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

被引：26

作者：

Sarantos, Melissa R. ^{[1
]}

Papanikolaou, Theodora ^{[1
]}

Ellerby, Lisa M. ^{[1
]}

Hughes, Robert E. ^{[1
]}

机构：

[1] Buck Inst Res Aging, 8001 Redwood Blvd, Novato, CA 94945 USA

来源：

JOURNAL OF HUNTINGTONS DISEASE | 2012年 / 1卷 / 02期

关键词：

Huntington's disease; Drug screening; Pizotifen; ERK Pathway; R6/2 HD mouse model;

D O I：

10.3233/JHD-120033

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：195 / 210

页数：16

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