PMID- 24285878
OWN - NLM
STAT- MEDLINE
DCOM- 20140128
LR  - 20240327
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 33
IP  - 48
DP  - 2013 Nov 27
TI  - A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 
      and BACHD mouse models of Huntington's disease.
PG  - 18712-27
LID - 10.1523/JNEUROSCI.1310-13.2013 [doi]
AB  - Loss of neurotrophic support in the striatum caused by reduced brain-derived 
      neurotrophic factor (BDNF) levels plays a critical role in Huntington's disease 
      (HD) pathogenesis. BDNF acts via TrkB and p75 neurotrophin receptors (NTR), and 
      restoring its signaling is a prime target for HD therapeutics. Here we sought to 
      determine whether a small molecule ligand, LM22A-4, specific for TrkB and without 
      effects on p75(NTR), could alleviate HD-related pathology in R6/2 and BACHD mouse 
      models of HD. LM22A-4 was administered to R6/2 mice once daily (5-6 d/week) from 
      4 to 11 weeks of age via intraperitoneal and intranasal routes simultaneously to 
      maximize brain levels. The ligand reached levels in the R6/2 forebrain greater 
      than the maximal neuroprotective dose in vitro and corrected deficits in 
      activation of striatal TrkB and its key signaling intermediates AKT, PLCgamma, and 
      CREB. Ligand-induced TrkB activation was associated with a reduction in HD 
      pathologies in the striatum including decreased DARPP-32 levels, neurite 
      degeneration of parvalbumin-containing interneurons, inflammation, and 
      intranuclear huntingtin aggregates. Aggregates were also reduced in the cortex. 
      Notably, LM22A-4 prevented deficits in dendritic spine density of medium spiny 
      neurons. Moreover, R6/2 mice given LM22A-4 demonstrated improved downward 
      climbing and grip strength compared with those given vehicle, though these groups 
      had comparable rotarod performances and survival times. In BACHD mice, long-term 
      LM22A-4 treatment (6 months) produced similar ameliorative effects. These results 
      support the hypothesis that targeted activation of TrkB inhibits HD-related 
      degenerative mechanisms, including spine loss, and may provide a disease 
      mechanism-directed therapy for HD and other neurodegenerative conditions.
FAU - Simmons, Danielle A
AU  - Simmons DA
AD  - Department of Neurology and Neurological Sciences and Behavioral and Functional 
      Neuroscience Laboratory, Institute for Neuro-Innovation and Translational 
      Neurosciences, Stanford University School of Medicine, Stanford, California 
      94305, Department of Psychiatry, Weill Cornell Medical College, New York, New 
      York 10021, and Department of Neurology and Laboratory for Computational 
      Neurochemistry and Drug Discovery, Department of Veterans Affairs Medical Center 
      and Department of Neurology, University of California, San Francisco, San 
      Francisco, California 94121.
FAU - Belichenko, Nadia P
AU  - Belichenko NP
FAU - Yang, Tao
AU  - Yang T
FAU - Condon, Christina
AU  - Condon C
FAU - Monbureau, Marie
AU  - Monbureau M
FAU - Shamloo, Mehrdad
AU  - Shamloo M
FAU - Jing, Deqiang
AU  - Jing D
FAU - Massa, Stephen M
AU  - Massa SM
FAU - Longo, Frank M
AU  - Longo FM
LA  - eng
GR  - P30 NS069375/NS/NINDS NIH HHS/United States
GR  - R21 NS071024/NS/NINDS NIH HHS/United States
GR  - R21 NS071024-01/NS/NINDS NIH HHS/United States
GR  - P30 NS069375-01A1/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Benzamides)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (HTT protein, human)
RN  - 0 (Huntingtin Protein)
RN  - 0 (Ligands)
RN  - 0 (N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide)
RN  - 0 (Nerve Tissue Proteins)
RN  - 63231-63-0 (RNA)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
EIN - J Neurosci. 2014 Jan 29;34(5):2012
MH  - Animals
MH  - Behavior, Animal/drug effects/physiology
MH  - Benzamides/pharmacokinetics/*therapeutic use
MH  - Blotting, Western
MH  - Body Weight/drug effects
MH  - Brain-Derived Neurotrophic Factor/physiology
MH  - Dendritic Spines/physiology
MH  - Humans
MH  - Huntingtin Protein
MH  - Huntington Disease/*drug therapy/pathology/physiopathology
MH  - Immunohistochemistry
MH  - Ligands
MH  - Male
MH  - Mice
MH  - Mice, Neurologic Mutants
MH  - Mice, Transgenic
MH  - Movement Disorders/*drug therapy/pathology/physiopathology
MH  - Nerve Tissue Proteins/metabolism
MH  - Postural Balance/drug effects
MH  - RNA/biosynthesis/genetics
MH  - Real-Time Polymerase Chain Reaction
MH  - Receptor, trkB/*drug effects/physiology
MH  - Signal Transduction/drug effects
MH  - Survival
PMC - PMC3841443
EDAT- 2013/11/29 06:00
MHDA- 2014/01/29 06:00
PMCR- 2014/05/27
CRDT- 2013/11/29 06:00
PHST- 2013/11/29 06:00 [entrez]
PHST- 2013/11/29 06:00 [pubmed]
PHST- 2014/01/29 06:00 [medline]
PHST- 2014/05/27 00:00 [pmc-release]
AID - 33/48/18712 [pii]
AID - 1310-13 [pii]
AID - 10.1523/JNEUROSCI.1310-13.2013 [doi]
PST - ppublish
SO  - J Neurosci. 2013 Nov 27;33(48):18712-27. doi: 10.1523/JNEUROSCI.1310-13.2013.