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Reversal and Preventive Pleiotropic Mechanisms Involved in the Antipsychotic-Like Effect of Taurine, an Essential β-Amino Acid in Ketamine-Induced Experimental Schizophrenia in Mice

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Abstract

Schizophrenia is a life disabling, multisystem neuropsychiatric disease mostly derived from complex epigenetic-mediated neurobiological changes causing behavioural deficits. Neurochemical disorganizations, neurotrophic and neuroimmune alterations are some of the challenging neuropathologies proving unabated during psychopharmacology of schizophrenia, further bedeviled by drug-induced metabolic derangements including alteration of amino acids. In first-episode schizophrenia patients, taurine, an essential β-amino acid represses psychotic-symptoms. However, its anti-psychotic-like mechanisms remain incomplete. This study evaluated the ability of taurine to prevent or reverse ketamine-induced experimental psychosis and the underlying neurochemical, neurotrophic and neuroinmune mechanisms involved in taurine’s clinical action. The study consisted of three different experiments with Swiss mice (n = 7). In the drug alone, mice received saline (10 mL/kg/p.o./day), taurine (50 and 100 mg/kg/p.o./day) and risperidone (0.5 mg/kg/p.o./day) for 14 days. In the preventive study of separate cohort, mice were concomitantly given ketamine (20 mg/kg/i.p./day) from days 8 to 14. In the reversal study, mice received ketamine for 14 days before taurine or risperidone treatments from days 8 to 14 respectively. Afterwards, stereotypy behaviour, social, non-spatial memory deficits, and body weights were assessed. Neurochemical (dopamine, 5-hydroxytryptamine, glutamic acid decarboxylase, (GAD)), brain derived-neurotrophic factor (BDNF) and pro-inflammatory cytokines [tumor necrosis factor-alpha, (TNF-α), interleukin-6, (IL-6)] were assayed in the striatum, prefrontal-cortex and hippocampal area. Taurine attenuates ketamine-induced schizophrenia-like behaviour without changes in body weight. Taurine reduced ketamine-induced dopamine and 5-hydroxytryptamine changes, and increased GAD and BDNF levels in the striatum, prefrontal-cortex and hippocampus, suggesting increased GABAergic and neurotrophic transmissions. Taurine decreases ketamine-induced increased in TNF-α and IL-6 concentrations in the striatum, prefrontal-cortex and hippocampus. These findings also suggest that taurine protects against schizophrenia through neurochemical modulations, neurotrophic enhancement, and inhibition of neuropathologic cytokine activities.

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Data Availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Abbreviations

KET:

Ketamine

GAD:

Glutamic acid decarboxylase

BDNF:

Brain derived-neurotrophic factor

TNF- α:

Tumor necrosis factor alpha

IL-6:

Interleukin-6

DI:

Discrimination index

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Acknowledgements

The Authors are very grateful to the technical staff of the Department of Pharmacology, Faculty of Basic Medical Sciences, College of Health Sciences for their technical input during the course of the study. Also, the authors are thankful to the International Brain Research Organization (IBRO)-African Regional Committee (ARC) for the 2019 Bursary Fellowship award for this study.

Funding

Benneth Ben-Azu was supported by an International Brain Research Organization African Regional Committee (IBRO-ARC) 2019 Grant for a Postdoctoral Fellowship on Schizophrenia Research at the University of Victoria, BC Canada.

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Authors and Affiliations

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

    Benneth Ben-Azu, Bienose S. Chijioke, Marymagdalene G. Omonyeme, Chineye B. Ozege, Emmanuella C. Ofili, Ebidenara B. Warekoromor, Nwanneka L. Edigbue, Ufoma V. Esiekpe & Dabrechi E. Akaenyi

  2. Division of Medical Sciences, University of Victoria, Victoria, BC, Canada

    Benneth Ben-Azu

  3. Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, College of Medicine, Rivers State University, Port Harcourt, Rivers State, Nigeria

    Christian I. Uruaka

  4. Neuropharmacology Unit, Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria

    Abayomi M. Ajayi

  5. Department of Veterinary Pathology, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

    Thiophilus Aghogho Jarikre

  6. Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

    Kingsley E. Nwangwa

  7. Department of Pharmacology and Therapeutics, College of Health Sciences, Nnamdi Azikiwe University, Awka, Anambra State, Nigeria

    Kingsley C. Chilaka

  8. Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, Afe Babalo University, Ado-Ekiti, Ado-Ekiti, Nigeria

    Gladys O. Agu

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Contributions

BBA, GOA, CIU, KEN and DEA: conceived the study and designed the experimental protocol. BBA, MGO, CBO, ECO, EBW, NLE, UVE and DEA: carried out the experiment. BBA, KCC, MGO, GOA, and AMA: contributed new reagents and analytical tool. BBA, AMA, and KEN: supervised the study. BBA, AMA and BSC: analyzed the data. BBA, BSC and CUI: wrote the manuscript. All authors read and approved the manuscript. All data were generated in-house and no paper mill was used. All authors contributed to this research work and the development of the final manuscript.

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Correspondence to Benneth Ben-Azu.

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Authors declare that they have no conflict of interest.

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All applicable international, national, and/or institutional (Delta State University Animal Care and Use Research Ethics Committee) guidelines for the care and use of animals were followed according to the ethical approval number: REC/FBMS/DELSU/21/94.

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Ben-Azu, B., Uruaka, C.I., Ajayi, A.M. et al. Reversal and Preventive Pleiotropic Mechanisms Involved in the Antipsychotic-Like Effect of Taurine, an Essential β-Amino Acid in Ketamine-Induced Experimental Schizophrenia in Mice. Neurochem Res 48, 816–829 (2023). https://doi.org/10.1007/s11064-022-03808-5

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  • DOI: https://doi.org/10.1007/s11064-022-03808-5

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