BACKGROUND: Huntington's disease (HD) is a dominantly inherited neurodegenerative condition characterized by dysfunction in striatal and cortical neurons. There are currently no approved drugs known to slow the progression of HD. OBJECTIVE: To facilitate the development of therapies for HD, we identified approved drugs that can ameliorate mutant huntingtin-induced toxicity in experimental models of HD. METHODS: A chemical screen was performed in a mouse Hdh(Q111/Q111) striatal cell model of HD. This screen identified a set of structurally related approved drugs (pizotifen, cyproheptadine, and loxapine) that rescued cell death in this model. Pizotifen was subsequently evaluated in the R6/2 HD mouse model. RESULTS: We found that in striatal Hdh(Q111/Q111) cells, pizotifen treatment caused transient ERK activation and inhibition of ERK activation prevented rescue of cell death in this model. In the R6/2 HD mouse model, treatment with pizotifen activated ERK in the striatum, reduced neurodegeneration and significantly enhanced motor performance. CONCLUSIONS: These results suggest that pizotifen and related approved drugs may provide a basis for developing disease modifying therapeutic interventions for HD.
BACKGROUND:Huntington's disease (HD) is a dominantly inherited neurodegenerative condition characterized by dysfunction in striatal and cortical neurons. There are currently no approved drugs known to slow the progression of HD. OBJECTIVE: To facilitate the development of therapies for HD, we identified approved drugs that can ameliorate mutant huntingtin-induced toxicity in experimental models of HD. METHODS: A chemical screen was performed in a mouseHdh(Q111/Q111) striatal cell model of HD. This screen identified a set of structurally related approved drugs (pizotifen, cyproheptadine, and loxapine) that rescued cell death in this model. Pizotifen was subsequently evaluated in the R6/2 HDmouse model. RESULTS: We found that in striatal Hdh(Q111/Q111) cells, pizotifen treatment caused transient ERK activation and inhibition of ERK activation prevented rescue of cell death in this model. In the R6/2 HDmouse model, treatment with pizotifen activated ERK in the striatum, reduced neurodegeneration and significantly enhanced motor performance. CONCLUSIONS: These results suggest that pizotifen and related approved drugs may provide a basis for developing disease modifying therapeutic interventions for HD.
Authors: D W Bonhaus; K K Weinhardt; M Taylor; A DeSouza; P M McNeeley; K Szczepanski; D J Fontana; J Trinh; C L Rocha; M W Dawson; L A Flippin; R M Eglen Journal: Neuropharmacology Date: 1997 Apr-May Impact factor: 5.250
Authors: Barbara L Apostol; Katalin Illes; Judit Pallos; Laszlo Bodai; Jun Wu; Andrew Strand; Erik S Schweitzer; James M Olson; Aleksey Kazantsev; J Lawrence Marsh; Leslie Michels Thompson Journal: Hum Mol Genet Date: 2005-12-05 Impact factor: 6.150
Authors: L Djoussé; B Knowlton; M Hayden; E W Almqvist; R Brinkman; C Ross; R Margolis; A Rosenblatt; A Durr; C Dode; P J Morrison; A Novelletto; M Frontali; R J A Trent; E McCusker; E Gómez-Tortosa; D Mayo; R Jones; A Zanko; M Nance; R Abramson; O Suchowersky; J Paulsen; M Harrison; Q Yang; L A Cupples; J F Gusella; M E MacDonald; R H Myers Journal: Am J Med Genet A Date: 2003-06-15 Impact factor: 2.802
Authors: Leila Pirhaji; Pamela Milani; Simona Dalin; Brook T Wassie; Denise E Dunn; Robert J Fenster; Julian Avila-Pacheco; Paul Greengard; Clary B Clish; Myriam Heiman; Donald C Lo; Ernest Fraenkel Journal: Nat Commun Date: 2017-09-20 Impact factor: 14.919