title: A small molecule TrkB ligand reduces motor impairment and neuropathology in R6/2 and BACHD mouse models of Huntington's disease.
abstract: 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, 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.
authors.affiliation: 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.
authors.forename: Danielle A
authors.initials: DA
authors.lastname: Simmons
authors.forename: Nadia P
authors.initials: NP
authors.lastname: Belichenko
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.forename: Christina
authors.initials: C
authors.lastname: Condon
authors.forename: Marie
authors.initials: M
authors.lastname: Monbureau
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.forename: Deqiang
authors.initials: D
authors.lastname: Jing
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Massa
authors.forename: Frank M
authors.initials: FM
authors.lastname: Longo
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001549:Benzamides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology; D049229:Dendritic Spines / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009069:Movement Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D004856:Postural Balance / Q000187:drug effects; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020813:Receptor, trkB / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D013534:Survival
chemical_list: D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008024:Ligands; C585903:N,N',N'-tris(2-hydroxyethyl)-1,3,5-benzenetricarboxamide; D009419:Nerve Tissue Proteins; D012313:RNA; D020813:Receptor, trkB