Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington’s Disease Model [Molecular Bases of Disease]

December 11th, 2014 by Cong, W.-N., Chadwick, W., Wang, R., Daimon, C. M., Cai, H., Amma, J., Wood, W. H., Becker, K. G., Martin, B., Maudsley, S.

Huntington′s disease (HD) is a neurodegenerative disorder characterized by progressive motor impairment and cognitive alterations. Hereditary HD is primarily caused by the expansion of a CAG trinucleotide repeat in the Huntingtin (Htt) gene, which results in the production of mutant huntingtin protein (mHtt) with an expanded amino-terminal polyglutamine (PolyQ) stretch. Besides pathological mHtt aggregation, reduced brain-derived neurotrophic factor (BDNF) levels, impaired neurotrophin signaling and compromised mitochondrial functions also contribute to the deleterious progressive etiology of HD. As a well-tolerated, FDA approved antidepressant, Amitriptyline (AMI) has shown efficacy in treating neurodegenerative murine models via potentiation of BDNF levels and amelioration of alterations in neurotrophin signaling pathways. In the present study, we observed profound improvements in the motor coordination of AMI-treated N171-82Q HD model mice. The beneficial effects of AMI treatment were associated with its ability to reduce mHtt aggregation, potentiation of the BDNF-TrkB signaling system and support of mitochondrial integrity and functionality. Our study not only provides pre-clinical evidence for the therapeutic potency of AMI in treating HD, but also represents an important example of the usefulness of additional pharmacogenomic profiling of pre-existing drugs for novel therapeutic effects with often intractable pathological scenarios.
  • Posted in Journal of Biological Chemistry, Publications
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