Drug Res (Stuttg) 2018; 68(03): 159-167
DOI: 10.1055/s-0043-119127
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Morin Pretreatment Attenuates Schizophrenia-Like Behaviors in Experimental Animal Models

Benneth Ben-Azu
1   Neuropharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
,
Adegbuyi Oladele Aderibigbe
1   Neuropharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
,
Itivere Adrian Omogbiya
1   Neuropharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
2   Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, Delta State University, Abraka, Nigeria
,
Abayomi Mayowa Ajayi
1   Neuropharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
,
Ezekiel O. Iwalewa
1   Neuropharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria
› Author Affiliations
Further Information

Publication History

received 01 May 2017

accepted 31 August 2017

Publication Date:
29 September 2017 (online)

Abstract

Objectives Morin is a naturally occurring flavonoid with strong anti-oxidant and anti-inflammatory properties. Studies have shown that flavones modulate neurotransmission through enhancement of gamma amino butyric acid activity in the central nervous system; which led to the hypothesis that they could exert tranquilizing effects in rodents. Hence, this study was designed to evaluate the antipsychotic effect of morin on experimental animal models.

Methods The antipsychotic effect of morin (25, 50 and 100 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced locomotion, apomorphine-induced stereotypy, ketamine-induced stereotypy, ketamine-induced hyperlocomotion and ketamine-enhanced immobility in forced swim test (FST). Catalepsy and rota rod tests were also carried out to evaluate the extrapyramidal side effects of morin.

Results Morin (25, 50 and 100 mg/kg, i.p.) pretreatments significantly (p<0.05) demonstrated anti-schizophrenia-like behavior by inhibiting ketamine-induced hyperlocomotion in mice. Moreover, morin (50 and 100 mg/kg, i.p.) significantly (p<0.05) reduced spontaneous locomotor activity. Also, morin suppressed apomorphine-induced stereotypy and ketamine-induced stereotypy. The increase in immobility in FST due to ketamine administration was reduced by morin in a significant dose-dependent manner. Furthermore, the antipsychotic activity of morin was not associated with extrapyramidal side effects, as evidenced by decreased decent latency and increased motoric coordination and performance in mice.

Conclusion The results of the study revealed that morin demonstrated antipsychotic-like property devoid of extrapyramidal side effects in experimental animal models and may be beneficial in the treatment of schizophrenia-like behaviors; particularly in patients with behavioral hyperactivity and negative symptoms.

 
  • References

  • 1 Havsteen BH. The biochemistry and medical significance of the flavonoids. Pharmacol Ther 2002; 96: 67-202
  • 2 Fang SH, Hou YC, Chang WC. “Morin sulfates/glucuronides exert anti inflammatory activity on activated macrophages and decreased the incidence of septic shock”. Life Sci 2003; 74: 743-756
  • 3 Kapoor R, Kakkar P. Protective role of morin, a flavonoid, against high glucose induced oxidative stress mediated apoptosis in primary Rat hepatocytes. PLoS One 2012; 7: 416-463
  • 4 Nandhakumar R, Salini K, Niranjali Devaraj S. Morin augments anticarcinogenic and antiproliferative efficacy against 7,12-dimethylbenz(a)-anthracene induced experimental mammary carcinogenesis. Mol Cell Biochem 2012; 364: 79-92
  • 5 Sreedharan V, Venkatachalam KK, Namasivayam N. Effect of morin on tissue lipid peroxidation and antioxidant status in 1, 2- dimethylhydrazine induced experimental colon carcinogenesis. Invest New Drugs 2009; 27: 21 -30
  • 6 Merwid-Lad A, Trocha M, Chlebda E. et al. Effects of morin-5'-sulfonic acid sodium salt (NaMSA) on cyclophosphamide-induced changes in oxidoredox state in rat liver and kidney. Hum Exp Toxicol 2012; 31: 812-819
  • 7 Kawabata K, Tanaka T, Honjo S. et al. Chemopreventive effect of dietary flavonoid morin on chemically induced rat tongue carcinogenesis. Int J Cancer 1999; 83: 381-386
  • 8 Kuo HM, Chang LS, Lin YL. et al. Morin inhibits the growth of human leukemia HL-60 cells via cell cycle arrest and induction of apoptosis through mitochondria dependent pathway. Anticancer Res 2007; 27: 395-405
  • 9 Yu ZF, Fong WP, Cheng CHK. “The dual actions of morin (3, 5, 7, 2, 4-penta hydroxyl flavone) as a hypouricemic agent: Uricosuric effect and xanthine oxidase inhibitory activity”. J Pharmacol Exp Ther 2006; 316: 169-175
  • 10 Subash S, Subramanian P. Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: A biochemical and histopathological study. Mol Cell Biochem 2009; 327: 153-161
  • 11 Gottlieb M, Rocı’o L, Marı’a RC. et al. Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia. Neurobiol Dis 2006; 23: 374-386
  • 12 Marder M, Paladini AC. GABA-A receptor ligands of flavonoid structure. Curr Top Med Chem 2002; 2: 853-867
  • 13 Wang F, Shing M, Huen Y. et al. Neuroactive flavonoids interacting with GABAA receptor complex. Curr. Drug Targets CNS Neurol. Disord 2005; 4: 575-585
  • 14 Benes FM, Vincent SL, Alsterberg G. et al. Increased GABAA receptor binding in superficial layers of cingulate cortex in schizophrenics. J Neurosci 1992; 12: 924-929
  • 15 Lewis DA, Pierri JN, Volk DW. et al. Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol Psychiatry 1999; 46: 616-626
  • 16 Chatterjee M, Rajkumar V, Surajit G. et al. Neurochemical and molecular characterization of ketamine-induced experimental psychosis model in mice. Neuropharmacology 2012; 63: 1161-1171
  • 17 Davis KL, Kahn RS, Ko G. et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474-1486
  • 18 Krystal JH, Karper LP, Seibyl JP. et al. Subanaesthetic effects of the non competitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 1994; 51: 199-214
  • 19 Stahl SM. Beyond the dopamine hypothesis to the NMDA glutamate receptor hypofunction hypothesis of schizophrenia. CNS Spectr 2007; 12: 265-268
  • 20 Chatterjee M, Seema S, Reena K. et al. Evaluation of the antipsychotic potential of Panax quinquefolium in ketamine induced experimental psychosis model in mice. Neurochem Res 2012; 37: 759-770
  • 21 Coyle JT. Glutamate and schizophrenia: beyond the dopamine hypothesis. Cell Mol Neurobiol 2006; 26: 365-384
  • 22 Lewis DA, Pierri JN, Volk DW. et al. Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biol Psychiatry 1999; 46: 616-626
  • 23 Pogarell O, Koch W, Karch S. et al. Dopaminergic neurotransmission in patients with schizophrenia in relation to positive and negative symptoms. Pharmacopsychiatry 2012; 45: 36-41
  • 24 Krebs MO, Gauchy C, Desban M. et al. Role of dynorphin and GABA in the inhibitory regulation of NMDA-induced dopamine release in striosome- and matrix-enriched areas of the rat striatum. J Neurosci 1994; 14: 2435-2443
  • 25 Kapur S, Seeman P. NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2) receptors—implications for models of schizophrenia. Mol Psychiatry 2002; 7: 837-844
  • 26 Chindo BA, Bulus A, Tijani AY. et al. Ketamine-enhanced immobility in forced swim test: A possible animal model for the negative symptoms of schizophrenia. Prog Neuropsychopharm Biol Psychiatry 2012; 38: 310-316
  • 27 Mangaiarkkarasi A, Viswanathan S, Ramaswamy S. et al. Anxiolytic effect of morin in mice. Int J life sci Pharma Res 2012; 3: 52-60
  • 28 Brown RE, Corey SC, Moore AK. Differences in measures of exploration and fear in MHC-congenic C578L/61 and B6-H-2K mice. Behav Genet 1999; 26: 263-271
  • 29 Taïwe GS, Elisabeth NB, Emmanuel T. et al. Antipsychotic and sedative effects of the leaf extract of crassocephalumbauchiense(Hutch.) Milne-Redh (Asteraceae) in Rodents. J Ethnopharmacol 2012; 143: 213-220
  • 30 Annafi OS, Aluko OM, Eduviere AT. et al. Probable mechanisms involved in the antipsychotic-like activity of methyl jasmonate in mice. Naunyn-Schmiedeberg's Arch Pharmacol 2017; DOI: 10.1007/s00210-017-1386-z.
  • 31 Ben-Azu B, Aderibigbe AO, Adeoluwa OA. et al. Ethanol extracts of terminalia ivorensis (Chev A.) Stem bark attenuates the positive, negative and cognitive symptoms of psychosis in experimental animal models. Br J Pharm Res 2016; 12: 1-14
  • 32 Costall B, Domeney AM, Naylor RJ. Behavioural and biochemical consequences of persistent overstimulation of mesolimbic dopamine systems in the rat. Neuropharmacology 1982; 21: 327-335
  • 33 Arruda MV, Soares PM, Honório JER. et al. Activities of the antipsychotic drugs haloperidol and risperidone on behavioural effects induced by ketamine in mice. Sci Pharm 2008; 76: 673-687
  • 34 Akanmu MA, Adeosu SO, Ilesanmi OR. Neuropharmacological effects of oleaminde in male and female mice. Behav Brain Res 2007; 182: 88-94
  • 35 Meltzer H. Antipsychotic agents & Lithium. In: Basic & Clinical Pharmacology. 12th Katzung BG, Masters SB, Trevor AJ. McGraw-Hill Companies; New York: 2010. pp 501-513
  • 36 Gupta G, Imran K, Muhammad A. et al. Sedative, antiepileptic and antipsychotic effects of Viscum album L. (Loranthaceae) in mice and rats. J Ethnopharmacol 2012; 141: 810-816
  • 37 Geyer MA, Bita M. Animal models relevant to schizophrenia disorders. Neuropsychopharmacology: The Fifth Generation of Progress 2002; 50: 690-701
  • 38 Monte AS, de Souza GC, Roger S. et al. Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathway. J Psychopharmacol 2013; 27: 1032-1043
  • 39 Irifune M, Shimizu T, Nomoto M. Ketamine-induced hyperlocomotion associated with alteration of presynaptic component of dopamine neurons in the nucleus accumbens of mice. Pharmacol Biochem Behav 1991; 40: 399-407
  • 40 Green MF, Kern RS, Braff DL. et al. Neurocognitive deficits and functional outcome in schizophrenia: are we measuring the "right stuff"?. Schizophr Bull 2000; 26: 119-136
  • 41 Yee BK, Singer P. A conceptual and practical guide to the behavioural evaluation of animal models of the symptomatology and therapy of schizophrenia. Cell Tissue Res 2013; 354: 221-246
  • 42 Laruelle M, Abi-Dargham A, van Dyck C. et al. Dopamine and serotonin transporters in patients with schizophrenia: an imaging study with [(123)I]beta-CIT. Biol Psychiatry 2000; 47: 371 -379
  • 43 Becker A, Grecksch G. Ketamine-induced changes in rat behaviour: A possible animal model of schizophrenia. Test of predictive validity. Prog Neuropsychopharmacol Biol Psychiatry 2004; 28: 1267-177
  • 44 Hołuj M, Popik P, Nikiforuk A. Improvement of ketamine-induced social withdrawal in rats: the role of 5-HT7 receptors. Behav Pharmacol 2015; 26: 766-775
  • 45 Neill JC, Barnes S, Cook S. et al. Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism. Pharmacol Ther 2010; 128: 419-432
  • 46 Spielewoy C, Roubert C, Hamon M. et al. Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav Pharmacol 2000; 11: 279-290
  • 47 Onaolapo OJ, Ayanwale T, Agoi O. et al. Zinc tempers haloperidol- induced behavioural changes in healthy mice. International J Neurosci Behav Sci 2016; 4: 21-31
  • 48 Zhang XY, Zhou DF, Su JM. et al. The effect of extract of Ginkgo biloba added to haloperidol on superoxide dismutase in inpatients with chronic schizophrenia. J Clin Psychopharmacol 2001; 21: 85-88
  • 49 Selvakumar GP, Dhanraj V, Krishnamoorthy M. et al. Morin Attenuates Haloperidol Induced Tardive Dyskinesia and Oxidative Stress in Mice. J Nat Sci Res 2012; 2: 153-165
  • 50 Abd E, Mohsen MM, Kuhnle G. et al. Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic Biol Med 2002; 33: 1693-1702
  • 51 Youdim KA, Qaiser MZ, Begley DJ. et al. Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med 2004; 36: 592-604
  • 52 Cho YM, Onodera H, Ueda M. et al. A 13-week subchronic toxicity study of dietary administered morin in F344 rats. Food Chem Toxicol 2006; 44: 891-897
  • 53 Jonnalagadda VG, Srinivas P, Mangala L. et al. Ameliorative effect of morin hydrate, a flavonoid against gentamicin induced oxidative stress and nephrotoxicity in sprague-dawley rats. Int J Pharm Pharm Sci 2013; 6: 852-856