Tangxin Gao1,2, Bai Li1,2, Yangyang Hou1,2, Shaolei Luo1,2, Lei Feng3, Jun Nie1,2, Yi Ma1,2, Le Xiao3, Xu Chen3, Hongkun Bao1,2, Xianmin Lu4, Feilong Huang5, Gang Wang3, Chunjie Xiao1,2, Jing Du6,7,8. 1. State Key Laboratory for Conservation and Utilization of Bio-resources in Yunnan, Yunnan University, Kunming, 650091, Yunnan, China. 2. School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, Yunnan, China. 3. The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders & Beijing Anding Hospital, Capital Medical University, Beijing, 100088, China. 4. Beijing Gragen Biotechnology Co. Ltd, Beijing, 102206, China. 5. Beijing Los-Portland Academy of Medicine, Beijing, 100079, China. 6. State Key Laboratory for Conservation and Utilization of Bio-resources in Yunnan, Yunnan University, Kunming, 650091, Yunnan, China. dujing@ynu.edu.cn. 7. School of Medicine, Yunnan University, 2 Cuihu North Road, Kunming, 650091, Yunnan, China. dujing@ynu.edu.cn. 8. Beijing Gragen Biotechnology Co. Ltd, Beijing, 102206, China. dujing@ynu.edu.cn.
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.
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.
Authors: E P P Gomes; J C A Aguiar; T Fonseca-Silva; L C Dias; K P Moura-Boas; A Roy; N A Velloso; J F Rodrigues-Neto; A M B De-Paula; A L S Guimarães Journal: J Periodontal Res Date: 2012-08-14 Impact factor: 4.419
Authors: Rachael M Clarke; Anthony Lyons; Florence O'Connell; Brian F Deighan; Claire E Barry; Ngozi G Anyakoha; Anna Nicolaou; Marina A Lynch Journal: J Biol Chem Date: 2007-11-02 Impact factor: 5.157
Authors: Ekaterina Likhtik; Joseph M Stujenske; Mihir A Topiwala; Alexander Z Harris; Joshua A Gordon Journal: Nat Neurosci Date: 2013-11-17 Impact factor: 24.884