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Neurobiol Dis. 2011 Feb;41(2):436-44. doi: 10.1016/j.nbd.2010.10.015. Epub 2010 Oct 23.

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

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1
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.

Abstract

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.

PMID:
20977939
PMCID:
PMC3014441
DOI:
10.1016/j.nbd.2010.10.015
[Indexed for MEDLINE]
Free PMC Article
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