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

Tiantian Liu; Xinlu Chen; Ziqi Wei; Xue Han; Yujia Liu; Zhengliang Ma; Tianjiao Xia; Xiaoping Gu

doi:10.1515/tnsci-2022-0317

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

Transl Neurosci. 2023 Nov 15;14(1):20220317. doi: 10.1515/tnsci-2022-0317. eCollection 2023 Jan 1.

Authors

Tiantian Liu^{1

2

3

4}, Xinlu Chen^{1

2

3

4}, Ziqi Wei^{2

3

4}, Xue Han^{1

2

3

4}, Yujia Liu^{1

2

3

4}, Zhengliang Ma¹, Tianjiao Xia^{2

3

4}, Xiaoping Gu¹

Affiliations

¹ Department of Anesthesiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing 210008, China.
² Medical School, Nanjing University, Nanjing 210093, China.
³ Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, China.
⁴ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China.

Abstract

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 α (PPARα) 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 PPARα intervention in POCD warrants consideration.

Objective: The present study is aimed to investigate whether PPARα 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 PPARα 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 γ coactivator 1α, carnitine palmitoyltransferase 1A, and PPARα) both in the hippocampus of POCD mice and in N2a cells. In the N2a cell model, pretreatment of PPARα 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 PPARα agonist FF can protect against long-term isoflurane anesthesia-induced POCD by enhancing fatty acid oxidation.

Keywords: PPARα; fatty acid oxidation; fenofibrate; isoflurane; postoperative cognitive dysfunction.