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Naringin Ameliorates Haloperidol-Induced Neurotoxicity and Orofacial Dyskinesia in a Rat Model of Human Tardive Dyskinesia

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Abstract

Animal models of haloperidol (HAL)-induced neurotoxicity and orofacial dyskinesia (OD) have long been used to study human tardive dyskinesia (TD). Similar to patients with TD, these models show strong pathophysiological characteristics such as striatal oxidative stress and neural cytoarchitecture alteration. Naringin (NAR), a bioflavonoid commonly found in citrus fruits, has potent antioxidative, anti-inflammatory, antiapoptotic, and neuroprotective properties. The present study evaluated the potential protective effects of NAR against HAL-induced OD in rats and the neuroprotective mechanisms underlying these effects. HAL treatment (1 mg/kg i.p. for 21 successive days) induced OD development, characterized by increased vacuous chewing movement (VCM) and tongue protrusion (TP), which were recorded on the 7th, 14th, and 21st day of drug treatment. NAR (30, 100, and 300 mg/kg) was administered orally 60 min before HAL injection for 21 successive days. On the 21st day, after behavioral testing, the rats were sacrificed, and the nitrosative and oxidative status, antioxidation power, neurotransmitter levels, neuroinflammation, and apoptotic markers in the striatum were measured. HAL induced OD development, with significant increases in the frequency of VCM and TP. NAR treatment (100 and 300 mg/kg) prevented HAL-induced OD significantly. Additionally, NAR treatment reduced the HAL-induced nitric oxide and lipid peroxide production, increased the antioxidation power and neurotransmitter levels in the striatum, and significantly reduced the levels of neuroinflammatory and apoptotic markers. Our results first demonstrate the neuroprotective effects of NAR against HAL-induced OD, suggesting that NAR may help in delaying or treating human TD in clinical settings.

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Abbreviations

C:

Control group

H:

HAL treatment group

HAL:

Haloperidol

NAR:

Naringin

N30:

NAR 30 mg/kg + normal saline treatment group

N100:

NAR 100 mg/kg + normal saline treatment group

N300:

NAR 300 mg/kg + normal saline treatment group

N30 + H:

NAR 30 mg/kg + HAL 1 mg/kg treatment group

N100 + H:

NAR 100 mg/kg + HAL 1 mg/kg treatment group

N300 + H:

NAR 300 mg/kg + HAL 1 mg/kg treatment group

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Funding

This study was supported by the Yuan-Shan Branch of Taipei Veteran General Hospital (VGH-10802) and Mackay Memorial Hospital (MMH-107-90).

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Author notes

  1. Mao-Hsien Wang, Chih-Chuan Yang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesia, En Chu Kon Hospital, Sanshia District, 23702, New Taipei City, Taiwan, Republic of China

    Mao-Hsien Wang

  2. Department of Neurosurgery, Mackay Memorial Hospital, 10449, Taipei, Taiwan, Republic of China

    Chih-Chuan Yang

  3. Department of Medicine, Mackay Medical College, 252, New Taipei City, Taiwan, Republic of China

    Chih-Chuan Yang

  4. Department of Anesthesiology, Su Memorial Hospital, Shin Kong Wu Ho, 11101, Taipei, Taiwan, Republic of China

    Hsiang-Chien Tseng

  5. School of Medicine, Fu Jen Catholic University, 24205, New Taipei City, Taiwan, Republic of China

    Hsiang-Chien Tseng

  6. Institute of Biomedical Engineering, National Taiwan University, 10051, Taipei, Taiwan, Republic of China

    Chih-Hsiang Fang & Yi-Wen Lin

  7. Department of Psychiatry, Yuan-Shan Br. of Taipei Veteran General Hospital, 26604, Yilan County, Taiwan, Republic of China

    Hung-Sheng Soung

  8. Department of Biomedical Engineering, National Defense Medical Center, 11490, Taipei, Taiwan, Republic of China

    Hung-Sheng Soung

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  1. Mao-Hsien Wang
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Contributions

M.-H.W. collected the data, executed the performing animal study of the experiments, and initially drafted the manuscript. C.-C.Y. and H.-C.T. contributed to the active discussion of experimental design and assisted with study conceptualization. C.-H.F. and Y.-W.L. contributed to the active performing of the animal study. M.-H.W., C.-C.Y., and H.-S.S. supervised the study, assisted with study conceptualization, and made a substantial contribution to the revision of the manuscript. All authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to Hung-Sheng Soung.

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The authors declare that they have no conflict of interest.

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All animal experiments were carried out in compliance with the National Taiwan University, College of Medicine, Institutional Animal Care and Use Committee (IACUC). The experimental protocol received prior approval by the Institutional Animal Care and Use Committee (IACUC) (No. 20180274, date of approval: 20180274).

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Wang, MH., Yang, CC., Tseng, HC. et al. Naringin Ameliorates Haloperidol-Induced Neurotoxicity and Orofacial Dyskinesia in a Rat Model of Human Tardive Dyskinesia. Neurotox Res 39, 774–786 (2021). https://doi.org/10.1007/s12640-021-00333-1

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