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Lipopolysaccharide Exacerbates Ketamine-Induced Psychotic-Like Behavior, Oxidative Stress, and Neuroinflammation in Mice: Ameliorative Effect of Diosmin

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Abstract

Schizophrenia, a neuropsychiatric disorder has been associated with aberrant neurotransmission affecting behaviors, social preference, and cognition. Limitations in understanding its pathogenesis via the dopamine hypothesis have engendered other hypotheses such as the glutamate hypothesis. That antagonism of the N-methyl-D-aspartate receptor (NMDAR) elicits schizophrenia-like behaviors indistinguishable from the disorder in animal and human models. There are growing concerns that redox imbalance and neuro-immuno dysfunction may play role in aggravating the symptomologies of this disorder. This 14-day treatment study was designed to investigate the effect of diosmin on lipopolysaccharide (LPS) plus ketamine (NMDAR antagonist). Mice were divided into 4 groups (n = 6). Group 1 was administered 5% DMSO (10 mL/kg, i.p) while group 2–4 received LPS (0.1 mg/kg, i.p) daily for 14 days. Diosmin (50 mg/kg, i.p) and risperidone (0.5 mg/kg, i.p) were given to groups 3 and 4 respectively. Groups 2–4 were given KET (20 mg/kg, i.p.) daily from days 8–14. Behavioral tests were done 30 min after the last dose, and oxidative stress and neuroinflammatory maker were assayed. LPS plus ketamine-induced hyperlocomotion, stereotypy, decreased social preference, and memory impairment. Furthermore, LPS plus-ketamine-induced oxidative stress (reduced GSH, CAT, SOD, and increased MDA and nitrite levels) and marked pro-inflammatory cytokines TNF-α and IL-6 suggesting neuroinflammation. However, diosmin attenuated behavioral deficits and improved memory. Additionally, diosmin potentiated antioxidant level via increased GSH, CAT, and SOD while reducing MDA and nitrite levels. Finally, diosmin reduced TNF-α and IL-6 suggesting anti-neuro-immuno activity. Conclusively, diosmin attenuated LPS plus ketamine-induced behavioral deficits, oxidative stress, neuroinflammation, and improved memory.

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Abbreviations

CAT:

Catalase

KET:

Ketamine

TNF-α:

Tumor necrosis factor-alpha

DSM:

Diosmin

LPS:

Lipopolysaccharide

GSH:

Glutathione

MDA:

Malondialdehyde

IL-6:

Interleukin-6

MPO:

Myeloperoxidase

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Delta State University, Abraka, Delta State, Nigeria

    Aya-Ebi Okubo Eneni

  2. Department of Pharmacology, Faculty of Basic Medical Sciences, Delta State University, Abraka, Delta State, Nigeria

    Benneth Ben-Azu

  3. Department of Pharmacology and Therapeutics, Faculty of Basic Medical Science, College of Medicine, Neuropharmacology Unit, University of Ibadan, Ibadan, Oyo state, Nigeria

    Aya-Ebi Okubo Eneni, Benneth Ben-Azu, Abayomi Mayowa Ajayi & Adegbuyi Oladele Aderibibge

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  1. Aya-Ebi Okubo Eneni
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  4. Adegbuyi Oladele Aderibibge
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Contributions

The study was conceptualized and designed by Aya-Ebi Okubo Eneni, Ben-Azu Benneth, and Aderibigbe Oladele Adegbuyi. Aya-Ebi Okubo and Ben-Azu Benneth performed the study under the supervision of Aderibigbe Oladele Adegbuyi. Abayomi Mayowa Ajayi assisted with the biochemical analysis in the laboratory. All authors were involved in material preparation, data collection, and analysis. The first draft of the manuscript was written by Aya-Ebi, and all other authors revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Aya-Ebi Okubo Eneni.

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All experiments were approved and performed under the guidelines of the University of Ibadan’s Animals Ethical Committee (ethical number: UI-ACUREC/2017/0111) and in strict compliance with the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication number: 85–23, Revised 1985).

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Eneni, AE.O., Ben-Azu, B., Ajayi, A.M. et al. Lipopolysaccharide Exacerbates Ketamine-Induced Psychotic-Like Behavior, Oxidative Stress, and Neuroinflammation in Mice: Ameliorative Effect of Diosmin. J Mol Neurosci 73, 129–142 (2023). https://doi.org/10.1007/s12031-022-02077-9

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