Investigating the Therapeutic Potential of Cinnamic Acid in Vascular Dementia Through PARP1 Inhibition and Microglial M2 Polarization

ABSTRACT Vascular dementia (VD) is a cerebrovascular disease‐associated cognitive disorder characterized by chronic neuroinflammation. Cinnamic acid (CA), a natural aromatic carboxylic acid, has been demonstrated to mitigate neurological dysfunction. In this study, a two‐vessel occlusion (2‐VO) rat model was established, and the rats were treated with CA at doses of 45 mg/kg and 90 mg/kg via intragastric gavage. CA treatment significantly restored cognitive function in 2‐VO rats, which was attributed to the reduction of neuronal apoptosis. Furthermore, CA administration downregulated the expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2) in the hippocampal tissues, while upregulating the expressions of arginase‐1 (Arg‐1), found in inflammatory zone 1 (Fizz1), and chitinase 3‐like 3 (YM‐1). These observations suggest that CA promotes the alternatively activated (M2) polarization of microglia in hippocampal tissues. To simulate the neuroinflammatory environment in vitro, BV2 cells were subjected to oxygen‐glucose deprivation/reoxygenation (OGD/R) treatment. CA pretreatment promotes M2 polarization in OGD/R‐induced BV2 cells, opposing OGD/R‐driven M1 polarization in these cells. Importantly, network pharmacology analysis identified poly (ADP‐ribose) polymerase 1 (PARP1) as a downstream target of CA. PARP1 expression was upregulated in the hippocampal tissues of 2‐VO rats and OGD/R‐induced BV2 cells, while CA treatment significantly reduced PARP1 expression. Notably, exogenous PARP1 reversed the CA‐induced promotion of the microglial M2 phenotype, as evidenced by increased iNOS expression and decreased Arg‐1 expression. In conclusion, CA targets PARP1 to promote the M2 polarization of microglia, thereby alleviating neuroinflammation and contributing to the recovery of neurological function in 2‐VO rats.