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Fingolimod ameliorates cognitive impairments in a phencyclidine-induced rat model of schizophrenia
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  • Tao Li,
  • Xueli Yu,
  • Xueyu Qi,
  • Long Wei,
  • Liansheng Zhao,
  • Wei Deng,
  • Wanjun Guo,
  • Qiang Wang,
  • Xiaohong Ma,
  • Xun Hu,
  • Peiyan Ni
Tao Li
Zhejiang University School of Medicine

Corresponding Author:[email protected]

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Xueli Yu
Zhejiang University School of Medicine
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Xueyu Qi
Zhejiang University School of Medicine
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Long Wei
Sichuan University West China Hospital
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Liansheng Zhao
Sichuan University West China Hospital
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Wei Deng
Zhejiang University School of Medicine
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Wanjun Guo
Sichuan University West China Hospital
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Qiang Wang
Sichuan University West China Hospital
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Xiaohong Ma
Sichuan University West China Hospital
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Xun Hu
Zhejiang University School of Medicine
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Peiyan Ni
Sichuan University West China Hospital
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Abstract

Background and Purpose: Improvement of cognitive deficits in schizophrenia remains an unmet need due to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia. Experimental Approach: Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated by immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis. Key Results: Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signalling pathway. Conclusion and Implications: To the best of our knowledge, this is the first preclinical study to assess the effects of fingolimod on cognitive function in schizophrenia models. Our results support the role of the immune system in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.
29 Jan 2022Submitted to British Journal of Pharmacology
29 Jan 2022Submission Checks Completed
29 Jan 2022Assigned to Editor
04 Feb 2022Reviewer(s) Assigned
24 Feb 2022Review(s) Completed, Editorial Evaluation Pending
25 Feb 2022Editorial Decision: Revise Minor
23 Jun 20221st Revision Received
24 Jun 2022Assigned to Editor
24 Jun 2022Submission Checks Completed
12 Jul 2022Reviewer(s) Assigned
15 Aug 2022Review(s) Completed, Editorial Evaluation Pending
19 Aug 2022Editorial Decision: Revise Minor
24 Aug 20222nd Revision Received
27 Aug 2022Submission Checks Completed
27 Aug 2022Assigned to Editor
05 Sep 2022Editorial Decision: Accept