Abstract
To investigate the effect of 14,15-EET on the parthanatos in neurons induced by cerebral ischemia and reperfusion, middle cerebral artery occlusion and reperfusion (MCAO/R) and oxygen glucose deprivation/reoxygenation (OGD/R) were used to simulate cerebral ischemia reperfusion in vivo and in vitro, respectively. TTC staining and the Tunel method were used to detect cerebral infarct volume and neuronal apoptosis. Western blot and immunofluorescence were used to detect poly (ADP-ribose) polymerase-1 (PARP-1) activation and AIF nuclear translocation. The production of reactive oxygen species (ROS) and the expression of antioxidant genes were detected by Mito SOX, DCFH-DA and qPCR methods. MCAO/R increased cerebral infarct volume and neuronal apoptosis in mice, while 14,15-EET pretreatment increased cerebral infarct volume and neuronal apoptosis. OGD/R induced reactive oxygen species generation, PARP-1 cleavage, and AIF nuclear translocation in cortical neurons. 14,15-EET pretreatment could enhance the antioxidant gene expression of glutathione peroxidase (GSH-Px), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD) in cortical neurons after ischemia and reperfusion. 14,15-EET inhibits the neuronal parthanatos induced by MCAO/R through upregulation of the expression of antioxidant genes and by reducing the generation of reactive oxygen species. This study advances the EET neuroprotection theory and provides a scientific basis for targeted clinical drugs that reduce neuronal parthanatos following cerebral ischemia and reperfusion.
Highlights
Ischemic stroke is currently the disease with the highest mortality and disability rates in humans [1,2,3]
QPCR results showed that the pretreatment of 14,15-EET via tail vein injection increased the transcription of certain antioxidant genes such as glutathione peroxidase (GSH- Px), heme oxygenase-1 (HO-1) and superoxide dismutase (SOD), while catalase (CAT) gene expression showed no increase, suggesting that 14,15-EET can inhibit the production of reactive oxygen species induced by cerebral ischemia and reperfusion by upregulating the expression of antioxidant genes such as GSH-Px, HO-1 and SOD (Figure 7)
The excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) catalyzes the formation of PAR polymers and induces apoptosis-inducing factor (AIF) to translocate from mitochondria to the nucleus, causing large DNA fragmentation and leading to cell death, which is the main process of parthanatos
Summary
Ischemic stroke is currently the disease with the highest mortality and disability rates in humans [1,2,3]. Parthanatos is a unique form of cell death that is mediated by poly ADP-ribose polymerase (PARP) and is completely different from programmed cell apoptosis. It is widely involved in cell oxidative damage and the pathological processes of neurodegenerative disease [5,6,7]. In the case of DNA damage, PARP-1 is activated by DNA double-strand breaks (DSBs) and is cleaved into p89 and p24 The latter irreversibly binds to broken ends of DNA, inhibits DNA repair and leads to cell apoptosis. Our previous studies have showed that sEH gene knockout or 14,15-EET preconditioning can reduce cortical neuronal apoptosis and cerebral infarction volume induced by cerebral ischemia and reperfusion [13,14]. This research provides a scientific reference for the in-depth understanding of the neuroprotective mechanism of EET and the development of neuroprotective drugs for cerebral ischemia and reperfusion
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