Cottonseed oil alleviates ischemic stroke injury by inhibiting ferroptosis

Miao Sun; Min Liu; Qingxiao Li; Xiaoying Zhang; Siyuan Liu; Huikai Yang; Le Yang; Jiahe Tian; Weidong Mi; Yulong Ma

doi:10.1002/brb3.3179

Cottonseed oil alleviates ischemic stroke injury by inhibiting ferroptosis

Brain Behav. 2023 Oct;13(10):e3179. doi: 10.1002/brb3.3179. Epub 2023 Jul 21.

Authors

Miao Sun^#^{1

2}, Min Liu^#³, Qingxiao Li^#⁴, Xiaoying Zhang¹, Siyuan Liu⁵, Huikai Yang¹, Le Yang⁶, Jiahe Tian⁴, Weidong Mi¹, Yulong Ma¹

Affiliations

¹ Department of Anesthesiology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
² Department of Anesthesiology, The First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning Province, China.
³ Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
⁴ Department of Nuclear Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
⁵ Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China.
⁶ Department of Pharmacy, Tangdu Hospital, Air Force Military Medical University, Xi'an, Shaanxi Province, China.

^# Contributed equally.

Abstract

Introduction: Ferroptosis has recently been recognized as a new cause of ischemia reperfusion injury due to blood-brain barrier (BBB) disruption followed by secondary iron-loaded transferrin (TF) influx. As a novel and independent cell death pathway, ferroptosis was characterized by iron-dependent lipid peroxidation, decline of GSH, GPX4, and shrinking mitochondria. Cottonseed oil (CSO), a liposoluble solvent, can alleviate ischemia stroke injuries and oxidative stress. However, the effect of CSO on ischemic stroke-induced ferroptosis has not been explored. In this study, we investigated the effect of CSO on ferroptosis caused by cerebral ischemic injury in rats.

Methods: We conducted the subcutaneous injection of 1.3 mL/kg CSO every other day for 3 weeks on rats with middle cerebral artery occlusion-reperfusion (MCAO-R) injury. We used Garcia Test, TTC staining, HE, Nissl and NeuN staining, Evans blue test, ⁶⁸ Ga-citrate PET, Western blot, immunofluorescence staining, Elisa kits, and transmission electron microscopy to detect the infarct volume, neural injuries, and ferroptosis-related indexes.

Results: CSO treatment could significantly ameliorate MCAO-R-induced neurological dysfunction in a male rat model. Furthermore, it reduced infarct volume and neuronal injuries; protected BBB integrity; reduced the influx of iron ion, TF, and TF receptors; up-regulated anti-ferroptosis proteins (GPX4, xCT, HO1, FTH1), while down-regulating ferroptosis-related protein ACSL4; increased the activity of GSH and SOD; and decreased MDA and LPO levels. Mitochondrial destruction induced by ischemic stroke was also alleviated by CSO treatment.

Conclusion: CSO treatment can alleviate ischemic stroke injury via ferroptosis inhibition, which provides a new potential therapeutic mechanism for CSO neuroprotection against ischemic stroke.

Keywords: 68Ga-citrate; cottonseed oil (CSO); ferroptosis; ischemic stroke; neuroprotection; positron emission tomography (PET).

Abstract

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