14,15-EET Reduced Brain Injury from Cerebral Ischemia and Reperfusion via Suppressing Neuronal Parthanatos

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.

14, 15‐EET alleviates neurological impairment through maintaining mitochondrial dynamics equilibrium via AMPK/SIRT1/FoxO1 signal pathways in mice with cerebral ischemia reperfusion

“…14, 15‐EET is an important intermediate in the process of arachidonic acid metabolism in organisms and has various cytoprotective effects. Our previous study has found that 14, 15‐EET can reduce cerebral ischemia–reperfusion‐induced neuronal apoptosis by promoting mitochondrial biogenesis and inhibiting the mitochondrial apoptosis pathway and parthanatos in neurons 26–28 . This study shows that 14, 15‐EET can reduce neuronal apoptosis and cerebral infarct volume, and alleviate neurological impairment following MCAO, which is consistent with previous findings.…”

“…Our previous study has found that 14, 15-EET can reduce cerebral ischemia-reperfusion-induced neuronal apoptosis by promoting mitochondrial biogenesis and inhibiting the mitochondrial apoptosis pathway and parthanatos in neurons. [26][27][28] This study shows that 14, 15-EET can reduce neuronal apoptosis and…”

“…Due to its structure–activity, 14, 15‐EET is readily hydrolyzed to inactive 14, 15‐DHET by soluble epoxide hydrolase 25 . Our previous studies have shown that 14, 15‐EET reduces neuronal apoptosis caused by cerebral ischemia–reperfusion through regulating mitochondrial biogenesis and inhibiting mitochondrial apoptosis pathways 26–28 . This study intends to investigate the effect of 14, 15‐EET on mitochondrial dynamics of neurons induced by middle cerebral artery occlusion (MCAO) and reperfusion in mice, and to elucidate the neuroprotective mechanism of 14, 15‐EET regulating mitochondrial dynamics through AMPK/SIRT1/FoxO1 signaling pathway to alleviate neurological impairment induced by cerebral ischemia–reperfusion, so as to provide a target for the development of drugs for the treatment of cerebral ischemia–reperfusion.…”

Xuebijing Injection Attenuates Heat Stroke-Induced Brain Injury through Oxidative Stress Blockage and Parthanatos Modulation via PARP-1/AIF Signaling

“…The levels of ROS indicators such as MDA, SOD, and nitric oxide (NO) in rat neurons were detected, and XBJ injection was demonstrated to partially offset the HS-induced elevation in the MDA and NO levels, while upregulated SOD levels in rat neurons (Figure E; p < 0.05, p < 0.01 and p < 0.001). Neuron cell death occurs during pathology, and our previous work has revealed that the death rate of neuron cells after HS is approximately 25–30%, which indicates other potential mechanisms of cell death besides apoptosis and autophagy. − ROS is reported to induce PARP-1-dependent cell death, also named Parthanatos, which is potentially involved in HS-induced brain injury. , We, therefore, detected the involvement of PARP-1 in HS-induced neuron cells. Our results demonstrated that HS induced an increase in PARP-1 mRNA and protein levels, which was counteracted by the treatment of XBJ injection, suggesting that XBJ injection mitigates the HS-induced Parthanatos of neurons by inhibiting the activation of PARP-1 (Figure F,G; p < 0.001).…”

“…29−31 ROS is reported to induce PARP-1-dependent cell death, also named Parthanatos, which is potentially involved in HS-induced brain injury. 32,33 We, therefore, detected the involvement of PARP-1 in HS-induced neuron cells. Our results demonstrated that HS induced an increase in PARP-1 mRNA and protein levels, which was counteracted by the treatment of XBJ injection, suggesting that XBJ injection mitigates the HS-induced Parthanatos of neurons by inhibiting the activation of PARP-1 (Figure 2F,G; p < 0.001).…”