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 (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. 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.
Subject(s)
Epoxide Hydrolases/antagonists & inhibitors , Scrapie/drug therapy , Animals , Benzoates/pharmacology , Benzoates/therapeutic use , Blotting, Western , Brain/pathology , Disease Models, Animal , Disease Progression , Epoxide Hydrolases/physiology , Female , Injections, Intraperitoneal , Injections, Intraventricular , Mice , Prions/administration & dosage , Prions/drug effects , Scrapie/pathology , Urea/analogs & derivatives , Urea/pharmacology , Urea/therapeutic useABSTRACT
L112 and FF45 are two polyglucosamines with similar characteristics and molecular weights. Three groups of 15 young male rats each were fed a standard diet or a diet containing 2% L112 or FF45 for 4 weeks, and we measured their body weight; water and food intake; triglyceride and total, low-density lypoproteins (LDL) and high-density lypoproteins (HDL) cholesterol levels; and the amount of feces and fecal water and lipid concentrations. The results showed that both L112 and FF45 reduced the increase in body weight in comparison with controls (respectively 152+/-18.7 g and 155+/-18.7 g vs 166+/-18.1 g; ANOVA P<0.05). Total food intake during the study period was significantly greater in the animals treated with L112 or FF45 (respectively 780+/-49.9 g and 787+/-61.7 g vs 742+/-53.0 g), with a significant loss of "food efficiency". Water intake was similar in all three groups. There was no significant change in plasma lipid profiles in any of the groups except for a significant decrease in HDL cholesterol in the animals treated with L112. Twenty-four-hour fecal weight was 7.8+/-1.70 g in the controls, 10.1+/-1.98 g in the rats treated with L112, and 9.0+/-1.21 g in those treated with FF45 (Dunnet's test vs controls: P<0.05). Fecal lipid and water concentrations were significantly higher in the polyglucosamine-treated groups (P<0.05 Dunnet's test).
