Hydroxycinnamates alleviate chronic unpredictable mild stress-induced depressive-like behavior and neuroinflammation in mice

The polyphenolic compounds ferulic acid (FA) and p-coumaric acid (PCA) have been extensively studied for their free radical scavenging and anti-inflammatory properties. Both compounds are present in food and beverages commonly consumed globally. Our molecular modeling, in-vitro, and in-vivo studies suggest that the compounds may be neuroprotective by modulating the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome pathway. The current study explored the dose-dependent neuroprotective potential of FA and PCA in a chronic unpredictable mild stress (CUMS) mouse model. Male Swiss albino mice were divided into nine groups consisting of control (CON), CUMS, FA10 (10 mg/kg FA), FA40 (40 mg/kg FA), FA160 (160 mg/kg FA), PCA10 (10 mg/kg PCA), PCA40 (40 mg/kg PCA), PCA160 (160 mg/kg PCA), and FLX (10 mg/kg fluoxetine). All animals, except the CON group, received random mild stressors for 21 days, and from day 22-42, the treatments were administered alongside the stressors. Behavioral assessments were performed on day 42, followed by sample collection. Brain homogenates from CUMS-exposed animals expressed elevated levels of the pro-inflammatory cytokines interleukin (IL)-1β, IL-6 and tumor necrosis factor-alpha (TNF-α), and oxidative stress markers. Treatment with FA and PCA effectively reduced cytokine release and oxidative stress, alleviating the depressive-like behavior.