CY-09 Alleviates the Depression-like Behaviors via Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation in Lipopolysaccharide-Induced Mice

Abstract

Depression is a serious mental illness, mainly characterized as large mood swings and sleep, diet, and cognitive function disorders. NLPR3, one of the inflammasomes that can be activated by a variety of stimuli to promote the maturation and secretion of pro-inflammatory cytokines, has been considered to be involved in the pathophysiology of depression. In this study, the putative role of CY-09, a selective and direct inhibitor of NLRP3, was evaluated in the lipopolysaccharide (LPS)-induced mice. The results of the study indicated that CY-09 significantly decreased the levels of NLRP3 in the hippocampus of LPS-induced mice. In addition, CY-09 increased the sucrose preference and shortened the immobility time in LPS-induced mice, suggesting the antidepressant-like effects of inhibiting NLRP3 inflammasome. Biochemical analysis showed that LPS significantly activated the NLRP3/ASC/cytokine signaling pathway and caused microglial activation, while CY-09 prevented the changes. Moreover, CY-09 increased the brain-derived neurotrophic factor (BDNF) only in microglia but not in the whole hippocampus. Meanwhile, CY-09 did not promote neurogenesis in the hippocampus of LPS mice. In conclusion, the results of the study showed that the antidepressant-like effects of NLRP3 inhibitor CY-09 were mediated by alleviating neuroinflammation in microglia and independent of the neurotrophic function in the hippocampus.

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development

“…CY-09 repressed the expression of NLRP3, IL-1 and IL-18 in injured brain tissue in the rat TBI models [145]. The findings from Wang et al showed that CY-09 attenuates depression-like behaviors by inhibiting the NLRP3-mediated neuroinflammation in LPS-induced mice [146]. In a clinical trial, CY-09 was found to be effective in reducing the number and severity of seizures in people with focal epilepsy when compared to placebo.…”

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development

“…CY-09 repressed the expression of NLRP3, IL-1b and IL-18 in injured brain tissue in the rat TBI models [147]. The findings from Wang et al showed that CY-09 attenuates depression-like behaviors by inhibiting the NLRP3-mediated neuroinflammation in LPS-induced mice [148]. In clinical trial, CY-09 was found to be effective in reducing the number and severity of seizures in people with focal epilepsy when compared to placebo.…”

NLRP3 Inflammasome Inhibitors for Antiepileptogenic Drug Discovery and Development

“…CY-09 repressed the expression of NLRP3, IL-1β, and IL-18 in injured brain tissue in the rat TBI models [ 145 ]. The findings from Wang et al showed that CY-09 attenuates depression-like behaviors by inhibiting the NLRP3-mediated neuroinflammation in LPS-induced mice [ 146 ]. In a clinical trial, CY-09 was found to be effective in reducing the number and severity of seizures in people with focal epilepsy when compared to placebo.…”