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

Danielle A. Simmons; Rishi A. Mehta; Julie C. Lauterborn; Christine M. Gall; Gary Lynch

Neurobiology of Disease (Feb 2011)

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

Danielle A. Simmons,
Rishi A. Mehta,
Julie C. Lauterborn,
Christine M. Gall,
Gary Lynch

Affiliations

Danielle A. Simmons: Department of Psychiatry and Human Behavior, University of California, Irvine, CA, 92697, USA
Rishi A. Mehta: Department of Psychiatry and Human Behavior, University of California, Irvine, CA, 92697, USA
Julie C. Lauterborn: Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA
Christine M. Gall: Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA; Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA; Corresponding author. Department of Anatomy and Neurobiology, Gillespie Neuroscience Research Facility, 837 Health Science Road, University of California at Irvine, Irvine, CA 92697-4291, USA. Fax: +1 949 824 1255.
Gary Lynch: Department of Psychiatry and Human Behavior, University of California, Irvine, CA, 92697, USA; Department of Anatomy and Neurobiology, University of California, Irvine, CA, 92697, USA

Journal volume & issue: Vol. 41, no. 2
pp. 436 – 444

Abstract

Read online

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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

About the journal

Abstract

Keywords