Fenofibrate Reduces Ischemic Cerebral Edema via the Suppression of Aquaporin‐4

ABSTRACT The study aimed to investigate the neuroprotective effects of fenofibrate (FENO), a triglyceride‐lowering drug, in rats with cerebral ischemia. An ischemic cerebral edema model was established in rats, and an oxygen–glucose deprivation/reoxygenation (OGD/R) model was created in astrocytes. Neurological deficits were quantified using a standardized deficit score. Protein expression levels were assessed through immunohistochemical staining, western blot analysis, and enzyme‐linked immunosorbent assays (ELISA). Gene expression was determined using real‐time polymerase chain reaction (RT‐PCR), while luciferase activity was measured using a commercially available kit. We found that FENO significantly reduced infarct volume and neurological deficits in rats subjected to middle cerebral artery occlusion (MCAO). Additionally, FENO inhibited increased brain water content and upregulated the expression of aquaporin‐4 (AQP4), a protein associated with cerebral edema, in the ischemic hemisphere. Furthermore, FENO suppressed the inflammatory response in cortical tissue by reducing the expression of cytokines such as interleukin‐6 (IL‐6), monocyte chemoattractant protein‐1 (MCP‐1), and tumor necrosis factor‐alpha (TNF‐α). It also increased the expression of myeloperoxidase (MPO) and promoted activation of astrocytes by increasing glial fibrillary acidic protein (GFAP). In vitro experiments further demonstrated that FENO reduced the expression of AQP4 against OGD/R in primary rat astrocytes. FENO also inhibited the activation of p38 by reducing its phosphorylation. Correspondingly, FENO suppressed the activation of activator protein 1 (AP‐1) by reducing the levels of c‐Jun and c‐Fos, as well as the luciferase activity of AP‐1. These effects were enhanced by the p38 specific inhibitor SB203580. Notably, the presence of the AP‐1 specific inhibitor T5224 further promoted the effects of FENO in suppressing the expression of AQP4, implicating that the inhibitory effects of FENO on AQP4 expression are mediated by the p38/AP‐1 signaling pathway. These findings suggest that FENO may have potential therapeutic benefits in stroke by targeting the p38/AP‐1 signaling pathway and reducing AQP4 expression, thereby alleviating cerebral edema and inflammation.