Brief ampakine treatments slow the progression of Huntington's disease phenotypes in R6/2 mice

NEUROBIOLOGY OF DISEASE

卷:41

Article

Simmons, Danielle A.³  Mehta, Rishi A.³  Gall, Christine M.^1,2  Lynch, Gary³ 

[1] Univ Calif Irvine, Dept Anat & Neurobiol, Gillespie Neurosci Res Facil, Irvine, CA 92697 USA

[2] Univ Calif Irvine, Dept Neurobiol & Behav, Irvine, CA 92697 USA

[3] Univ Calif Irvine, Dept Psychiat & Human Behav, Irvine, CA 92697 USA

关键词: Therapeutic;    DARPP-32;    Rotarod;    Huntingtin;    BDNF;    Neurotrophin;    Striatum;    Neuropathology;   

DOI  :  10.1016/j.nbd.2010.10.015

来源: Elsevier

【 摘 要 】

Daily, systemic injections of a positive AMPA-type glutamate receptor modulator (ampakine) have been shown to reduce synaptic plasticity defects in rodent models of aging and early-stage Huntington's disease (HD). Here we report that long-term ampakine treatment markedly slows the progression of striatal neuropathology and locomotor dysfunction in the R6/2 HD mouse model. Remarkably, these effects were produced by an ampakine. CX929, with a short half-life. Injected once daily for 4-7 weeks, the compound increased protein levels of brain-derived neurotrophic factor (BDNF) in the neocortex and striatum of R6/2 but not wild-type mice. Moreover, ampakine treatments prevented the decrease in total striatal area, blocked the loss of striatal DARPP-32 immunoreactivity and reduced by 36% the size of intra-nuclear huntingtin aggregates in R6/2 striatum. The CX929 treatments also markedly improved motor performance of R6/2 mice on several measures (rotarod. vertical pole descent) but did not influence body weight or lifespan. These findings describe a minimally invasive, pharmacologically plausible strategy for treatment of HD and, potentially, other neuropathological diseases. (C) 2010 Elsevier Inc. All rights reserved.

【 授权许可】

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