title: Antihypertensive drug guanabenz is active in vivo against both yeast and mammalian prions.
abstract: BACKGROUND
  Prion-based diseases are incurable transmissible neurodegenerative disorders affecting animals and humans.
  
  
  RESULTS
  Here we report the discovery of the in vivo antiprion activity of Guanabenz (GA), an agonist of alpha2-adrenergic receptors routinely used in human medicine as an antihypertensive drug. We isolated GA in a screen for drugs active in vivo against two different yeast prions using a previously described yeast-based two steps assay. GA was then shown to promote ovine PrP(Sc) clearance in a cell-based assay. These effects are very specific as evidenced by the lack of activity of some GA analogues that we generated. GA antiprion activity does not involve its agonist activity on alpha2-adrenergic receptors as other chemically close anti-hypertensive agents possessing related mechanism of action were found inactive against prions. Finally, GA showed activity in a transgenic mouse-based in vivo assay for ovine prion propagation, prolonging slightly but significantly the survival of treated animals.
  
  
  CONCLUSIONS
  GA thus adds to the short list of compounds active in vivo in animal models for the treatment of prion-based diseases. Because it has been administrated for many years to treat hypertension on a daily basis, without major side-effects, our results suggest that it could be evaluated in human as a potential treatment for prion-based diseases.
authors.affiliation: INSERM U613, Brest, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Tribouillard-Tanvier
authors.forename: Vincent
authors.initials: V
authors.lastname: Béringue
authors.forename: Nathalie
authors.initials: N
authors.lastname: Desban
authors.forename: Fabienne
authors.initials: F
authors.lastname: Gug
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bach
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisset
authors.forename: Hervé
authors.initials: H
authors.lastname: Galons
authors.forename: Hubert
authors.initials: H
authors.lastname: Laude
authors.forename: Didier
authors.initials: D
authors.lastname: Vilette
authors.forename: Marc
authors.initials: M
authors.lastname: Blondel
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004195:Disease Models, Animal; D006143:Guanabenz / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy; D011328:Prions / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D012756:Sheep; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D015996:Survival Rate; D013619:Tacrine / Q000494:pharmacology
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D000959:Antihypertensive Agents; D018620:PrPSc Proteins; D011328:Prions; D013619:Tacrine; D006143:Guanabenz