Butein ameliorates chronic stress induced atherosclerosis via targeting anti-inflammatory, anti-fibrotic and BDNF pathways

Chronic stress is a major risk factor for various diseases, including cardiovascular diseases (CVDs). Chronic stress enhances the release of pro-inflammatory cytokines like IL-1 beta, IL-6, and TNF-alpha, making individuals susceptible to atherosclerosis which is dominant cause for CVDs. In present study, we validated a mouse model of chronic unpredictable stress (CUS), and assessed the characteristic features of atherosclerosis in thoracic aortas of CUS mice. The CUS procedure consisted of exposing groups of mice to random stressors daily for 10-weeks. The stress response was verified by presence of depressive-like behaviors and increased serum corticosterone in mice which was determined by battery of behavioural tests (SPT, EPMT, NSFT) and ELISA, respectively. Atherosclerosis parameters in CUS mice were evaluated by lipid indices estimation followed by histological assessment of plaque deposition and fibrosis in thoracic aorta. Further, we assessed the efficacy of a polyphenol, i.e. Butein in conferring protection against chronic stress-induced atherosclerosis and the possible mechanism of action. Butein (20 mg/kg x 28 days, alternatively, i.p.) was administered to CUS mice after 6-weeks of CUS exposure till the end of the protocol. Butein treatment decreased peripheral IL-1 beta and enhanced peripheral as well as central BDNF levels. Histological assessment revealed decreased macrophage expression and reduced fibrosis in thoracic aorta of Butein treated mice. Further, treatment with Butein lowered lipid indices in CUS mice. Our findings thus, suggest that 10-weeks of CUS induce characteristic features of atherosclerosis in mice and Butein can offer protection in CUS-induced atherosclerosis through multiple mechanisms including anti-inflammatory, anti-fibrotic and anti-adipogenic actions.