declared.

  5. Honorarium: None declared.

  6. Competing interests: All funding organizations played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


[1] Harvey CA, Curson DA, Pantelis C, Taylor J, Barnes TRE. Four behavioural syndromes of schizophrenia. Br J Psychiatry. 1996;168:562–70.10.1192/bjp.168.5.562Search in Google Scholar PubMed

[2] Larson MK, Walker EF, Compton MT. Early signs, diagnosis and therapeutics of the prodromal phase of schizophrenia and related psychotic disorders. Expert Rev Neurother. 2010;10:1347–59.10.1586/ern.10.93Search in Google Scholar PubMed PubMed Central

[3] Meyer U, Feldon J. Epidemiology-driven neurodevelopmental animal models of schizophrenia. Prog Neurobiol. 2010;90:285–326.10.1016/j.pneurobio.2009.10.018Search in Google Scholar PubMed

[4] Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Möller HJ, et al. Diretrizes da Federação Mundial das Sociedades de Psiquiatria Biológica para o tratamento biológico da esquizofrenia parte 1: tratamento agudo. Revista de Psiquiatria Clinica. 2006;33:7–64.10.1590/S0101-60832006000700003Search in Google Scholar

[5] Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, ‘Just the Facts’ 5. Treatment and prevention Past, present, and future. Schizophr Res. 2010;122:1–23.10.1016/j.schres.2010.05.025Search in Google Scholar PubMed

[6] Lima EBC, de Sousa CNS, Vasconcelos GS, Meneses LN, e Silva Pereira YF, Ximenes NC, et al. Antidepressant, antioxidant and neurotrophic properties of the standardized extract of Cocos nucifera husk fiber in mice. J Nat Med. 2016;70:510–21.10.1007/s11418-016-0970-8Search in Google Scholar PubMed

[7] Lima EBC, de Sousa CNS, Meneses LN, e Silva Pereira YF, Matos NCB, de Freitas RB, et al. Involvement of monoaminergic systems in anxiolytic and antidepressive activities of the standardized extract of Cocos nucifera L. J Nat Med. 2017;71:227–37.10.1007/s11418-016-1053-6Search in Google Scholar PubMed

[8] Zhang Y, Li Q, Li X, Wan H–Y. Erythrina variegata extract exerts osteoprotective effects by suppression of the process of bone resorption. Br J Nutr. 2010;104:965–71.10.1017/S0007114510001789Search in Google Scholar PubMed

[9] Chukwujekwu JC, Van Heerden FR, Van Staden J. Antibacterial activity of flavonoids from the stem bark of Erythrina caffra thunb. Phyther Res. 2011;25:46–8.10.1002/ptr.3159Search in Google Scholar PubMed

[10] Nguyen PH, Le TVT, Thuong PT, Dao TT, Ndinteh DT, Mbafor JT, et al. Cytotoxic and PTP1B inhibitory activities from Erythrina abyssinica. Bioorganic Med Chem Lett. 2009;19:6745–9.10.1016/j.bmcl.2009.09.108Search in Google Scholar PubMed

[11] Carvalho ACB, Balbino EE, Maciel A, Perfeito JPS. Situação do registro de medicamentos fitoter??picos no Brasil. Brazilian J Pharmacogn. 2008;18:314–9.10.1590/S0102-695X2008000200028Search in Google Scholar

[12] Lorenzi H, Matos FJA. Plantas medicinais no Brasil: nativas e exóticas cultivadas. Nova Odessa: Instituto Plantarum, 2008;544.Search in Google Scholar

[13] Sarris J, McIntyre E, Camfield DA. Plant-based medicines for anxiety disorders, Part 1: a review of preclinical studies. CNS Drugs. 2013;27:207–19.10.1007/s40263-013-0044-3Search in Google Scholar PubMed

[14] Carvalho ACCS, Almeida DS, Melo MGD, Cavalcanti SCH, Marçal RM. Evidence of the mechanism of action of Erythrina velutina Willd (Fabaceae) leaves aqueous extract. J Ethnopharmacol. 2009;122:374–8.10.1016/j.jep.2008.12.019Search in Google Scholar PubMed

[15] Vasconcelos SM, Macedo DS, de Melo CT, Paiva Monteiro a, Rodrigues a C, Silveira ER, et al. Central activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu in mice. J Pharm Pharmacol. 2004;56:389–93.10.1211/0022357022746Search in Google Scholar PubMed

[16] Rodrigues FTS, de Sousa CNS, Ximenes NC, Almeida AB, Cabral LM, Patrocinio CFV, et al. Effects of standard ethanolic extract from Erythrina velutina in acute cerebral ischemia in mice. Biomed Pharmacother. 2017;96:1230–9.10.1016/j.biopha.2017.11.093Search in Google Scholar PubMed

[17] Silva AH, Fonseca FN, Pimenta ATA, Lima MS, Silveira ER, Viana GSB, et al. Pharmacognostical analysis and protective effect of standardized extract and rizonic acid from Erythrina velutina against 6-hydroxydopamine-induced neurotoxicity in Sh-Sy5Y cells. Pharmacogn Mag. 2016;12:307–12.Search in Google Scholar PubMed

[18] Vasconcelos SMM, Lima NM, Sales GTM, Cunha GMA, Aguiar LM V, Silveira ER, et al. Anticonvulsant activity of hydroalcoholic extracts from Erythrina velutina and Erythrina mulungu. J Ethnopharmacol. 2007;110:271–4.10.1016/j.jep.2006.09.023Search in Google Scholar PubMed

[19] Raupp IM, Sereniki A, Virtuoso S, Ghislandi C, Cavalcanti e Silva EL, Trebien HA, et al. Anxiolytic-like effect of chronic treatment with Erythrina velutina extract in the elevated plus-maze test. J Ethnopharmacol. 2008;118:295–9.10.1016/j.jep.2008.04.016Search in Google Scholar PubMed

[20] Onusic GM, Nogueira RL, Pereira AMS, Viana MB. Effect of acute treatment with a water-alcohol extract of Erythrina mulungu on anxiety-related responses in rats. Brazilian J Med Biol Res. 2002;35:473–7.10.1590/S0100-879X2002000400011Search in Google Scholar

[21] Ribeiro MD, Onusic GM, Poltronieri SC, Viana MB. Effect of Erythrina velutina and Erythrina mulungu in rats submitted to animal models of anxiety and depression. Brazilian J Med Biol Res. 2006;39:263–70.10.1590/S0100-879X2006000200013Search in Google Scholar

[22] Vasconcelos SMM, Lima NM, de Lucena LS, Praxedes Rodrigues AC, Silveira ER, Torres Aguiar CC et al. Behavioral study with Erythrina velutina fractions. Asian Pac J Trop Med. 2009;2:30–3.Search in Google Scholar

[23] Da-Cunha EVL, Dias C, Barbosa–Filho JM, Gray AI. Eryvellutinone, an isoflavanone from the stem bark of Erythrina vellutina. Phytochemistry. 1996;43:1371–3.10.1016/S0031-9422(96)00529-8Search in Google Scholar

[24] Rabelo LA, De Fátima Agra M, Da-Cunha EVL, Da Silva MS, Barbosa–Filho JM. Homohesperetin and phaseollidin from Erythrina velutina. Biochem Syst Ecol. 2001;29:543–4.10.1016/S0305-1978(00)00077-6Search in Google Scholar PubMed

[25] Pelletier AL, Mittal VA. Negative symptom measurement in individuals at-risk for psychosis. Psychiatry Res. 2013;205:181–2.10.1016/j.psychres.2012.08.020Search in Google Scholar PubMed

[26] Balhara YPS, Verma R. Schizophrenia and suicide. East Asian Archives Psychiatry. 2012;22:126–33.Search in Google Scholar

[27] Byrne P. Managing the acute psychotic episode. BMJ. 2007;334:686–92.10.1136/bmj.39148.668160.80Search in Google Scholar PubMed

[28] Monte AS, de Souza GC, McIntyre RS, Soczynska JK, dos Santos JV, Cordeiro RC, et al. Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: possible involvement of antioxidant and nitrergic pathways. J Psychopharmacol. 2013;27:1032–43.10.1177/0269881113503506Search in Google Scholar PubMed

[29] Deroza PF, Ghedim F V, Heylmann AS, de Luca RD, Budni J, Souza RP, et al. Effect of cigarette smoke exposure in the behavioral changes induced by ketamine. Schizophr Res. 2012;141:104–5.10.1016/j.schres.2012.07.004Search in Google Scholar PubMed

[30] Ninan I, Kulkarni SK. Differential effects of olanzapine at dopamine D1 and D2 receptors in dopamine depleted animals. Psychopharmacology (Berl). 1999;142:175–81.10.1007/s002130050877Search in Google Scholar PubMed

[31] Archer J. Tests for emotionality in rats and mice: a review. Animal Behaviour. 1973;21:205–35.10.1016/S0003-3472(73)80065-XSearch in Google Scholar PubMed

[32] Levin R, Calzavara MB, Santos CM, Medrano WA, Niigaki ST, Abílio VC. Spontaneously Hypertensive Rats (SHR) present deficits in prepulse inhibition of startle specifically reverted by clozapine. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1748–52.10.1016/j.pnpbp.2011.06.003Search in Google Scholar PubMed

[33] Yamada K, Noda Y, Hasegawa T, Komori Y, Nikai T, Sugihara H, et al. The role of nitric oxide in dizocilpine-induced impairment of spontaneous alternation behavior in mice. J Pharmacol Exp Ther. 1996;276:460–6.10.1016/0306-4522(96)00161-3Search in Google Scholar PubMed

[34] Radyushkin K, Hammerschmidt K, Boretius S, Varoqueaux F, El-Kordi A, Ronnenberg A, et al. Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes, Brain Behav. 2009;8:416–25.10.1111/j.1601-183X.2009.00487.xSearch in Google Scholar PubMed

[35] Thaker GK. Schizophrenia endophenotypes as treatment targets. Expert Opin Ther Targets. 2007;11:1189–206.10.1517/14728222.11.9.1189Search in Google Scholar PubMed

[36] Van Den Buuse M. Modeling the positive symptoms of schizophrenia in genetically modified mice: pharmacology and methodology aspects. Schizophrenia Bulletin. 2010;36:246–70.10.1093/schbul/sbp132Search in Google Scholar PubMed PubMed Central

[37] Vasconcelos GS, Ximenes NC, de Sousa CNS, Oliveira T de Q, Lima LLL, de Lucena DF, et al. Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: participation of antioxidant, nitrergic and neurotrophic mechanisms. Schizophr Res. 2015;165:163–70.10.1016/j.schres.2015.04.017Search in Google Scholar PubMed

[38] Braff DL, Freedman R, Schork NJ, Gottesman II. Deconstructing schizophrenia: an overview of the use of endophenotypes in order to understand a complex disorder. Schizophr Bull. 2007;33:21–32.10.1093/schbul/sbl049Search in Google Scholar PubMed PubMed Central

[39] Powell SB, Zhou X, Geyer MA. Prepulse inhibition and genetic mouse models of schizophrenia. Behav Brain Res. 2009;204:282–94.10.1016/j.bbr.2009.04.021Search in Google Scholar PubMed PubMed Central

[40] Desbonnet L, Waddington JL, O'Tuathaigh CMP. Mutant models for genes associated with schizophrenia. Biochem Soc Trans. 2009;37:308–12.10.1042/BST0370308Search in Google Scholar PubMed

[41] Lysaker PH, Erikson M, Macapagal KR, Tunze C, Gilmore E, Ringer JM. Development of personal narratives as a mediator of the impact of deficits in social cognition and social withdrawal on negative symptoms in Schizophrenia. J Nerv Ment Dis. 2012;200:290–5.10.1097/NMD.0b013e31824cb0f4Search in Google Scholar PubMed

[42] Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol. 2009;19:220–30.10.1016/j.conb.2009.05.001Search in Google Scholar PubMed

[43] Bitanihirwe BKY, Woo TUW. Oxidative stress in schizophrenia: an integrated approach. Neurosci Biobehav Rev. 2011;35:878–93.10.1016/j.neubiorev.2010.10.008Search in Google Scholar PubMed PubMed Central

[44] Bošković M, Vovk T, Kores Plesničar B, Grabnar I. Oxidative stress in schizophrenia. Curr Neuropharmacol. 2011;9:301–12.10.2174/157015911795596595Search in Google Scholar PubMed PubMed Central

[45] Ciobica A, Padurariu M, Dobrin I, Stefanescu C, Dobrin R. Oxidative stress in schizophrenia – Focusing on the main markers. Psychiatria Danubina. 2011;23:237–45.Search in Google Scholar PubMed

[46] O'Donnell P. Cortical interneurons, immune factors and oxidative stress as early targets for schizophrenia. Eur J Neurosci. 2012;35:1866–70.10.1111/j.1460-9568.2012.08130.xSearch in Google Scholar PubMed

[47] Sullivan EM, O'Donnell P. Inhibitory interneurons, oxidative stress, and schizophrenia. Schizophr Bull. 2012;38:373–6.10.1093/schbul/sbs052Search in Google Scholar PubMed

[48] Wu JQ, Kosten TR, Zhang XY. Free radicals, antioxidant defense systems, and schizophrenia. Prog Neuro-Psychopharmacol Biol Psychiatry. 2013;46:200–6.10.1016/j.pnpbp.2013.02.015Search in Google Scholar

[49] Yao JK, Keshavan MS. Antioxidants, redox signaling, and pathophysiology in Schizophrenia: an integrative view. Antioxid Redox Signal. 2011;15:2011–35.10.1089/ars.2010.3603Search in Google Scholar PubMed

[50] Packer L, Witt EH, Tritschler HJ. Alpha-lipoic acid as a biological antioxidant. Free Radic Biol Med. 1995;19:227–50.10.1016/0891-5849(95)00017-RSearch in Google Scholar PubMed

Received: 2018-04-11
Accepted: 2018-09-12
Published Online: 2018-10-12

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