Antihypertensive drug guanabenz is active in vivo against both yeast and mammalian prions.
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.
Tribouillard-Tanvier
Déborah
D
INSERM U613, Brest, France.
Béringue
Vincent
V
Desban
Nathalie
N
Gug
Fabienne
F
Bach
Stéphane
S
Voisset
Cécile
C
Galons
Hervé
H
Laude
Hubert
H
Vilette
Didier
D
Blondel
Marc
M
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
D058647:Adrenergic alpha-2 Receptor Agonists; D000959:Antihypertensive Agents; D018620:PrPSc Proteins; D011328:Prions; D013619:Tacrine; D006143:Guanabenz