Amitriptyline improves motor function in the N171-82Q model of Huntington's disease by protecting brain neurometabolic function

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 389-405-Signaling Originating from Membrane Receptors
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-402
Weina Cong*1, Caitlin M Daimon1, Huan Cai1, Rui Wang1, Jennifer Amma1, Kevin G Becker1, William H Wood III1, Yongqing Zhang1, Stuart Maudsley1, Bronwen Martin1 and Josephine Mary Egan2
1National Institute on Aging, Baltimore, MD, 2NIA/NIH, Baltimore, MD
Huntington’s disease (HD) is a neurodegenerative disorder characterized by progressive motor impairment and cognitive alterations. It is also becoming evident that numerous neurometabolic alterations also occur in HD. HD is caused by the expansion of a CAG trinucleotide repeat in the Huntingtin (Htt) gene, which results in the production of a mutant huntingtin (mHTT) protein with an expanded N-terminal polyglutamine (PolyQ) tract. mHTT aberrantly aggregates, blocking intracellular trafficking and significantly disrupts neurometabolic functions including: reduced brain-derived neurotrophic factor (BDNF) levels; impaired neurotrophin pathway signaling and altered mitochondrial function. Therapeutics that target both the neurodegenerative and metabolic aspects of HD may be more efficacious therapeutic treatments for HD than those solely targeting neurodegeneration. In this study, we tested the well-tolerated, FDA-approved, anti-depressant drug, Amitriptyline (AMI), to determine whether it could improve health and motor function in HD mice. AMI has been previously shown to increase BDNF levels and improve neurotrophin signaling in both in vitro and in vivo models. HD mice were treated with AMI for eight weeks, and motor function and neurometabolic function were assessed. We found that AMI treatment significantly improved motor function and mechanistic analyses revealed that the beneficial actions elicited by AMI could be attributed to its neurometabolic-supporting action, which involved attenuated mHTT aggregation, improved BDNF signaling and support of mitochondrial protein expression. Our study not only provides important pre-clinical evidence for the therapeutic potency of AMI in treating HD, but also offers an example to appreciate a new drug-development strategy, which is focused on studying FDA approved drugs in novel pharmacological disease contexts.

Nothing to Disclose: WC, CMD, HC, RW, JA, KGB, WHW, YZ, SM, BM, JME

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging.