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Interleukin-4 signalling pathway underlies the anxiolytic effect induced by 3-deoxyadenosine

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Abstract

Rationale

Converging evidence suggests that neuroimmunity plays an important role in the pathophysiology of anxiety. Interleukin (IL)-4 is a key cytokine regulating neuroimmune functions in the central nervous system. More efficient anxiolytics with neuro-immune mechanisms are urgently needed.

Objective

To determine whether 3′-deoxyadenosine (3′-dA) exerts an anxiolytic effect and to examine the role of IL-4 in the anxiolytic effect of 3′-dA in mice.

Methods

We investigated the effects of 3′-dA on anxiety-like behaviors using elevated plus maze (EPM) or light-dark box (LDB) tests after 45 min or 5 days of treatment. Expression of IL-4, IL-10, IL-1β, TNF-α, and IL-6 in the prefrontal cortex (PFC) was detected by Western blot and/or double immunostaining. Intracerebroventricular injection of RIL-4Rα (an IL-4-specific inhibitor) and intraperitoneal injection of 3′-dA or imipramine were co-administered, followed by EPM test.

Results

3′-dA exhibited a stronger and faster anxiolytic effect than imipramine in behavioral tests. Furthermore, 3′-dA enhanced IL-4 expression after 45 min or 5 days, TNF-α and IL-1β expression decreased significantly after a 5-day treatment with 3′-dA, and IL-10 expression increased after a 5-day treatment with 3′-dA or imipramine in the PFC. IL-4 was expressed in neurons and in some astrocytes and microglia. IL-4 expression showed a strong positive correlation with reduced anxiety behaviors. RIL-4Rα completely blocked the anxiolytic effects induced by 3′-dA and imipramine.

Conclusions

This study identifies a novel and common anxiolytic IL-4 signaling pathway and provides an innovative drug with a novel neuro-immune mechanism for treating anxiety disorder.

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 31560274, 31650005, and 81760651), Yunnan Province Funding (Grant No. KC1710123), and the Yunnan High-level Professional Funding (Grant No. 2012HA004) from the Department of Science and Technology of Yunnan Province.

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Author notes

  1. Tangxin Gao, Bai Li, and Yangyang Hou contributed equally to the paper as first authors.

Authors and Affiliations

  1. State Key Laboratory for Conservation and Utilization of Bio-resources in Yunnan, Yunnan University, Kunming, 650091, Yunnan, China

    Tangxin Gao, Bai Li, Yangyang Hou, Shaolei Luo, Jun Nie, Yi Ma, Hongkun Bao, Chunjie Xiao & Jing Du

  2. School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, Yunnan, China

    Tangxin Gao, Bai Li, Yangyang Hou, Shaolei Luo, Jun Nie, Yi Ma, Hongkun Bao, Chunjie Xiao & Jing Du

  3. The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China

    Lei Feng, Le Xiao, Xu Chen & Gang Wang

  4. Beijing Gragen Biotechnology Co. Ltd, Beijing, 102206, China

    Xianmin Lu & Jing Du

  5. Beijing Los-Portland Academy of Medicine, Beijing, 100079, China

    Feilong Huang

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  1. Tangxin Gao
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Correspondence to Jing Du.

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All experimental procedures were performed in accordance with the Medical Ethics Committee of the School of Medicine of Yunnan University and followed the Guide for the Care and Use of Laboratory Animals (ISBN 0-309-05377-3).

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This article belongs to a Special Issue on Neuroimmune Signaling in Psychiatric Disease

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Gao, T., Li, B., Hou, Y. et al. Interleukin-4 signalling pathway underlies the anxiolytic effect induced by 3-deoxyadenosine. Psychopharmacology 236, 2959–2973 (2019). https://doi.org/10.1007/s00213-019-5186-7

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