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Pizotifen Activates ERK and Provides Neuroprotection in vitro and in vivo in Models of Huntington's Disease

Article type: Research Article

Authors: Sarantos, Melissa R. | Papanikolaou, Theodora | Ellerby, Lisa M. | Hughes, Robert E.

Affiliations: The Buck Institute for Research on Aging, Novato, CA, USA

Note: [] The two first authors contributed equally.

Note: [] The two first authors contributed equally.

Note: [] Correspondence to: Lisa M. Ellerby, Tel.: +1 415 209 2088; Fax: +1 415 209 2230; E-mail: [email protected]

Note: [] Correspondence to: Robert E. Hughes, The Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA 94945, USA. Tel.: +1 415 209 2069; Fax: +1 415 209 2235; Email: [email protected]

Keywords: Huntington's disease, Drug screening, Pizotifen, ERK Pathway, R6/2 HD mouse model

DOI: 10.3233/JHD-120033

Journal: Journal of Huntington's Disease, vol. 1, no. 2, pp. 195-210, 2012

Published: 2012
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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 HdhQ111/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 HdhQ111/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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