Inhibition of soluble epoxide hydrolase after cardiac arrest/ cardiopulmonary resuscitation induces a neuroprotective phenotype in activated microglia and improves neuronal survival

Jianming Wang, Tetsuhiro Fujiyoshi, Yasuharu Kosaka, Jonathan D. Raybuck, Kennon (Matt) Lattal, Mizuko Ikeda, Paco S. Herson, Ines Koerner

Research output: Contribution to journalArticle

16 Scopus citations

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)- 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.

Original languageEnglish (US)
Pages (from-to)1574-1581
Number of pages8
JournalJournal of Cerebral Blood Flow and Metabolism
Volume33
Issue number10
DOIs
Publication statusPublished - Oct 2013

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Keywords

  • brain injury
  • global ischemia
  • microglia
  • neuroinflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Neurology

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