Pizotifen Activates ERK and Provides Neuroprotection in vitro and in vivo in Models of Huntington's Disease.
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Sarantos MR, Papanikolaou T, Ellerby LM, Hughes RE
Pizotifen Activates ERK and Provides Neuroprotection in vitro and in vivo in Models of Huntington's Disease.
J Huntingtons Dis. 2012;1(2):195-210. doi: 10.3233/JHD-120033.
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- 23393546 [ View in PubMed]
- Abstract
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.
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