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

DA Simmons, RA Mehta, JC Lauterborn, CM Gall… - Neurobiology of …, 2011 - Elsevier
DA Simmons, RA Mehta, JC Lauterborn, CM Gall, G Lynch
Neurobiology of disease, 2011Elsevier
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 4–7weeks, the compound increased protein …
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 4–7weeks, 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.
Elsevier