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.
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697, USA.
Danielle A
DA
Simmons
Rishi A
RA
Mehta
Julie C
JC
Lauterborn
Christine M
CM
Gall
Gary
G
Lynch
D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D018091:Receptors, AMPA / Q000819:agonists* / Q000502:physiology; D016896:Treatment Outcome; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology*
D018726:Anti-Dyskinesia Agents; D018690:Excitatory Amino Acid Agonists; D018091:Receptors, AMPA; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid