PMID- 25505248
OWN - NLM
STAT- MEDLINE
DCOM- 20150415
LR  - 20210205
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 290
IP  - 5
DP  - 2015 Jan 30
TI  - Amitriptyline improves motor function via enhanced neurotrophin signaling and 
      mitochondrial functions in the murine N171-82Q Huntington disease model.
PG  - 2728-43
LID - 10.1074/jbc.M114.588608 [doi]
AB  - 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.
CI  - (c) 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
FAU - Cong, Wei-Na
AU  - Cong WN
AD  - From the Metabolism Unit.
FAU - Chadwick, Wayne
AU  - Chadwick W
AD  - Receptor Pharmacology Unit.
FAU - Wang, Rui
AU  - Wang R
AD  - From the Metabolism Unit.
FAU - Daimon, Caitlin M
AU  - Daimon CM
AD  - From the Metabolism Unit.
FAU - Cai, Huan
AU  - Cai H
AD  - From the Metabolism Unit.
FAU - Amma, Jennifer
AU  - Amma J
AD  - From the Metabolism Unit.
FAU - Wood, William H 3rd
AU  - Wood WH 3rd
AD  - Gene Expression and Genomics Unit, NIA, National Institutes of Health, Baltimore, 
      Maryland 21224 and.
FAU - Becker, Kevin G
AU  - Becker KG
AD  - Gene Expression and Genomics Unit, NIA, National Institutes of Health, Baltimore, 
      Maryland 21224 and.
FAU - Martin, Bronwen
AU  - Martin B
AD  - From the Metabolism Unit, bronwenmartin@gmail.com.
FAU - Maudsley, Stuart
AU  - Maudsley S
AD  - 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.
LA  - eng
GR  - Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20141211
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Nerve Growth Factors)
RN  - 1806D8D52K (Amitriptyline)
SB  - IM
MH  - Amitriptyline/*therapeutic use
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor
MH  - Computational Biology
MH  - Disease Models, Animal
MH  - Female
MH  - Huntington Disease/*drug therapy/metabolism/*physiopathology
MH  - Male
MH  - Mice
MH  - Mitochondria/drug effects/*metabolism
MH  - Nerve Growth Factors/*metabolism
PMC - PMC4317004
OTO - NOTNLM
OT  - Amitriptyline
OT  - Bioinformatics
OT  - Brain-derived Neurotrophic Factor (BDNF)
OT  - Huntington Disease
OT  - Mitochondria
OT  - Motor Function
OT  - Neurodegenerative Disease
OT  - mHTT
EDAT- 2014/12/17 06:00
MHDA- 2015/04/16 06:00
PMCR- 2016/01/30
CRDT- 2014/12/16 06:00
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2015/04/16 06:00 [medline]
PHST- 2016/01/30 00:00 [pmc-release]
AID - S0021-9258(20)49247-6 [pii]
AID - M114.588608 [pii]
AID - 10.1074/jbc.M114.588608 [doi]
PST - ppublish
SO  - J Biol Chem. 2015 Jan 30;290(5):2728-43. doi: 10.1074/jbc.M114.588608. Epub 2014 
      Dec 11.