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

Abstract

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.

Post-exposure administration of diazepam combined with soluble epoxide hydrolase inhibition stops seizures and modulates neuroinflammation in a murine model of acute TETS intoxication

“…Since inhibition of sEH has been shown to exert potent anti-inflammatory action (Iliff and Alkayed, 2009; Inceoglu et al, 2008; Wang et al, 2013), we quantified the effects of administering TUPS, a small molecule inhibitor of sEH, on TETS-induced seizures and neuroinflammation. Initial experiments focused on determining whether pharmacologic inhibition of sEH was sufficient to protect against TETS-induced tonus and death in the absence of diazepam.…”

“…This cytosolic enzyme regulates the levels of the epoxy fatty acids, which are bioactive lipid metabolites with anti-inflammatory properties (Iliff and Alkayed, 2009; Inceoglu et al, 2007). The anti-inflammatory effects of epoxy fatty acids and sEHIs have been demonstrated in other models of neuroinflammation, including a mouse model of scrapie (Poli et al , 2013), a mouse model of neurodegeneration following cardiac arrest (Wang et al, 2013), and an in vitro model of amyloid peptide-induced neurotoxicity (Sarkar et al , 2011). We have previously shown that epoxy fatty acids and sEHIs protect against seizures induced by PTZ, and this anticonvulsant activity seems to be mediated, in part, by augmentation of GABAergic signaling (Inceoglu et al, 2013).…”

“…This suggests the possibility that combinatorial therapy with anticonvulsant and anti-inflammatory agents may better protect the brain following acute TETS intoxication. Epoxygenated fatty acids are produced in the brain and have been shown to be potent anti-inflammatory compounds (Iliff and Alkayed, 2009; Inceoglu et al , 2007; Wang et al , 2013). The beneficial effect of these naturally occurring epoxy fatty acids is severely limited by their rapid metabolism via soluble epoxide hydrolase (sEH) (Imig and Hammock, 2009; Newman et al , 2005).…”

“…The beneficial effect of these naturally occurring epoxy fatty acids is severely limited by their rapid metabolism via soluble epoxide hydrolase (sEH) (Imig and Hammock, 2009; Newman et al , 2005). Pharmacologic inhibition of sEH stabilizes these bioactive molecules (Spector and Norris, 2007) and small molecule sEH inhibitors (sEHI) have been shown to have significant anti-inflammatory and neuroprotective activity in animal models of pain, inflammation and ischemic stroke (Iliff and Alkayed, 2009; Inceoglu et al , 2008; Wang et al, 2013). In addition, we recently demonstrated that sEHI pretreatment delays the onset of clonic seizures and prevents lethality in NIH Swiss mice exposed to a lethal dose of other GABA A receptor antagonists, including picrotoxin and pentylenetetrazole (PTZ) (Inceoglu et al , 2013).…”

Three-dimensional rational approach to the discovery of potent substituted cyclopropyl urea soluble epoxide hydrolase inhibitors

“…15 In addition, the sEH inhibitor, 4-phenylchalcone oxide (4-PCO) treatment showed significantly reduced neuronal death and improve memory function after cardiac arrest/cardiopulmonary resuscitation. 16 Thus, the effectiveness of EETs and sEH inhibitor for the treatment of central nervous system disorders are expected recently.…”