The Inhibition of Caspase-1 Activity With a Dietary Polyphenol Reduces Anxiety and Depression in a Murine Model of Chronic Stress

Abstract Objectives Polyphenols constitute a broad class of natural compounds with anti-oxidant properties. We previously demonstrated that polyphenol-rich dietary supplements confer resilience against stress-induced depressive behaviors. Here, we aimed to characterize the mechanism by which individual phenolic metabolites improve depressive phenotypes induced by exposure to chronic stress. Methods To identify individual polyphenols with anti-inflammasome properties, we conducted a screening using primary microglial cultures. Through ELISA, we measured the ability of the metabolites to reduce the release of IL-1β upon activation of the NLRP3 inflammasome with LPS-ATP. Using LDH assays, we determine the cytotoxicity of a selected compound, and its anti-pyroptotic effect. We assessed the potency and specificity of the compound by ELISA, and its ability to modify the transcriptional expression of inflammatory genes using qPCR. Finally, we administrated mice with 5 μg/kg·day of the metabolite through gavage 14 days prior to start a Chronic Unpredictable Stress (CUS) protocol. The treatment was maintained during the 28 days of the CUS paradigm, during which the animals were subjected to randomized stressors. After that, anxiety and depression were assessed by the elevated plus maze and the forced-swim test. Results From the screened polyphenols, malvidin-glucoside (MG) inhibited NLRP3-mediated IL-1β production with the greater potency, presenting an IC50 value of 0.94 μM. MG also inhibited other inflammasomes, such as NLRC4 or AIM2, but it did not affect the production of IL-6 or TNF-α, and it neither the gene expression of inflammatory markers. MG was not toxic and inhibited pyroptosis, but not the oligomerization of the adaptor protein ASC. Taking all these data together, we hypothesized that MG reduced inflammation by its direct inhibition of the caspase-1 activity, what was verified by measuring the activity of purified caspase-1 protein and by molecular docking. From our in-vivo study, we inferred that CUS promoted anxiety and depression-like phenotypes, which were ameliorate by MG treatment. Conclusions MG reduces inflammation by inhibition of caspase-1 activity, which promotes resilience to stress-induced anxiety and depression. Funding Sources Grant AT008661 from the NIH's ODS and the NCCIH.