PMID- 23446639
OWN - NLM
STAT- MEDLINE
DCOM- 20131231
LR  - 20211021
IS  - 1460-2083 (Electronic)
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 22
IP  - 12
DP  - 2013 Jun 15
TI  - Small-molecule TrkB receptor agonists improve motor function and extend survival 
      in a mouse model of Huntington's disease.
PG  - 2462-70
LID - 10.1093/hmg/ddt098 [doi]
AB  - Huntington's disease (HD) is a fatal neurodegenerative disease characterized by 
      abnormal motor coordination, cognitive decline and psychiatric disorders. This 
      disease is caused by an expanded CAG trinucleotide repeat in the gene encoding 
      the protein huntingtin. Reduced levels of brain-derived neurotrophic factor 
      (BDNF) in the brain, which results from transcriptional inhibition and axonal 
      transport deficits mediated by mutant huntingtin, have been suggested as critical 
      factors underlying selective neurodegeneration in both HD patients and HD mouse 
      models. BDNF activates its high-affinity receptor TrkB and promotes neuronal 
      survival; restoring BDNF signaling is thus of particular therapeutic interest. In 
      the present study, we evaluated the ability of a small-molecule TrkB agonist 
      7,8-dihydroxyflavone (7,8-DHF) and its synthetic derivative 4'-dimethylamino-7,8- 
      dihydroxyflavone (4'-DMA-7,8-DHF) to protect neurons in the well-characterized 
      N171-82Q HD mouse model. We found that chronic administration of 7, 8-DHF (5 
      mg/kg) or 4'-DMA-7,8-DHF (1 mg/kg) significantly improved motor deficits, 
      ameliorated brain atrophy and extended survival in these N171-82Q HD mice. 
      Moreover, 4'-DMA-7,8-DHF preserved DARPP32 levels in the striatum and rescued 
      mutant huntingtin-induced impairment of neurogenesis in the N171-82Q HD mice. 
      These data highlight consideration of TrkB as a therapeutic target in HD and 
      suggest that small-molecule TrkB agonists that penetrate the brain have high 
      potential to be further tested in clinical trials of HD.
FAU - Jiang, Mali
AU  - Jiang M
AD  - Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns 
      Hopkins University School of Medicine, Baltimore, MD 21287, USA.
FAU - Peng, Qi
AU  - Peng Q
FAU - Liu, Xia
AU  - Liu X
FAU - Jin, Jing
AU  - Jin J
FAU - Hou, Zhipeng
AU  - Hou Z
FAU - Zhang, Jiangyang
AU  - Zhang J
FAU - Mori, Susumu
AU  - Mori S
FAU - Ross, Christopher A
AU  - Ross CA
FAU - Ye, Keqiang
AU  - Ye K
FAU - Duan, Wenzhen
AU  - Duan W
LA  - eng
GR  - P30 DK079637/DK/NIDDK NIH HHS/United States
GR  - NS074196/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130227
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (6,7-dihydroxyflavone)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Flavones)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/metabolism
MH  - Disease Models, Animal
MH  - Female
MH  - Flavones/*administration & dosage
MH  - Humans
MH  - Huntington Disease/*drug therapy/genetics/metabolism/*mortality
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - Motor Activity/drug effects
MH  - Neurons/drug effects/metabolism
MH  - Receptor, trkB/*agonists/genetics/metabolism
MH  - Signal Transduction/drug effects
MH  - Survival
PMC - PMC3658168
EDAT- 2013/03/01 06:00
MHDA- 2014/01/01 06:00
PMCR- 2014/06/15
CRDT- 2013/03/01 06:00
PHST- 2013/03/01 06:00 [entrez]
PHST- 2013/03/01 06:00 [pubmed]
PHST- 2014/01/01 06:00 [medline]
PHST- 2014/06/15 00:00 [pmc-release]
AID - ddt098 [pii]
AID - 10.1093/hmg/ddt098 [doi]
PST - ppublish
SO  - Hum Mol Genet. 2013 Jun 15;22(12):2462-70. doi: 10.1093/hmg/ddt098. Epub 2013 Feb 
      27.