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Naringin Confers Protection against Psychosocial Defeat Stress-Induced Neurobehavioral Deficits in Mice: Involvement of Glutamic Acid Decarboxylase Isoform-67, Oxido-Nitrergic Stress, and Neuroinflammatory Mechanisms

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Abstract

Psychosocial stress has been widely reported to contribute to psychiatric disturbances. Perturbations in the enzymes of GABAergic and cholinergic systems have been implicated as precursors in different stress-related neuropsychiatric diseases. Targeting glutamic acid decarboxylase-67 kDa (GAD67) and acetylcholinesterase (AChE) via oxidative, nitrergic, and neuroinflammatory mechanisms have been recognized as prospective strategies for the prevention of psychosocial stress-induced behavioral impairments. Naringin, a neuro-active flavonoid compound isolated from citrus fruits, has been shown to produce memory-enhancing, antiepileptic, antidepressant, and anti-inflammatory activities similarly to ginseng, a very potent adaptogen. In this communication, we assessed the effect of naringin on social-defeat stress (SDS)-induced behavioral, GABAergic, cholinergic, oxidative, nitrergic, and neuroinflammatory changes in mice using the resident–intruder paradigm. The intruder male mice were culled into six groups. Groups 1 and 2 (normal- and SDS-controls) received sterile saline, groups 3–5 were given naringin (25-100 mg/kg, i.p.) whereas group 6 had ginseng (50 mg/kg, i.p.) daily for 14 days, but followed by 10 min SDS (physical and psychological) exposure to groups 2–6 with aggressor–resident mice. Behavioral effects using Y-maze, elevated-plus maze, sociability, and tail-suspension tests were assessed on day 14. GAD67, AChE enzymes, and biomarkers of oxidative, nitrergic, and neuroinflammatory changes were assayed in the striatum, prefrontal cortex, and hippocampus. Naringin and ginseng reversed all SDS-induced behavioral impairments. Naringin increased the levels of GAD67 and decreased AChE activities in the striatum, prefrontal cortex, and hippocampus. Furthermore, naringin reduced pro-inflammatory cytokines (TNF-α, IL-6), malondialdehyde, nitrite concentrations, and increased glutathione levels in a region-dependent manner. Our study suggests that naringin attenuated SDS-induced behavioral endophenotypes of neuropsychiatric disease through increased GAD67 synthesis, inhibition of AChE activity, oxidative, nitrergic stress, and neuroinflammatory processes in stress-sensitive brain regions.

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Acknowledgements

The Authors are grateful to the technical staff of the Department of Pharmacology and Therapeutics, Faculty of Basic Medical Sciences, University of Ibadan for their technical assistance during the study.

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Authors and Affiliations

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

    Olawumi M. Oladapo, Benneth Ben-Azu, Abayomi Mayowa Ajayi, Aya-Ebi Okubo Eneni & Itivere Adrian Omogbiya

  2. Department of Pharmacology, Faculty of Basic Medical Sciences, PAMO University of Medical Sciences, Port Harcourt, River States, Nigeria

    Benneth Ben-Azu & Osagie Emokpae

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

    Itivere Adrian Omogbiya

  4. Inflammatory and immunopharmacology Unit, Department of Pharmacology and Therapeutics, College of Medicine, University of Ibadan, Ibadan, Oyo State, Nigeria

    Ezekiel O. Iwalewa

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  1. Olawumi M. Oladapo
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Correspondence to Benneth Ben-Azu.

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All experiments were approved and performed under the guidelines of the University of Ibadan’s Animals Ethic Committee (ACUREC/App/06/2018/18) and the National Institutes of Health Guide for Care and Use of Laboratory Animals (Publication number: 85-23, revised 1985).

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Oladapo, O.M., Ben-Azu, B., Ajayi, A.M. et al. Naringin Confers Protection against Psychosocial Defeat Stress-Induced Neurobehavioral Deficits in Mice: Involvement of Glutamic Acid Decarboxylase Isoform-67, Oxido-Nitrergic Stress, and Neuroinflammatory Mechanisms. J Mol Neurosci 71, 431–445 (2021). https://doi.org/10.1007/s12031-020-01664-y

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