Oleoylethanolamide attenuates apoptosis by inhibiting the TLR4/NF-κB and ERK1/2 signaling pathways in mice with acute ischemic stroke

Zhou, Hai-Rong; Yang, Wu; Liu, Ying; Ren, Tong; Lu, Peng; Guo, Hong-Fen; Liu, Jinfeng; Zhou, Yu; Zhao, Yun; Yang, Lichao; Jin, Xin

doi:10.1007/s00210-016-1309-4

Cited by 34 publications

(30 citation statements)

References 22 publications

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“…The PPAR-α antagonist, GW induced several significant effects when administered with VEH specifically in HI-lesioned mice. Because of the neuroprotective role of PPAR-α activation under HI conditions ( Sun et al, 2007 ; Zhou et al, 2012 , 2017 ; Yang et al, 2015 ), it was expected that the inhibitory action of GW would potentiate the detrimental effects of HI on the different behavioral, biochemical and genetic outcomes evaluated in our study. Accordingly, GW/VEH potentiated the decrease in NeuN immunostaining observed in HI-lesioned mice with respect to VEH/VEH administration in the somatosensory cortex, and selectively decreased this parameter in the dentate gyrus and CA1 area of the hippocampus in HI mice, indicating a greater neurotoxic effect.…”

Section: Discussionmentioning

confidence: 99%

“…A growing amount of evidence suggests that this receptor participates in inflammatory response modulating the expression of chemokines, chemokine receptors and adhesion molecules in endothelial cells, smooth muscle cells, monocytes/macrophages and T cells ( Duval et al, 2002 ; Blanquart et al, 2003 ), and also increases the expression of antioxidant enzymes, such as superoxide dismutase and catalase ( Toyama et al, 2004 ). In addition, endogenous PPAR-α agonists, such as oleoylethanolamide (OEA) have shown neuroprotective properties on ischemic stroke models through the activation of PPAR-α signaling ( Sun et al, 2007 ; Zhou et al, 2012 , 2017 ; Yang et al, 2015 ). However, the rapid degradation of the OEA by fatty acid amide hydrolase (FAAH) is known to represent a limitation for the development of an effective therapeutic approach.…”

Section: Introductionmentioning

confidence: 99%

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Octadecylpropyl Sulfamide Reduces Neurodegeneration and Restores the Memory Deficits Induced by Hypoxia-Ischemia in Mice

et al. 2018

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The PPAR-α agonist, oleoylethanolamide (OEA) has neuroprotective properties in stroke models. However, its rapid degradation represents a limitation for an effective therapeutic approach. In this study, we evaluated the effects of a stable OEA-modeled compound, octadecylpropyl sulfamide (SUL) on the cognitive, behavioral, cellular and molecular alterations associated with hypoxia-ischemia (HI) in mice. Mice subjected to HI were treated with the PPAR-α antagonist GW6471 (GW) (1 mg/kg) followed 15 min later by SUL (3 and 10 mg/kg). Behavioral, motor, and cognitive tests were carried out 24 h and 7 days after the HI. The levels of microglia, reactive astrocytes and neuronal nuclei were studied using immunofluorescence, and the expression of genes related to the N-acyl-ethanolamides/endocannabinoid signaling systems was determined by qRT-PCR at the end of the experimental sequence. HI induced brain damage in the ipsilateral hippocampus and cortex, which lead to severe memory impairments, and motor coordination deficits. Significant neuronal loss, increased microglia and reactive astrocytes, and compensatory changes in genes associated with the inflammation/immune and endocannabinoid systems were observed in these brain structures of lesioned mice. SUL reversed the memory and motor deficits, decreased the overexpression of microglia and astrocytes, and reduced neurodegeneration induced by HI. Cnr1 and Cnr2 gene expression was modulated by SUL in both sham and HI mice, while Pparα and Faah expression was regulated in HI mice. GW completely blocked the beneficial actions of SUL. These findings suggest that treatment with SUL reduces brain damage and the associated motor and memory deficits induced by HI probably by normalizing the changes in neuroinflammation/immune system mediators.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Octadecylpropyl Sulfamide Reduces Neurodegeneration and Restores the Memory Deficits Induced by Hypoxia-Ischemia in Mice

et al. 2018

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“…An effect similar to propofol is exhibited by an FAAH inhibitor (URB597) and an endocannabinoid reuptake inhibitor (VDM11) [118]. In addition, the exposure of neurons to another endocannabinoid-oleoylethanolamine (OEA)-also exerts a neuroprotective effect, in a manner dependent on the PPARα receptors of hypoxic neurons, which would otherwise cause their apoptosis, in part by increasing Bax expression and decreasing Bcl-2 levels [119,120].…”

Section: Endocannabinoidsmentioning

confidence: 99%

“…This is highly similar to the action of endocannabinoids, which also activate these pathways. However, in some cells, they act in a proapoptotic manner, and in others, act in an antiapoptotic manner [108,114,115,119,120].…”

Section: Exogenous Cannabinoidsmentioning

confidence: 99%

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

et al. 2020

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Apoptosis is the physiological mechanism of cell death and can be modulated by endogenous and exogenous factors, including stress and metabolic alterations. Reactive oxygen species (ROS), as well as ROS-dependent lipid peroxidation products (including isoprostanes and reactive aldehydes including 4-hydroxynonenal) are proapoptotic factors. These mediators can activate apoptosis via mitochondrial-, receptor-, or ER stress-dependent pathways. Phospholipid metabolism is also an essential regulator of apoptosis, producing the proapoptotic prostaglandins of the PGD and PGJ series, as well as the antiapoptotic prostaglandins of the PGE series, but also 12-HETE and 20-HETE. The effect of endocannabinoids and phytocannabinoids on apoptosis depends on cell type-specific differences. Cells where cannabinoid receptor type 1 (CB1) is the dominant cannabinoid receptor, as well as cells with high cyclooxygenase (COX) activity, undergo apoptosis after the administration of cannabinoids. In contrast, in cells where CB2 receptors dominate, and cells with low COX activity, cannabinoids act in a cytoprotective manner. Therefore, cell type-specific differences in the pro- and antiapoptotic effects of lipids and their (oxidative) products might reveal new options for differential bioanalysis between normal, functional, and degenerating or malignant cells, and better integrative biomedical treatments of major stress-associated diseases.

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“…In the mitochondrial signaling pathway, Bcl-2 family members play a key role in regulating apoptosis, and changes in the balance of Bcl-2 and Bax may result in either inhibition or induction of cell apoptosis [ 5 , 6 ]. There are many activating signaling pathways that regulate apoptosis during post-stroke, such as the ERK1/2, JNK, and p38 signaling pathways [ 7 – 9 ].…”

Section: Introductionmentioning

confidence: 99%

Electroacupuncture Inhibits Apoptosis of Peri-Ischemic Regions via Modulating p38, Extracellular Signal-Regulated Kinase (ERK1/2), and c-Jun N Terminal Kinases (JNK) in Cerebral Ischemia-Reperfusion-Injured Rats

et al. 2018

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BackgroundPrevious studies suggested that inhibition of apoptosis prevents the dysfunction of ischemia-reperfusion injury. In the pathogenesis of ischemia-reperfusion injury, JNK/ERK1/2 and p38 play an essential role in regulation of cell apoptosis. Electroacupuncture (EA), a form of acupuncture, has demonstrated superiority in preventing ischemia-reperfusion injury, but the underlying mechanism is unclear. In the present study, we explored the effects of electroacupuncture at Shenting (GV24) and Baihui (GV20) acupoints on focal cerebral ischemia-reperfusion (MCAO) rats, and explored whether JNK/ERK1/2- and p38-mediated cell apoptosis are involved.Material/MethodsThe rats were divided into a sham operation control group, an ischemia group, and an electroacupuncture group with acupuncture applied for 10 days (30 min per day). TTC staining was used to calculate the ischemic brain volume. TUNEL staining and transmission electron microscopy were used to detect cell apoptosis. Western blot analysis and Bio-Plex were used to detect JNK, p38, ERK1/2, Bcl-2, and Bax protein expression.ResultsWe found that electroacupuncture at day 10 significantly reduced cerebral infarction. In addition, electroacupuncture suppressed activation of JNK and p38, while enhancing the activation of ERK1/2 in the peri-ischemic regions. Consequently, the effect of electroacupuncture on these pathways resulted in the inhibition of apoptosis, which was demonstrated by TUNEL and transmission electron microscopy. We found that electroacupuncture upregulated the anti-apoptotic Bcl-2/Bax ratio in peri-ischemic regions.ConclusionsOur findings suggest that inhibition of cell apoptosis via regulating multiple signaling pathways might be a mechanism whereby electroacupuncture has a positive therapeutic effect on post-stroke impairment.

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Oleoylethanolamide attenuates apoptosis by inhibiting the TLR4/NF-κB and ERK1/2 signaling pathways in mice with acute ischemic stroke

Cited by 34 publications

References 22 publications

Octadecylpropyl Sulfamide Reduces Neurodegeneration and Restores the Memory Deficits Induced by Hypoxia-Ischemia in Mice

Octadecylpropyl Sulfamide Reduces Neurodegeneration and Restores the Memory Deficits Induced by Hypoxia-Ischemia in Mice

Involvement of Metabolic Lipid Mediators in the Regulation of Apoptosis

Electroacupuncture Inhibits Apoptosis of Peri-Ischemic Regions via Modulating p38, Extracellular Signal-Regulated Kinase (ERK1/2), and c-Jun N Terminal Kinases (JNK) in Cerebral Ischemia-Reperfusion-Injured Rats

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