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

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.