Therapeutic activity of inhibition of the soluble epoxide hydrolase in a mouse model of scrapie

Giorgio Poli, Erica Corda, Piera Anna Martino, Paola Dall'Ara, Silvio R. Bareggi, Giampietro Bondiolotti, Barbara Iulini, Maria Mazza, Cristina Casalone, Sung Hee Hwang, Bruce D. Hammock, Bora Inceoglu

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Aims The misfolding and the aggregation of specific proteins are key features of neurodegenerative diseases, specifically Transmissible Spongiform Encephalopathies (TSEs). In TSEs, neuronal loss and inflammation are associated with the accumulation of the misfolded isoform (PrPsc) of the cellular prion protein (PrPc). Therefore we tested the hypothesis that augmenting a natural anti-inflammatory pathway mediated by epoxygenated fatty acids (EpFAs) will delay lethality. EpFAs are highly potent but enzymatically labile molecules produced by the actions of a number of cytochrome P450 enzymes. Stabilization of these bioactive lipids by inhibiting their degradation mediated by the soluble epoxide hydrolase (sEH) results in potent anti-inflammatory effects in multiple disease models. Main methods Mice were infected with the mouse-adapted RML strain of scrapie by intracerebral or intraperitoneal routes. Animals received the sEH inhibitor, by oral route, administrated in drinking water or vehicle (PEG400). Infected mice were euthanized at a standard clinical end point. Histopathological, immunohistochemical and Western blot analyses of brain tissue confirmed the presence of pathology related to prion infection. Key findings Oral administration of the sEHI did not affect the very short survival time of the intracerebral prion infection group. However, mice infected by intraperitoneal route and treated with t-AUCB survived significantly longer than the control group mice (p < 0.001). Significance These findings support the idea that inhibition of sEH or augmentation of the natural EpFA signaling in the brain offers a potential and different route to understand prion diseases and may become a therapeutic strategy for diseases involving neuroinflammation.

Original languageEnglish (US)
Pages (from-to)1145-1150
Number of pages6
JournalLife Sciences
Volume92
Issue number23
DOIs
StatePublished - Jun 21 2013

Keywords

  • EET
  • Epoxy fatty acid
  • Inflammation
  • Inhibitor
  • Neuroinflammation
  • Prion
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Poli, G., Corda, E., Martino, P. A., Dall'Ara, P., Bareggi, S. R., Bondiolotti, G., Iulini, B., Mazza, M., Casalone, C., Hwang, S. H., Hammock, B. D., & Inceoglu, B. (2013). Therapeutic activity of inhibition of the soluble epoxide hydrolase in a mouse model of scrapie. Life Sciences, 92(23), 1145-1150. https://doi.org/10.1016/j.lfs.2013.04.014