NR AWID
AU Korth,C.; Klingenstein,R.; Stitz,L.
TI An antiprion cocktail against Creutzfeldt-Jakob disease
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions THE-08
PT Konferenz-Poster
AB Creutzfeldt-Jakob disease and other human or animal prion diseases have lacked an efficient pharmacotherapy so far. Although highly effective in the ScN2a cell model of prion disease, heterocyclic compound quinacrine has shown ambigous or insufficient power in in vivo experiments. Here, we present data on improved pharmacological options for prion diseases, particularly for patients with Creutzfeldt-Jakob disease. Combination therapies have been successful clinical strategies in infectious diseases like tuberculosis or AIDS. An antiprion cocktail of several blood-brain barrier-permeable pharmaceuticals already in clinical use was tested for antiprion activity in vitro and in vivo. In the ScN2a cell model, the tricyclic antidepressants or iminodibenzyl derivatives like clomipramine showed a clear structure-activity relationship for antiprion effects that were additive to those of quinacrine. We found that the mechanism of action of these heterocyclic compounds can sufficiently be explained with a redistribution of cholesterol from the plasma membrane into intracellular compartments, thereby destabilizing conversion-mandatory lipid rafts. Adding another drug alterning cellular lipid metabolism, HMG-CoA reductase inhibitor simvastatin to quinacrine and clomipramine proved to be a highly efficient cocktail with synergistic antiprion effects. When such a cocktail was administered orally to mice of the fast-replicating tg20 mouse strain that had been inoculated with RML prion several weeks before, a significant delay of incubation time was observed compared to mock treated controls. We thus could significantly improve a pharmacotherapeutical regimen for treating prion disease and propose such a combination therapy for treating patients with Creutzfeldt-Jakob disease.
AD C. Korth, R. Klingenstein: Institute for Neuropathology, University of Düsseldorf, Düsseldorf, Germany; L. Stitz: Friedrich Löffler Institute, Tübingen, Germany
SP englisch
PO Italien