G721-0282 Exerts Anxiolytic-Like Effects on Chronic Unpredictable Mild Stress in Mice Through Inhibition of Chitinase-3-Like 1-Mediated Neuroinflammation.

Hyeon Joo Ham,Young Wan Ham,Yong Sun Lee,Jin Tae Hong,Sang Bae Han,Jaesuk Yun,Hee Pom Lee

doi:10.3389/fncel.2022.793835

Hyeon Joo Ham, Young Wan Ham + Show 5 more

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https://doi.org/10.3389/fncel.2022.793835

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Abstract

Chronic stress is thought to be a major contributor to the onset of mental disorders such as anxiety disorders. Several studies have demonstrated a correlation between anxiety state and neuroinflammation, but the detailed mechanism is unclear. Chitinase-3-like 1 (CHI3L1) is expressed in several chronic inflammatorily damaged tissues and is well known to play a major role in mediating inflammatory responses. In the present study, we investigated the anxiolytic-like effect of N-Allyl-2-[(6-butyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl)sulfanyl]acetamide (G721-0282), an inhibitor of CHI3L1, on mice treated with chronic unpredictable mild stress (CUMS), as well as the mechanism of its action. We examined the anxiolytic-like effect of G721-0282 by conducting several behavioral tests with oral administration of G721-0282 to CUMS-treated BALB/c male mice. We found that administration of G721-0282 relieves CUMS-induced anxiety. Anxiolytic-like effects of G721-0282 have been shown to be associated with decreased expressions of CUMS-induced inflammatory proteins and cytokines in the hippocampus. The CUMS-elevated levels of CHI3L1 and IGFBP3 were inhibited by treatment with G721-0282 in vivo and in vitro. However, CHI3L1 deficiency abolished the anti-inflammatory effects of G721-0282 in microglial BV-2 cells. These results suggest that G721-0282 could lower CUMS-induced anxiety like behaviors by regulating IGFBP3-mediated neuroinflammation via inhibition of CHI3L1.

Highlights

Anxiety disorders characterized by anxiety and fear are types of mental disorders that include generalized anxiety disorder, panic disorder, phobias, social anxiety disorder, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) (Bandelow and Michaelis, 2015)
Since G721-0282 targets Chitinase-3-like 1 (CHI3L1) and exhibits a CHI3L1 inhibitory effect, we investigated whether G721-0282 could interact physically with CHI3L1 through a pull-down assay and a docking experiment
CHI3L1 level was much higher in G7210282-Sepharose 6B beads, suggesting that G721-0282 binds to CHI3L1 (Figure 1B)

Summary

Introduction

Anxiety disorders characterized by anxiety and fear are types of mental disorders that include generalized anxiety disorder, panic disorder, phobias, social anxiety disorder, obsessive-compulsive disorder (OCD), and post-traumatic stress disorder (PTSD) (Bandelow and Michaelis, 2015). There have been numerous studies of anxiety disorders, the pathogenesis of anxiety disorders has yet to be elucidated. There is increasing evidence that pro-inflammatory and antiinflammatory cytokines play an important role in anxiety disorders (Simen et al, 2006; Koo and Duman, 2009; Furtado and Katzman, 2015; Hou et al, 2017). Several studies have found that Imipramine and Fluoxetine, widely used for the treatment of depressive and anxiety disorders, have NF-κB-inhibitory and anti-inflammatory effects (Troib and Azab, 2015). These data indicate that production of NF-κBdependent neuroinflammatory cytokines could be significantly associated with the development of anxiety disorder

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