Abstract
The current drug therapy for schizophrenia effectively treats acute psychosis and its recurrence; however, this mental disorder’s cognitive and negative symptoms are still poorly controlled. Antipsychotics present important side effects, such as weight gain and extrapyramidal effects. The essential oil of Alpinia zerumbet (EOAZ) leaves presents potential antipsychotic properties that need further preclinical investigation. Here, we determined EAOZ effects in preventing and reversing schizophrenia-like symptoms (positive, negative, and cognitive) induced by ketamine (KET) repeated administration in mice and putative neurobiological mechanisms related to this effect. We conducted the behavioral evaluations of prepulse inhibition of the startle reflex (PPI), social interaction, and working memory (Y-maze task), and verified antioxidant (GSH, nitrite levels), anti-inflammatory [interleukin (IL)-6], and neurotrophic [brain-derived neurotrophic factor (BDNF)] effects of this oil in hippocampal tissue. The atypical antipsychotic olanzapine (OLZ) was used as standard drug therapy. EOAZ, similarly to OLZ, prevented and reversed most KET-induced schizophrenia-like behavioral alterations, i.e., sensorimotor gating deficits and social impairment. EOAZ had a modest effect on the prevention of KET-associated working memory deficit. Compared to OLZ, EOAZ showed a more favorable side effects profile, inducing less cataleptic and weight gain changes. EOAZ efficiently protected the hippocampus against KET-induced oxidative imbalance, IL-6 increments, and BDNF impairment. In conclusion, our data add more mechanistic evidence for the anti-schizophrenia effects of EOAZ, based on its antioxidant, anti-inflammatory, and BDNF up-regulating actions. The absence of significant side effects observed in current antipsychotic drug therapy seems to be an essential benefit of the oil.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data will be made available under request.
References
Abel KM, Drake R, Goldstein JM (2010) Sex differences in schizophrenia. Int Rev Psychiatry 22:417–428. https://doi.org/10.3109/09540261.2010.515205
Ahmed MN, Kabidul Azam MN (2014) Traditional knowledge and formulations of medicinal plants used by the traditional medical practitioners of bangladesh to treat schizophrenia like psychosis. Schizophr Res Treat 2014:1–10. https://doi.org/10.1155/2014/679810
Aleman A, Kahn RS, Selten J-P (2003) Sex differences in the risk of schizophrenia. Arch Gen Psychiatry 60:565. https://doi.org/10.1001/archpsyc.60.6.565
Aly E, Khajah MA, Masocha W (2020) β-caryophyllene, a CB2-receptor-selective phytocannabinoid, suppresses mechanical allodynia in a mouse model of antiretroviral-induced neuropathic pain. Molecules 25. https://doi.org/10.3390/molecules25010106
Araújo S, Jose A, Chaves M et al (2016) Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs. J Psychiatr Res. https://doi.org/10.1016/j.jpsychires.2016.09.017
Bahi A, Al Mansouri S, Al Memari E et al (2014) β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav 135:119–124. https://doi.org/10.1016/j.physbeh.2014.06.003
Bähner F, Demanuele C, Schweiger J et al (2015) Hippocampal–dorsolateral prefrontal coupling as a species-conserved cognitive mechanism: a human translational imaging study. Neuropsychopharmacology 40:1674–1681. https://doi.org/10.1038/npp.2015.13
Bannerman D, Rawlins JN, McHugh S et al (2004) Regional dissociations within the hippocampus—memory and anxiety. Neurosci Biobehav Rev 28:273–283. https://doi.org/10.1016/j.neubiorev.2004.03.004
Becker A, Grecksch G (2004) Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol Biol Psychiatry 28:1267–1277. https://doi.org/10.1016/j.pnpbp.2004.06.019
Ben-Azu B, Aderibigbe AO, Ajayi AM et al (2018a) Involvement of GABAergic, BDNF and Nox-2 mechanisms in the prevention and reversal of ketamine-induced schizophrenia-like behavior by morin in mice. Brain Res Bull 139:292–306. https://doi.org/10.1016/j.brainresbull.2018.03.006
Ben-Azu B, Aderibigbe AO, Eneni A-EO et al (2018b) Morin attenuates neurochemical changes and increased oxidative/nitrergic stress in brains of mice exposed to ketamine: prevention and reversal of schizophrenia-like symptoms. Neurochem Res 43:1745–1755. https://doi.org/10.1007/s11064-018-2590-z
Ben-Azu B, Aderibigbe AO, Omogbiya IA et al (2018c) Probable mechanisms involved in the antipsychotic-like activity of morin in mice. Biomed Pharmacother 105:1079–1090. https://doi.org/10.1016/j.biopha.2018.06.057
Ben-Azu B, Aderibigbe AO, Ajayi AM et al (2019) Morin decreases cortical pyramidal neuron degeneration via inhibition of neuroinflammation in mouse model of schizophrenia. Int Immunopharmacol 70:338–353. https://doi.org/10.1016/j.intimp.2019.02.052
Bernstein HG, Krell D, Braunewell KH et al (2001) Increased number of nitric oxide synthase immunoreactive Purkinje cells and dentate nucleus neurons in schizophrenia. J Neurocytol 30:661–670. https://doi.org/10.1023/A:1016520932139
Bezerra MAC, Leal-Cardoso JH, Coelho-de-Souza AN et al (2000) Myorelaxant and antispasmodic effects of the essential oil of Alpinia speciosa on rat ileum. Phyther Res 14:549–551. https://doi.org/10.1002/1099-1573(200011)14:7<549::AID-PTR623>3.0.CO;2-T
Bitanihirwe BKY, Woo TUW (2011) Oxidative stress in schizophrenia: An integrated approach. Neurosci Biobehav Rev 35:878–893
Bošković M, Vovk TT, Kores Plesničar B et al (2011) Oxidative stress in schizophrenia. Curr Neuropharmacol 9:301–312. https://doi.org/10.2174/157015911795596595
Bowie CR, Harvey PD (2006) Cognitive deficits and functional outcome in schizophrenia. Neuropsychiatr Dis Treat 2:531–536
Braff DL, Light GA (2005) The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia. Dialogues Clin Neurosci 7:125–135
Burton S (2006) Symptom domains of schizophrenia: the role of atypical antipsychotic agents. J Psychopharmacol 20:6–19. https://doi.org/10.1177/1359786806071237
Campbell M, Young PI, Bateman DN et al (1999) The use of atypical antipsychotics in the management of schizophrenia. Br J Clin Pharmacol 47:13–22. https://doi.org/10.1046/j.1365-2125.1999.00849.x
Carpenter WT, Davis JM (2012) Another view of the history of antipsychotic drug discovery and development. Mol Psychiatry 17:1168–1173. https://doi.org/10.1038/mp.2012.121
Charan J, Kantharia N (2013) How to calculate sample size in animal studies? J Pharmacol Pharmacother 4:303–306. https://doi.org/10.4103/0976-500X.119726
Chatterjee M, Ganguly S, Srivastava M, Palit G (2011) Effect of “chronic” versus “acute” ketamine administration and its “withdrawal” effect on behavioural alterations in mice: Implications for experimental psychosis. Behav Brain Res 216:247–254. https://doi.org/10.1016/j.bbr.2010.08.001
Chompoo J, Upadhyay A, Gima S et al (2012) Antiatherogenic properties of acetone extract of Alpinia zerumbet seeds. Molecules. https://doi.org/10.3390/molecules17066249
Costall B, Naylor RJ (1974) On catalepsy and catatonia and the predictability of the catalepsy test for neuroleptic activity. Psychopharmacologia 34:233–241
Craveiro AA, Matos FJA, de Alencar JW (1976) A simple and inexpensive steam generator for essential oils extraction. J Chem Educ 53:652. https://doi.org/10.1021/ed053p652
Cuesta MJ, Peralta V, Zarzuela A (2001) Effects of olanzapine and other antipsychotics on cognitive function in chronic schizophrenia: A longitudinal study. Schizophr Res 48:17–28. https://doi.org/10.1016/S0920-9964(00)00112-2
da Silva Araújo T, Maia Chaves Filho AJ, Monte AS et al (2017) Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs. J Psychiatr Res 84. https://doi.org/10.1016/j.jpsychires.2016.09.017
Dall’Igna OP, Fett P, Gomes MW et al (2007) Caffeine and adenosine A2a receptor antagonists prevent β-amyloid (25–35)-induced cognitive deficits in mice. Exp Neurol 203:241–245. https://doi.org/10.1016/j.expneurol.2006.08.008
De Araújo FYR, De Oliveira GV, Gomes PXL et al (2011) Inhibition of ketamine-induced hyperlocomotion in mice by the essential oil of Alpinia zerumbet: Possible involvement of an antioxidant effect. J Pharm Pharmacol 63:1103–1110. https://doi.org/10.1111/j.2042-7158.2011.01312.x
de Araújo FYR, Silva MIG, Moura BABA et al (2009) Central nervous system effects of the essential oil of the leaves of Alpinia zerumbet in mice. J Pharm Pharmacol 61:1521–1527. https://doi.org/10.1211/jpp/61.11.0012
De Araújo Pinho FVS, Coelho-De-Souza AN, Morais SM et al (2005) Antinociceptive effects of the essential oil of Alpinia zerumbet on mice. Phytomedicine 12:482–486. https://doi.org/10.1016/j.phymed.2004.04.006
de Sousa DP, Nóbrega FFF, de Morais LCSL, de Almeida RN (2015) Evaluation of the anticonvulsant activity of terpinen-4-ol. Z Naturforsch C 64:1–5. https://doi.org/10.1515/znc-2009-1-201
Dey A, Das S, Mukherjee A (2016) Possible natural therapeutics against schizophrenia and its acute and treatment resistant forms: a review. J Biol Act Prod Nat 6:1–24. https://doi.org/10.1080/22311866.2016.1175318
Edris AE (2007) Pharmaceutical and therapeutic potentials of essential oils and their individual volatile constituents: A review. Phyther Res 21:308–323
Elmslie JL, Porter RJ, Joyce PR et al (2009) Comparison of insulin resistance, metabolic syndrome and adiponectin in overweight bipolar patients taking sodium valproate and controls. Aust New Zeal J Psychiatry 43:53–60. https://doi.org/10.1080/00048670802534341
Erta M, Quintana A, Hidalgo J (2012) Interleukin-6, a major cytokine in the central nervous system. Int J Biol Sci 8:1254–1266. https://doi.org/10.7150/ijbs.4679
Favalli G, Li J, Belmonte-de-Abreu P et al (2012) The role of BDNF in the pathophysiology and treatment of schizophrenia. J Psychiatr Res 46:1–11. https://doi.org/10.1016/j.jpsychires.2011.09.022
Fernandes BSSS, Gama CS, Maria Cereser K et al (2011) Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res 45:995–1004. https://doi.org/10.1016/j.jpsychires.2011.03.002
Fraga DB, Réus GZ, Abelaira HM et al (2013) Ketamine alters behavior and decreases BDNF levels in the rat brain as a function of time after drug administration. Rev Bras Psiquiatr 35:262–266. https://doi.org/10.1590/1516-4446-2012-0858
Frohlich J, Van Horn JD (2014) Reviewing the ketamine model for schizophrenia. J Psychopharmacol 28:287–302. https://doi.org/10.1177/0269881113512909
Gaebel W, Stricker J, Riesbeck M (2019) The long-term antipsychotic treatment of schizophrenia: a selective review of clinical guidelines and clinical case examples. Schizophr Res. https://doi.org/10.1016/j.schres.2019.10.049
Gama CS, Canever L, Panizzutti B et al (2012) Effects of omega-3 dietary supplement in prevention of positive, negative and cognitive symptoms: a study in adolescent rats with ketamine-induced model of schizophrenia. Schizophr Res 141:162–167. https://doi.org/10.1016/j.schres.2012.08.002
Gobira PH, Ropke J, Aguiar DC et al (2013) Animal models for predicting the efficacy and side effects of antipsychotic drugs. Rev Bras Psiquiatr 35:S132–S139. https://doi.org/10.1590/1516-4446-2013-1164
Grace AA, Floresco SB, Goto Y, Lodge DJ (2007) Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci 30:220–227. https://doi.org/10.1016/j.tins.2007.03.003
Green LC, Goldman P, Tannenbaum SR, Goldman P (1981) Nitrate synthesis in the germfree and conventional rat. Science 212:56–58. https://doi.org/10.1126/science.6451927
Harrison P (2004) The hippocampus in schizophrenia: a review of the neuropathological evidence and its pathophysiological implications. Psychopharmacology 174:151–162. https://doi.org/10.1007/s00213-003-1761-y
Howes O, McCutcheon R, Stone J (2015) Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol 29:97–115. https://doi.org/10.1177/0269881114563634
Hwang ES, Kim HB, Lee S et al (2020) Antidepressant-like effects of β-caryophyllene on restraint plus stress-induced depression. Behav Brain Res 380:. https://doi.org/10.1016/j.bbr.2019.112439
Irifune M, Shimizu T, Nomoto M (1991) Ketamine-induced hyperlocomotion associated with alteration of presynaptic components of dopamine neurons in the nucleus accumbens of mice. Pharmacol Biochem Behav 40:399–407. https://doi.org/10.1016/0091-3057(91)90571-I
Javitt DC, Zukin SR, Heresco-Levy U, Umbricht D (2012) Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia. Schizophr Bull 38:958–966. https://doi.org/10.1093/schbul/sbs069
Kapur S, Mizrahi R, Li M (2005) From dopamine to salience to psychosis-linking biology, pharmacology and phenomenology of psychosis. In: Schizophrenia Research. pp59–68
Kapur S, Zipursky R, Jones C et al (2000) Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry. https://doi.org/10.1176/appi.ajp.157.4.514
Kekesi G, Petrovszki Z, Benedek G, Horvath G (2015) Sex-specific alterations in behavioral and cognitive functions in a “three hit” animal model of schizophrenia. Behav Brain Res 284:85–93. https://doi.org/10.1016/j.bbr.2015.02.015
Kennedy DO, Wightman EL (2011) Herbal extracts and phytochemicals: plant secondary metabolites and the enhancement of human brain function. Adv Nutr 2:32–50. https://doi.org/10.3945/an.110.000117
Kinkead B, Selz KA, Owens MJ, Mandell AJ (2006) Algorithmically designed peptides ameliorate behavioral defects in animal model of ADHD by an allosteric mechanism. J Neurosci Methods 151:68–81. https://doi.org/10.1016/j.jneumeth.2005.07.015
Lahlou S, Galindo CAB, Leal-Cardoso JH et al (2002) Cardiovascular effects of the essential oil of Alpinia zerumbet leaves and its main constituent, terpinen-4-ol, in rats: role of the autonomic nervous system. Planta Med 68:1097–1102. https://doi.org/10.1055/s-2002-36336
Li P, Snyder GL, Vanover KE (2016) Dopamine targeting drugs for the treatment of schizophrenia: past, present and future. Curr Top Med Chem 16:3385–3403. https://doi.org/10.2174/1568026616666160608084834
Liapi C, Anifantis G, Chinou I et al (2007) Antinociceptive properties of 1,8-cineole and β- pinene, from the essential oil of Eucalyptus camaldu lensis leaves, in rodents. Planta Med 73:1247–1254. https://doi.org/10.1055/s-2007-990224
Lieberman JA, Girgis RR, Brucato G et al (2018) Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention. Mol Psychiatry 23:1764–1772. https://doi.org/10.1038/mp.2017.249
Maurice T, Lockhart BP, Privat A (1996) Amnesia induced in mice by centrally administered beta-amyloid peptides involves cholinergic dysfunction. Brain Res 706:181–193
Meltzer HY, Park S, Kessler R (1999) Cognition, schizophrenia, and the atypical antipsychotic drugs. Proc Natl Acad Sci USA 96:13591–13593
Monte AS, de Souza GC, McIntyre R et al (2013) Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: possible involvement of antioxidant and nitrergic pathways. J Psychopharmacol 27:1032–1043. https://doi.org/10.1177/0269881113503506
Muller N, Schwarz M (2006) Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 10:131–148
NIH (1996) Guide for the care and use of laboratory animals- institute of laboratory animal research- national research council. Natl Acad Press, Washington, D.C.
Nóbrega FFF, Salvadori MGSS, Masson CJ et al (2014) Monoterpenoid terpinen-4-ol exhibits anticonvulsant activity in behavioural and electrophysiological studies. Oxid Med Cell Longev 2014. https://doi.org/10.1155/2014/703848
Osimo EF, Beck K, Reis Marques T, Howes OD (2019) Synaptic loss in schizophrenia: a meta-analysis and systematic review of synaptic protein and mRNA measures. Mol Psychiatry 24:549–561. https://doi.org/10.1038/s41380-018-0041-5
Radenovic L, Selakovic V (2005) Differential effects of NMDA and AMPA/kainate receptor antagonists on nitric oxide production in rat brain following intrahippocampal injection. Brain Res Bull 67:133–141. https://doi.org/10.1016/j.brainresbull.2005.06.019
Radyushkin K, Hammerschmidt K, Boretius S et al (2009) Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav 8:416–425. https://doi.org/10.1111/j.1601-183X.2009.00487.x
Rahmatullah M, Rahman MA, Hossan MS et al (2010) A pharmacological and phytochemical evaluation of medicinal plants used by the Harbang clan of the Tripura tribal community of Mirsharai area, Chittagong district, Bangladesh. J Altern Complement Med 16:769–785. https://doi.org/10.1089/acm.2009.0497
Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661. https://doi.org/10.1096/fj.07-9574LSF
Sadowska-Bartosz I, Galiniak S, Bartosz G et al (2016) Antioxidant properties of atypical antipsychotic drugs used in the treatment of schizophrenia. Schizophr Res 176:245–251. https://doi.org/10.1016/j.schres.2016.07.010
Satou T, Kasuya H, Takahashi M et al (2011) Relationship between duration of exposure and anxiolytic-like effects of essential oil from Alpinia zerumbet. Flavour Fragr J. https://doi.org/10.1002/ffj.2047
Satou T, Murakami S, Matsuura M et al (2010) Anxiolytic effect and tissue distribution of inhaled Alpinia zerumbet essential oil in mice. Nat Prod Commun. https://doi.org/10.1177/1934578x1000500133
Schwieler L, Larsson MK, Skogh E et al (2015) Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia–significance for activation of the kynurenine pathway. J Psychiatry Neurosci 40:126–133
Sedlak J, Lindsay RH (1968) Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 25:192–205. https://doi.org/10.1016/0003-2697(68)90092-4
Smith SEP, Li J, Garbett K et al (2007) Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci 27:10695–10702. https://doi.org/10.1523/JNEUROSCI.2178-07.2007
Sparkman OD (2005) Identification of essential oil components by gas chromatography/quadrupole mass spectroscopy Robert P. Adams. J Am Soc Mass Spectrom 16:1902–1903. https://doi.org/10.1016/j.jasms.2005.07.008
Tan S, Lam WP, Wai MSM et al (2012) Chronic ketamine administration modulates midbrain dopamine system in mice. PLoS One 7:e43947. https://doi.org/10.1371/journal.pone.0043947
Tu PTB, Tawata S (2015) Anti-oxidant, anti-aging, and anti-melanogenic properties of the essential oils from two varieties of Alpinia zerumbet. Molecules 20:16723–16740. https://doi.org/10.3390/molecules200916723
Turetsky BI, Calkins ME, Light GA et al (2007) Neurophysiological endophenotypes of schizophrenia: the viability of selected candidate measures. Schizophr Bull 33:69–94. https://doi.org/10.1093/schbul/sbl060
Vasconcelos GSGS, Ximenes NCNC, de Sousa CNSCNS et al (2015) 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 165:163–170. https://doi.org/10.1016/j.schres.2015.04.017
Wadenberg M-LG, Kapur S, Soliman A et al (2000) Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats. Psychopharmacology 150:422–429. https://doi.org/10.1007/s002130000466
Ximenes NC, Dos Santos Júnior MA, Vasconcelos GS et al (2019) Ethanolic extract of Erythrina velutina Willd ameliorate schizophrenia-like behavior induced by ketamine in mice. J Complement Integr Med 16. https://doi.org/10.1515/jcim-2018-0038
Yamada K, Noda Y, Hasegawa T et al (1996) The role of nitric oxide in dizocilpine-induced impairment of spontaneous alternation behavior in mice. J Pharmacol Exp Ther 276:460–466
Zagrebelsky M, Korte M (2014) Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. Neuropharmacology 76:628–638. https://doi.org/10.1016/j.neuropharm.2013.05.029
Acknowledgements
We thank the Brazilian Institutions, CNPq, CAPES, and FUNCAP for the financial support of this study.
Funding
Brazilian Institutions, CNPq, CAPES, and FUNCAP partially funded this study.
Author information
Authors and Affiliations
Contributions
FYRA, DFL, MOM, MEM – Designed the study
AJMCF, AMN, GVO, PXLG – treated the animals and performed behavioral tests
GSV, AJMCF, JC – Performed neurochemical determinations
DFL, DSM, FCFS – Performed statistical analysis of the data
DFL, DSM – constructed the graphics
FYRA, DSM, JC, AJMCF – Wrote the first draft of the manuscript
All authors approved the final version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
ESM 1
(PDF 286 KB)
Rights and permissions
About this article
Cite this article
de Araújo, F.Y.R., Chaves Filho, A.J.M., Nunes, A.M. et al. Involvement of anti-inflammatory, antioxidant, and BDNF up-regulating properties in the antipsychotic-like effect of the essential oil of Alpinia zerumbet in mice: a comparative study with olanzapine. Metab Brain Dis 36, 2283–2297 (2021). https://doi.org/10.1007/s11011-021-00821-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-021-00821-5