@entity3645 reduce prion conversion, reduce @entity528 , and prolong male survival in models of XXXX .

@entity1 @entity15204 @entity13805 @entity2835 @entity19 @entity5219 @entity16689 @entity409 @entity2033 @entity191 @entity1579 @entity3669 @entity18253 @entity179 @entity76 @entity746 @entity3645 @entity528 @entity10055
UNASSIGNED: Prion diseases are @entity179 associated with the conversion of cellular prion protein ( @entity3669 ) into its aberrant infectious form ( @entity3669 (Sc)). There is no treatment available for these diseases. The bile acids @entity13805 ( @entity13805 ) and @entity10055 ( @entity18253 ) have been recently shown to be neuroprotective in other protein misfolding disease models including @entity191 , @entity2033 , and also in @entity1 with @entity746 ( @entity746 ). Here we studied the therapeutic efficacy of these compounds in @entity1579 . We demonstrated that @entity13805 and @entity18253 substantially reduced @entity3669 conversion in cell-free aggregation assays as well as in chronically and acutely infected cell cultures. This effect was mediated through reduction of @entity3669 (Sc) seeding ability, rather than an effect on @entity3669 . We also demonstrated the ability of @entity13805 and @entity18253 to reduce @entity528 in prion @entity76 . @entity18253 treatment reduced @entity5219 and prolonged survival in RML prion-infected @entity19 . Interestingly, these effects were limited to the males, implying a gender-specific difference in drug metabolism. Beyond effects on @entity3669 (Sc), we found that levels of phosphorylated @entity15204 were increased at early time points, with correlated reductions in @entity16689 . As demonstrated for other @entity179 , we now show that @entity13805 and @entity18253 may have a therapeutic role in @entity1579 , with effects on both prion conversion and neuroprotection. Our findings, together with the fact that these natural compounds are orally bioavailable, permeable to the blood-brain barrier and FDA-approved for use in @entity1 , make these compounds promising alternatives for the treatment of @entity1579 . IMPORTANCE: Prion diseases are @entity179 that are transmissible to @entity1 and other mammals. There are no disease-modifying therapies available, despite decades of research. Treatment targets have included @entity409 , clearance of toxic aggregates, and prevention of downstream neurodegeneration. No one target may be sufficient; rather, compounds which have a multi-modal mechanism, acting on different targets, would be ideal. @entity13805 and @entity18253 are @entity3645 that may fulfill this dual role; previous studies have demonstrated their neuroprotective effects in several @entity179 models, and we now demonstrate that this effect occurs in @entity1579 , with an added mechanistic target of upstream prion seeding. Importantly, these are natural compounds which are orally bioavailable, permeable to the blood-brain barrier and FDA-approved for use in @entity1 with @entity2835 . They have recently been proven efficacious in @entity1 @entity746 . Therefore, these compounds are promising options for the treatment of @entity1579 .
