scholarly journals Inhibition of Soluble Epoxide Hydrolase after Cardiac Arrest/Cardiopulmonary Resuscitation Induces a Neuroprotective Phenotype in Activated Microglia and Improves Neuronal Survival

2013 ◽  
Vol 33 (10) ◽  
pp. 1574-1581 ◽  
Author(s):  
Jianming Wang ◽  
Tetsuhiro Fujiyoshi ◽  
Yasuharu Kosaka ◽  
Jonathan D Raybuck ◽  
K Matthew Lattal ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Neuronal Death ◽  
Epoxide Hydrolase ◽  
Memory Function ◽  
Specific Treatment ◽  
Neuronal Loss ◽  
Soluble Epoxide Hydrolase ◽  
Activated Microglia ◽  
Tnf Α

Cardiac arrest (CA) causes hippocampal neuronal death that frequently leads to severe loss of memory function in survivors. No specific treatment is available to reduce neuronal death and improve functional outcome. The brain's inflammatory response to ischemia can exacerbate injury and provides a potential treatment target. We hypothesized that microglia are activated by CA and contribute to neuronal loss. We used a mouse model to determine whether pharmacologic inhibition of the proinflammatory microglial enzyme soluble epoxide hydrolase (sEH) after CA alters microglial activation and neuronal death. The sEH inhibitor 4-phenylchalcone oxide (4-PCO) was administered after successful cardiopulmonary resuscitation (CPR). The 4-PCO treatment significantly reduced neuronal death and improved memory function after CA/CPR. We found early activation of microglia and increased expression of inflammatory tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the hippocampus after CA/CPR, which was unchanged after 4-PCO treatment, while expression of antiinflammatory IL-10 increased significantly. We conclude that sEH inhibition after CA/CPR can alter the transcription profile in activated microglia to selectively induce antiinflammatory and neuroprotective IL-10 and reduce subsequent neuronal death. Switching microglial gene expression toward a neuroprotective phenotype is a promising new therapeutic approach for ischemic brain injury.

Abstract 3602: Inhibition of Soluble Epoxide Hydrolase Improves Neuronal Survival after Cardiac Arrest and Alters Microglial Activation towards a Neuroprotective Phenotype

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Jianming Wang ◽  
Tetsuhiro Fujiyoshi ◽  
Yasuharu Kosaka ◽  
Paco S Herson ◽  
Ines P Koerner
Keyword(s):  
Cardiac Arrest ◽  
Brain Injury ◽  
Inflammatory Cytokines ◽  
Neuronal Death ◽  
Epoxide Hydrolase ◽  
Microglial Activation ◽  
Soluble Epoxide Hydrolase ◽  
Functional Deficit ◽  
Tnf Α ◽  
Pro Inflammatory Cytokines

Introduction: Ischemia/reperfusion during cardiac arrest and cardiopulmonary resuscitation (CA/CPR) causes significant neuronal death and leads to long-term functional deficits. While neuronal death in the hippocampus is one likely cause of memory loss after CA/CPR, the local inflammatory milieu present after CA/CPR also contributes to functional deficit. However, the signaling pathways involved in the inflammatory response are poorly understood. Microglia, the brain resident immune cells, are activated in response to different types of brain injury. We hypothesized that CA/CPR activates microglia, which then contribute to subsequent neuronal loss and functional deficit. We tested whether pharmacologic inhibition of the pro-inflammatory enzyme soluble epoxide hydrolase (sEH) alters microglial activation and neuronal death in a mouse model of CA/CPR. Methods: Male adult C57Bl/6 mice underwent 8 minutes of CA followed by CPR. The sEH inhibitor 4-phenylchalcone oxide (4-PCO; 5 mg/kg ip) was administered at 5 minutes and 24 hours after CA/CPR. Microglial activation was assessed histologically by immunostaining for the activation marker Mac-2 at 24 and 72 hours after CA/CPR. Surviving CA1 hippocampal neurons were counted at 72 hours after CA/CPR. Hippocampal expression of inflammatory cytokines was measured by quantitative RT-PCR. Results: Phenotypically activated microglia expressing Mac-2 appeared in the hippocampus as early as 24 hours after CA/CPR, before significant neuronal death was present. Concurrently, expression of the pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-1β increased. In animals treated with 4-PCO, hippocampal expression of the anti-inflammatory cytokine IL-10 was significantly increased (2-fold vs. vehicle), while expression of pro-inflammatory TNF- α and IL-1 β was unchanged. Subsequent death of CA1 neurons at 72 hours after CA/CPR was significantly reduced in animals treated with 4-PCO (34+/-3.7% 4-PCO vs. 52+/-7.1% vehicle), whereas the number of Mac-2 positive microglia was unchanged. Conclusions: Microglia are activated and produce pro-inflammatory cytokines early after CA/CPR. Inhibition of sEH induces hippocampal expression of anti-inflammatory and neuroprotective IL-10 and reduces subsequent neuronal death after CA/CPR, without altering the number of phenotypically activated Mac-2 positive microglia or expression of pro-inflammatory cytokines in the hippocampus. This suggests that sEH inhibition may alter gene expression in activated microglia after brain ischemia, thus protecting neurons and maintaining function. IL-10 induction by sEH inhibition is a promising therapeutic approach after ischemic brain injury from CA/CPR.

scholarly journals Soluble epoxide hydrolase gene deletion reduces survival after cardiac arrest and cardiopulmonary resuscitation

Resuscitation ◽  
2008 ◽  
Vol 76 (1) ◽  
pp. 89-94 ◽  
Author(s):  
Michael P. Hutchens ◽  
Takaaki Nakano ◽  
Jennifer Dunlap ◽  
Richard J. Traystman ◽  
Patricia D. Hurn ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Epoxide Hydrolase ◽  
Gene Deletion ◽  
Soluble Epoxide Hydrolase

scholarly journals Neurologic effects of short-term treatment with a soluble epoxide hydrolase inhibitor after cardiac arrest in pediatric swine

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Caitlin E. O’Brien ◽  
Polan T. Santos ◽  
Ewa Kulikowicz ◽  
Jennifer K. Lee ◽  
Raymond C. Koehler ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Motor Cortex ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Spontaneous Circulation ◽  
Term Treatment ◽  
Swine Model ◽  
Neurocognitive Deficits ◽  
Nuclear Condensation ◽  
Short Term Treatment

Abstract Background Cardiac arrest (CA) is the most common cause of acute neurologic insult in children. Many survivors have significant neurocognitive deficits at 1 year of recovery. Epoxyeicosatrienoic acids (EETs) are multifunctional endogenous lipid signaling molecules that are involved in brain pathobiology and may be therapeutically relevant. However, EETs are rapidly metabolized to less active dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH), limiting their bioavailability. We hypothesized that sEH inhibition would improve outcomes after CA in an infant swine model. Male piglets (3–4 kg, 2 weeks old) underwent hypoxic-asphyxic CA. After resuscitation, they were randomized to intravenous treatment with an sEH inhibitor (TPPU, 1 mg/kg; n = 8) or vehicle (10% poly(ethylene glycol); n = 9) administered at 30 min and 24 h after return of spontaneous circulation. Two sham-operated groups received either TPPU (n = 9) or vehicle (n = 8). Neurons were counted in hematoxylin- and eosin-stained sections from putamen and motor cortex in 4-day survivors. Results Piglets in the CA + vehicle groups had fewer neurons than sham animals in both putamen and motor cortex. However, the number of neurons after CA did not differ between vehicle- and TPPU-treated groups in either anatomic area. Further, 20% of putamen neurons in the Sham + TPPU group had abnormal morphology, with cell body attrition and nuclear condensation. TPPU treatment also did not reduce neurologic deficits. Conclusion Treatment with an sEH inhibitor at 30 min and 24 h after resuscitation from asphyxic CA does not protect neurons or improve acute neurologic outcomes in piglets.

scholarly journals Carbon Monoxide Releasing Molecule-2 Protects Intestinal Mucosal Barrier Function of Rat Undergoing Cardiopulmonary Resuscitation via Attenuation of TNF-α/NF-κB Signaling

2021 ◽  
Author(s):  
Qingsheng Niu ◽  
Fang Liu ◽  
Jun Zhang ◽  
Xiaojun Yang ◽  
Xiaohong Wang
Keyword(s):  
Carbon Monoxide ◽  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Intestinal Mucosa ◽  
Barrier Function ◽  
Mucosal Barrier ◽  
Intestinal Mucosal Barrier ◽  
Expression Levels ◽  
Tnf Α ◽  
Mucosal Barrier Function

Abstract The unique features of post–cardiac arrest pathophysiology are often superimposed on the disease or injury, causing the cardiac arrest, as well as underlying comorbidities. Exogenous carbon monoxide (CO) was reported to reduce ischemia-reperfusion injury (IRI). This study aimed to assess the effects of CO releasing molecule-2 (CORM-2) on intestinal mucosal barrier function after cardiopulmonary resuscitation (CPR) in rats. For this purpose, we established a rat model of asphyxiation-induced cardiac arrest and resuscitation to study intestinal IRI, and measured the serum level of intestinal fatty-acid binding protein (I-FABP). The expression levels of claudin-3, occludin, ZO-1, tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and nuclear factor kappa B (NF-κB) p65 were detected by Western blotting. CORM-2 up-regulated the expression levels of tight junction proteins (claudin-3, occludin, and ZO-1) in intestinal mucosa, leading to the reduction of the permeability of intestinal mucosa and reduced the release of proinflammatory cytokines. Besides, the CORM-2 exhibited anti-inflammatory effects by regulating the TNF-α/NF-κB pathway. In conclusion, CORM-2 treatment is clinically significant, preventing intestinal mucosal damage as a result of IRI during CPR.

Abstract 174: Effects of Melatonin (N-Acetyl-5-Methoxytryptamine) on Inflammation and Cerebral Microcirculation After Cardiopulmonary Resuscitation in a Rat Model of Cardiac Arrest

Circulation ◽  
2019 ◽  
Vol 140 (Suppl_2) ◽  
Author(s):  
Juntao Hu ◽  
Guanghui Zheng ◽  
Fenglian He ◽  
Weiwei Ge ◽  
Jing Xu ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cardiopulmonary Resuscitation ◽  
Rat Model ◽  
Animal Studies ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Flow Index ◽  
Cerebral Microcirculation ◽  
Sprague Dawley ◽  
Tnf Α

Introduction: Cerebral ischemia-reperfusion injury produces inflammation and cerebral microcirculatory dysfunction after cardiopulmonary resuscitation (CPR). Melatonin (N-acetyl-5-methoxytryptamine) has both anti-inflammatory and anti-oxidative properties. In this study, we investigated the effects of melatonin on inflammation and cerebral microcirculation after cardiopulmonary resuscitation in a rat model of cardiac arrest. Hypothesis: Melatonin decreases the systemic inflammatory response after cardiopulmonary resuscitation and will preserve cerebral microcirculation in a rat model of cardiac arrest. Method: Eighteen male Sprague Dawley rats weighing between 450-550 g were randomized into three groups: 1) sham: no ventricular fibrillation (VF) and CPR; 2) CPR control: untreated VF for 6 min followed by 8 min CPR; 3) CPR+melatonin: untreated VF for 6 min followed by 8 min CPR. Melatonin (10 mg/kg) was administered intraperitoneal (IP) in line with hypoxia-ischemia animal studies after return of spontaneous circulation (ROSC). Serum TNF- α, IL-1 β and cerebral microcirculation were measured at baseline and 6 h following ROSC. Result: Serum TNF-α and IL-1β were significantly lower in the CPR+melatonin group at 6h after ROSC compared to CPR controls ( p <0.01, Fig. 1). Animals treated with melatonin had improved cerebral microcirculation including perfused vessel density (PVD), proportion of perfused vessels (PPV) and microvascular flow index (MFI) compared to control animals ( p <0.05, Fig. 2). Conclusion: In a rat model of cardiac arrest, melatonin reduced systemic inflammation and preserved cerebral microcirculation following resuscitation.

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