PT  - JOURNAL ARTICLE
AU  - Simmons, Danielle A.
AU  - Belichenko, Nadia P.
AU  - Yang, Tao
AU  - Condon, Christina
AU  - Monbureau, Marie
AU  - Shamloo, Mehrdad
AU  - Jing, Deqiang
AU  - Massa, Stephen M.
AU  - Longo, Frank M.
TI  - A Small Molecule TrkB Ligand Reduces Motor Impairment and Neuropathology in R6/2 and BACHD Mouse Models of Huntington's Disease
AID  - 10.1523/JNEUROSCI.1310-13.2013
DP  - 2013 Nov 27
TA  - The Journal of Neuroscience
PG  - 18712--18727
VI  - 33
IP  - 48
4099  - http://www.jneurosci.org/content/33/48/18712.short
4100  - http://www.jneurosci.org/content/33/48/18712.full
SO  - J. Neurosci.2013 Nov 27; 33
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 p75NTR, 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, PLCγ, 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.