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

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.

Research Highlights►Spaced ampakine treatments are well tolerated, for weeks, in HD-model mice. ►Ampakine treatments sustain elevated cortical and striatal BDNF levels for weeks. ►Ampakine treatments prevent striatal atrophy and decreased DARPP-32 in HD mice. ►Ampakine treatments eliminate some measures of motor impairment in HD-model mice. ►Results suggest a plausible, non-invasive therapy for Huntington's disease.