PPAR agonist fenofibrate prevents postoperative cognitive dysfunction by enhancing fatty acid oxidation in mice

Background - Due to high rates of incidence and disability, postoperative cognitive dysfunction (POCD) currently receives a lot of clinical attention. Disturbance of fatty acid oxidation is a potential pathophysiological manifestation underlying POCD. Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a significant transcription factor of fatty acid oxidation that facilitates the transfer of fatty acids into the mitochondria for oxidation. The potential role of PPAR alpha intervention in POCD warrants consideration.Objective -The present study is aimed to investigate whether PPAR alpha agonist fenofibrate (FF) could protect long-term isoflurane anesthesia-induced POCD model and to explore the potential underlying function of fatty acid oxidation in the process.Methods - We established the POCD model via 6 h long-term isoflurane anesthesia in vivo with C57BL/6J mice and in vitro with N2a cells. Cells and mice were pretreated with PPAR alpha agonist FF before anesthesia, after which fatty acid oxidation and cognitive function were assessed. The level of fatty acid oxidation-related proteins was determined using western blotting. The contextual fear conditioning test was utilized to evaluate mice's learning and memory.Results - Our results showed that 6 h long-term isoflurane anesthesia induced contextual memory damage in mice, accompanied by decreases of fatty acid oxidation-related proteins (peroxisome proliferator-activated receptor gamma coactivator 1 alpha, carnitine palmitoyltransferase 1A, and PPAR alpha) both in the hippocampus of POCD mice and in N2a cells. In the N2a cell model, pretreatment of PPAR alpha agonist FF led to the upregulation of fatty acid oxidation-related proteins. In vivo results showed that preconditioned FF reached similar effects. More crucially, FF has been shown to reduce cognitive damage in mice after long-term isoflurane anesthesia. Additionally, our data showed that after blocking fatty acid oxidation by Etomoxir, FF failed to protect cognitive function from long-term isoflurane anesthesia.Conclusions - Pretreatment of PPAR alpha agonist FF can protect against long-term isoflurane anesthesia-induced POCD by enhancing fatty acid oxidation.