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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Dyskinesia Agents / chemistry
  • Anti-Dyskinesia Agents / pharmacology*
  • Anti-Dyskinesia Agents / therapeutic use
  • Corpus Striatum / drug effects*
  • Corpus Striatum / pathology
  • Disease Models, Animal
  • Disease Progression
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Agonists / therapeutic use
  • Humans
  • Huntington Disease / drug therapy*
  • Huntington Disease / genetics
  • Huntington Disease / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Phenotype*
  • Receptors, AMPA / agonists*
  • Receptors, AMPA / physiology
  • Treatment Outcome
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology*


  • Anti-Dyskinesia Agents
  • Excitatory Amino Acid Agonists
  • Receptors, AMPA
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid