Role of Polyphenol-Derived Phenolic Acid in Mitigation of Inflammasome-Mediated Anxiety and Depression

Overexposure to mental stress throughout life is a significant risk factor for the development of neuropsychiatric disorders, including depression and anxiety. The immune system can in-itiate a physiological response, releasing stress hormones and pro–inflammatory cytokines, in response to stressors. These effects can overcome allostatic physiological mechanisms and generate a pro–inflammatory environment with deleterious effects if occurring chronically. Previous studies in our lab have identified key anti–inflammatory properties of a bioavailable polyphenolic prepa-ration BDPP and its ability to mitigate stress responses via the attenuation of NLRP3 inflammasome-dependent responses. Inflammasome activation is part of the first line of defense against stimuli of different natures, provides a rapid response, and, therefore, is of capital importance within the innate immunity response. malvidin–3–O–glucoside (MG), a natural anthocyanin present in high pro-portions in grapes, has been reported to exhibit anti-inflammatory effects, but its mechanisms re-main poorly understood. This study aims to elucidate the therapeutic potential of MG on inflam-masome-induced inflammation in vitro and in a mouse model of chronic unpredictable stress (CUS). Here, it is shown that MG is an anti-pyroptotic phenolic metabolite that targets NLRP3, NLRC4, and AIM2 inflammasomes, subsequently reducing caspase–1 and IL–1β protein levels in murine primary cortical microglia and the brain, as its beneficial effect to counteract anxiety and depression is also demonstrated. The present study supports the role of MG to mitigate bacterial-mediated inflammation (lipopolysaccharide or LPS) in vitro and CUS-induced behavior impair-ment in vivo to address stress-induced inflammasome-mediated innate response.