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.