Skip to main content

Advertisement

SpringerLink
Log in

Molecular mechanisms involved in the prevention and reversal of ketamine-induced schizophrenia-like behavior by rutin: the role of glutamic acid decarboxylase isoform-67, cholinergic, Nox-2-oxidative stress pathways in mice

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Mounting evidences have shown that nicotinamide adenine dinucleotide phosphate oxidase-2 (Nox-2) pathway modifies glutamic-acid decarboxylase-67 (GAD67) (GABAergic enzyme) and cholinergic systems via oxidative-nitrergic mechanisms in schizophrenia pathology. Rutin, a neuroactive antioxidant compound, with proven neuroprotective property has been shown to reduce schizophrenic-like behavior in mice. This study sought to investigate the mechanisms of action of the psychopharmacological activity of rutin in the preventive and reversal effects of ketamine-induced schizophrenic-like behavior, oxidative-nitrergic stress, cholinergic and GABAergic derangements in mice. In the preventive treatment, male mice were given rutin (0.1, 0.2 and 0.4 mg/kg) or risperidone (0.5 mg/kg) orally for 14 days prior to ketamine (20 mg/kg, i.p.) treatment from the 8 to 14th day. However, in the reversal treatment, ketamine was given for 14 days prior to rutin and risperidone. Behavioral (open-field, social-interaction and Y-maze tests), biochemical (oxidative/nitrergic stress markers, acetylcholinesterase activity), immunohistochemical (GAD67, Nox-2) and neuronal cell deaths in the striatum, prefrontal cortex, and hippocampus were evaluated. Ketamine-induced behavioral impairments were prevented and reversed by rutin. Exposure of mice to ketamine increased malondialdehyde, nitrite contents, acetylcholinesterase activity, neuronal cell death and Nox-2 expressions in the striatum, prefrontal cortex and hippocampus. Conversely, these derangements were prevented and reversed by rutin. The decreased glutathione levels due to ketamine were marked increased by rutin. Rutin only prevented ketamine-induced decrease in GAD67 expression in the striatal-hippocampal region. Altogether, the study showed that the prevention and reversal treatments of mice with rutin attenuated ketamine-induced schizophrenic-like behaviors via reduction of Nox-2 expression, oxidative/nitrergic stresses, acetylcholinesterase activity, and increased GAD67 enzyme.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

GAD67:

Glutamic-acid decarboxylase-67

NADPH:

Nicotinamide adenine dinucleotide phosphate

NMDA:

N-methyl-d-Aspartate

KET:

Ketamine

RUT:

Rutin

SAB:

Spontaneous alternation behavior

YMT:

Y-maze test

SIT:

Social interaction test

DTNB:

5′,5′-Dithio-bis-(2-nitrobenzoic acid)

CA:

Cornu ammonis

NO:

Nitric oxide

GSH:

Glutathione

MDA:

Malondialdehyde

SOD:

Superoxide-dismutase

AChE:

Acetyl-cholinesterase

PFC:

Prefrontal cortex

ST:

Striatum

HC:

Hippocampus

References

  1. Orrico-Sánchez A, López-Lacort M, Muñoz-Quiles C, Sanfélix-Gimeno G, Díez-Domingo J (2020) Epidemiology of schizophrenia and its management over 8-years period using real-world data in Spain. BMC Psychiatry 20:149

    Article  PubMed  PubMed Central  Google Scholar 

  2. Charlson FJ, Ferrari AJ, Santomauro DF, Diminic S, Stockings E, Scott JG, McGrath JJ, Whiteford HA (2018) Global epidemiology and burden of schizophrenia: findings from the global burden of disease study 2016. Schizophr Bull 44:1195–1203

    Article  PubMed  PubMed Central  Google Scholar 

  3. Larson MK, Walker EF, Compton MT (2010) Early signs, diagnosis and therapeutics of the prodromal phase of schizophrenia and related psychotic disorders. Expert Rev Neurother 10:1347–1359

    Article  PubMed  PubMed Central  Google Scholar 

  4. Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD (1994) Subanaesthetic effects of the non-competitive NMDA antagonist, ketamine, in humans: psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry 51:199–214

    Article  CAS  PubMed  Google Scholar 

  5. Chatterjee M, Rajkumar V, Surajit G, Gautam P (2012) Neurochemical and molecular characterization of ketamine-induced experimental psychosis model in mice. Neuropharmacology 63:1161–1171

    Article  CAS  PubMed  Google Scholar 

  6. Ben-Azu B, Aderibigbe AO, Eneni AO, Ajayi AM, Umukoro S, Iwalewa EO (2018) Orin 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

    Article  CAS  PubMed  Google Scholar 

  7. Fujihara K, Hideki M, Toshikazu K, Ryosuke K, Masahiko M, Chiyoko T, Nobuaki T, Yuchio Y (2015) Glutamate decarboxylase 67 deficiency in a subset of GABAergic neurons induces schizophrenia-related phenotypes. Neuropsychopharmacology 40:2475–2486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schmidt MJ, Mirnics K (2015) Neurodevelopment, GABA system dysfunction, and schizophrenia. Neuropsychopharmacology 40:190–206

    Article  PubMed  Google Scholar 

  9. Riga D, Matos MR, Glas A, Smit AB, Spijker S, Van den Oever MC (2014) Optogenetic dissection of medial prefrontal cortex circuitry. Front Syst Neurosci 8:230

    Article  PubMed  PubMed Central  Google Scholar 

  10. Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni AO, Umukoro S, Iwalewa EO (2018) 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

    Article  CAS  PubMed  Google Scholar 

  11. Sorce S, Krause KH (2009) NOX enzymes in the central nervous system: from signaling to disease. Antioxid Redox Signal 11:2481–2504

    Article  CAS  PubMed  Google Scholar 

  12. Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni AO, Omogbiya IA, Owoeye O, Umukoro S, Iwalewa EO (2019) Morin decreases cortical pyramidal neuron degeneration via inhibition of neuroinflammation in mouse model of schizophrenia. Int Immunopharmacol 70:338–435

    Article  CAS  PubMed  Google Scholar 

  13. Behrens MM, Ali SS, Laura LD (2008) Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci 28:13957–13966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Włodarczyk A, Szarmach J, Cubała WJ, Wiglusz MS (2017) Benzodiazepines in combination with antipsychotic drugs for schizophrenia: GABA-ergic targeted therapy. Psychiatr Danub 29:345–348

    Article  PubMed  Google Scholar 

  15. Nunes EA, Leila C, de Oliveira L, de Luca RD, João Q, Zugno A, Peregrino A, Alexandre J (2012) Effects of pregabalin on behavioral alterations induced by ketamine in rats. Rev Bras Psiquiatr 34:329–333

    Article  PubMed  Google Scholar 

  16. Kreft S, Knapp M, Kreft I (1997) Extraction of rutin from buckwheat (Fagopyrum esculentum Moench) seeds and determination by capillary electrophoresis. J Agric Food Chem 47:4649–4652

    Article  CAS  Google Scholar 

  17. Javed H, Khan MM, Ahmad A, Vaibhav K, Ahmad ME, Khan A, Ashafaq M, Islam F, Siddiqui MS, Safhi MM, Islam F (2012) Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type. Neuroscience 17:340–352

    Article  CAS  Google Scholar 

  18. Ahmed OM, Moneim AA, Yazid IA (2010) Antihyperglycemic, antihyperlipidemic and antioxidant effects and the probable mechanisms of action of ruta graveolens infusion and rutin in Nicotinamide streptozotocin-induced diabetic rat. Diabetol Croat 39:15–35

    CAS  Google Scholar 

  19. Webster RP, Gawde MD, Bhattacharya RK (1996) Protective effect of rutin, a flavonol glycoside, on the carcinogen-induced DNA damage and repair enzymes in rats. Cancer Lett 109:185–191

    Article  CAS  PubMed  Google Scholar 

  20. Panasiak W, Wleklik M, Oraczewska A, Luczak M (1989) Influence of flavonoids on combined experimental infections with EMC virus and Staphylococcus aureus in mice. Acta Microbiol Pol 38:185–188

    CAS  PubMed  Google Scholar 

  21. Fernandez SP, Wasowski C, Loscalzo LM, Granger RE, Johnston GA, Paladini AC, Marder M (2006) Central nervous system depressant action of flavonoid glycosides. Eur J Pharmacol 539:168–176

    Article  CAS  PubMed  Google Scholar 

  22. Nieoczym D, Socała K, Raszewski G, Wlaz P (2014) Effect of quercetin and rutin in some acute seizure models in mice. Prog Neuropsychopharmacol Biol Psychiatry 54:50–58

    Article  CAS  PubMed  Google Scholar 

  23. Paladini AC, Marder M, Viola H, Wolfman C, Wasowski C, Medina JH (1999) Flavonoids and the central nervous system: from forgotten factors to potent anxiolytic compounds. J Pharm Pharmacol 51:519–526

    Article  CAS  PubMed  Google Scholar 

  24. Wang FM, Shing Y, Huen SY, Xue TH (2005) Neuroactive flavonoids interacting with GABAA receptor complex. Curr Drug Targets CNS Neurol Disord 4:575–585

    Article  CAS  PubMed  Google Scholar 

  25. Pandy V, Vijeepallam K (2017) Antipsychotic-like activity of scopoletin and rutin against the positive symptoms of schizophrenia in mouse models. Exp Anim 66:417–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bishnoi M, Chopra K, Kulkarni SK (2007) Protective effect of rutin, a polyphenolic flavonoid against haloperidol-induced orofacial dyskinesia and associated behavioural, biochemical and neurochemical changes. Fundam Clin Pharmacol 21:521–529

    Article  CAS  PubMed  Google Scholar 

  27. Monte AS, de Souza GC, Mclntyre RS, Joanna KS, dos Santos JV, Rafaela CC, Bruna MM, de Lucena RDF (2013) Prevention and reversal of ketamine-induced schizophrenia related behaviour by minocycline in mice: possible involvement of antioxidant and nitrergic pathway. J Psychopharmacol 27:1032–1043

    Article  PubMed  CAS  Google Scholar 

  28. Jollow DJ, Michell JR, Zampaglione H, Gillete J (1974) Bromobenzene-induced liver necrosis. Protective role of glutathione an evidence for 3,4 bromobenzene oxide as the hepatotoxic metabolite. Pharmacology 11:151–169

    Article  CAS  PubMed  Google Scholar 

  29. Ohkawa H, Ohishi N, Yagi E (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  CAS  PubMed  Google Scholar 

  30. Ellman GL, Courtney KD, Andres V, Feather-Stone RM Jr (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88–95

    Article  CAS  PubMed  Google Scholar 

  31. Ben-Azu B, Aderibigbe AO, Omogbiya IA, Ajayi AM, Owoeye O, Olonode T, Iwalewa EO (2018) Probable mechanisms involved in the antipsychotic-like activity of morin in mice. Biomed Pharmacother 105:1079–1090

    Article  CAS  PubMed  Google Scholar 

  32. 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

    Article  CAS  PubMed  Google Scholar 

  33. Neill JC, Barnes S, Cook S, Grayson B, Idris NF, McLean SL, Snigdha S, Rajagopal L, Harte MK (2010) Animal models of cognitive dysfunction and negative symptoms of schizophrenia: Focus on NMDA receptor antagonism. Pharmacol Ther 128:419–432

    Article  CAS  PubMed  Google Scholar 

  34. Johnston A, Chris J, McBain AF (2014) 5-Hydroxytryptamine1A receptor-activation hyperpolarizespyramidal cells and suppresses hippocampal gammaoscillations via Kir3 channel activation. J Physiol 592:4187–4199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schiavone S, Sorce S, Dubois-Dauphin M, Jaquet V, Colaianna M, Zotti M, Cuomo V, Trabace L et al (2009) Involvement of NOX2 in the development of behavioral and pathologic alterations in isolated rats. Biol Psychiatry 66:384–392

    Article  CAS  PubMed  Google Scholar 

  36. Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM (2006) A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J Neurosci 26:1604–1615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Alpak MG, Unal A, Ari M, Savas HA (2015) Increased oxidative stress and oxidative DNA damage in non-remission schizophrenia patients. Psychiatry Res 229(1–2):200–205

    PubMed  Google Scholar 

  38. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT (2011) Decreased levels of glutathione, the major brain antioxidant, in post-mortem prefrontal cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol 14:123–130

    Article  CAS  PubMed  Google Scholar 

  39. Shinkai T, Ohmori O, Hori H, Nakamura J (2002) Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia. Mol Psychiatry 7:560–563

    Article  CAS  PubMed  Google Scholar 

  40. Tian R, Yang W, Xue Q, Gao L, Huo J, Ren D, Chen X (2016) Rutin ameliorates diabetic neuropathy by lowering plasma glucose and decreasing oxidative stress via Nrf2 signaling pathway in rats. Eur J Pharmacol 771:84–92

    Article  CAS  PubMed  Google Scholar 

  41. Szwajgier D, Borowiec K, Zapp J (2020) Activity-guided isolation of cholinesterase inhibitors quercetin, rutin and kaempferol from Prunus persica fruit. Z Naturforsch 75:87–96

    Article  CAS  Google Scholar 

  42. Ademosun AO, Oboh G, Bello F, Ayeni PO (2016) Antioxidative properties and effect of quercetin and its glycosylated form (rutin) on acetylcholinesterase and butyrylcholinesterase activities. J Evid Based Complement Altern Med 21:11–17

    Article  CAS  Google Scholar 

  43. Omar SH, Scott CJ, Hamlin AS, Obied HK (2018) Biophenols: enzymes (β-secretase, cholinesterases, histone deacetylase and tyrosinase) inhibitors from olive (Olea europaea L.). Fitoterapia 128:118–129

    Article  CAS  PubMed  Google Scholar 

  44. Vijayakumar S, Manogar P, Prabhu S, Singh RA (2018) Novel ligandbased docking; molecular dynamic simulations; and absorption, distribution, metabolism, and excretion approach to analyzing potential acetylcholinesterase inhibitors for Alzheimer’s disease. J Pharm Anal 8:413–420

    Article  PubMed  Google Scholar 

  45. Yan X, Chen T, Zhang L, Du H (2018) Study of the interactions of forsythiaside and rutin with acetylcholinesterase (AChE). Int J Biol Macromol 119:1344–1352

    Article  CAS  PubMed  Google Scholar 

  46. Ou-yang Z, Cao X, Wei Y, Wei-Wan-Qi Z, Ming Z, Jin-ao D (2013) Pharmacokinetic study of rutin and quercetin in rats after oral administration of total flavones of mulberry leaf extract. Rev Bras Farmacogn 23:776–782

    Article  CAS  Google Scholar 

  47. Manach C, Morand C, Demigné C, Texier O, Régérat F, Rémésy C (1997) Bioavailability of rutin and quercetin in rats. FEBS Lett 409:12–16

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The Authors are grateful to Dr. Theophilus Jarikre of the Department of Veterinary Pathology, University of Ibadan for his technical assistance during the immunohistochemistry

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Therapeutics and Toxicology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Lagos State, Nigeria

    Tolulope Olabode Oshodi & Ismail O. Ishola

  2. Neuropharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria

    Benneth Ben-Azu, Abayomi Mayowa Ajayi, Osagie Emokpae & Solomon Umukoro

  3. Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

    Benneth Ben-Azu

Authors
  1. Tolulope Olabode Oshodi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benneth Ben-Azu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ismail O. Ishola
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Abayomi Mayowa Ajayi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Osagie Emokpae
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Solomon Umukoro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Benneth Ben-Azu or Ismail O. Ishola.

Ethics declarations

Conflict of interest

Authors declare that they have no conflict of interest.

Ethical approval

All experiments were approved and performed under the guidelines of University of Lagos’s Animals Ethic Committee (CMUL/HREC/01/19/481) and the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication number: 85–23, revised 1985).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oshodi, T.O., Ben-Azu, B., Ishola, I.O. et al. Molecular mechanisms involved in the prevention and reversal of ketamine-induced schizophrenia-like behavior by rutin: the role of glutamic acid decarboxylase isoform-67, cholinergic, Nox-2-oxidative stress pathways in mice. Mol Biol Rep 48, 2335–2350 (2021). https://doi.org/10.1007/s11033-021-06264-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06264-6

Keywords

Search

Navigation