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

• Published in: Neurobiology of disease Vol. 41; no. 2; pp. 436 - 444
• Main Authors: Simmons, Danielle A, Mehta, Rishi A, Lauterborn, Julie C, Gall, Christine M, Lynch, Gary
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2011; Elsevier
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; Animals; Anti-Dyskinesia Agents - chemistry; Anti-Dyskinesia Agents - pharmacology; Anti-Dyskinesia Agents - therapeutic use; BDNF; Corpus Striatum - drug effects; Corpus Striatum - pathology; DARPP-32; Disease Models, Animal; Disease Progression; Excitatory Amino Acid Agonists - pharmacology; Excitatory Amino Acid Agonists - therapeutic use; Humans; Huntingtin; Huntington Disease - drug therapy; Huntington Disease - genetics; Huntington Disease - pathology; Male; Mice; Mice, Transgenic; Neurology; Neuropathology; Neurotrophin; Phenotype; Receptors, AMPA - agonists; Receptors, AMPA - physiology; Rotarod; Striatum; Therapeutic; Treatment Outcome; Neurotrophin; Striatum; Rotarod; Huntingtin; BDNF; Neuropathology; Therapeutic; DARPP-32
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2010.10.015

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.