title: Amitriptyline improves motor function via enhanced neurotrophin signaling and mitochondrial functions in the murine N171-82Q Huntington disease model.
abstract: Huntington 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 (poly(Q)) 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 Food and Drug Administration-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 this 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 preclinical evidence for the therapeutic potency of AMI in treating HD, but it 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.
authors.affiliation: From the Metabolism Unit.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Cong
authors.affiliation: Receptor Pharmacology Unit.
authors.forename: Wayne
authors.initials: W
authors.lastname: Chadwick
authors.affiliation: From the Metabolism Unit.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: From the Metabolism Unit.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Daimon
authors.affiliation: From the Metabolism Unit.
authors.forename: Huan
authors.initials: H
authors.lastname: Cai
authors.affiliation: From the Metabolism Unit.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Amma
authors.affiliation: Gene Expression and Genomics Unit, NIA, National Institutes of Health, Baltimore, Maryland 21224 and.
authors.forename: William H
authors.initials: WH
authors.lastname: Wood
authors.affiliation: Gene Expression and Genomics Unit, NIA, National Institutes of Health, Baltimore, Maryland 21224 and.
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Becker
authors.affiliation: From the Metabolism Unit, bronwenmartin@gmail.com.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.affiliation: Receptor Pharmacology Unit, the VIB Department of Molecular Genetics, Institute Born-Bunge Laboratory of Neurogenetics, University of Antwerp, 2000 Antwerp, Belgium stuart.maudsley@molgen.vib-ua.be.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
mesh_terms: D000639:Amitriptyline / Q000627:therapeutic use*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor; D019295:Computational Biology; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D000639:Amitriptyline
keywords: Amitriptyline; Bioinformatics; Brain-derived Neurotrophic Factor (BDNF); Huntington Disease; Mitochondria; Motor Function; Neurodegenerative Disease; mHTT