title: Therapeutic activity of inhibition of the soluble epoxide hydrolase in a mouse model of scrapie.
abstract: OBJECTIVE
  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 (PrP(sc)) of the cellular prion protein (PrP(c)). 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.
  
  
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Veterinary Science and Public Health, Faculty of Veterinary Medicine, University of Milan, Milan, Italy.
authors: Giorgio
authors: G
authors: Poli
authors: Erica
authors: E
authors: Corda
authors: Piera Anna
authors: PA
authors: Martino
authors: Paola
authors: P
authors: Dall'ara
authors: Silvio R
authors: SR
authors: Bareggi
authors: Giampietro
authors: G
authors: Bondiolotti
authors: Barbara
authors: B
authors: Iulini
authors: Maria
authors: M
authors: Mazza
authors: Cristina
authors: C
authors: Casalone
authors: Sung Hee
authors: SH
authors: Hwang
authors: Bruce D
authors: BD
authors: Hammock
authors: Bora
authors: B
authors: Inceoglu
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use; D015153:Blotting, Western; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D051379:Mice; D011328:Prions / Q000008:administration & dosage / Q000187:drug effects; D012608:Scrapie / Q000188:drug therapy* / Q000473:pathology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C524106:4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid; D001565:Benzoates; D011328:Prions; D014508:Urea; D004851:Epoxide Hydrolases
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