title: LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington's Disease.
abstract: Modulation of gene transcription by HDAC inhibitors has been shown repeatedly to be neuroprotective in cellular, invertebrate, and rodent models of Huntington's disease (HD). It has been difficult to translate these treatments to the clinic, however, because existing compounds have limited potency or brain bioavailability.
  
  
  
  In the present study, we assessed the therapeutic potential of LBH589, an orally bioavailable hydroxamic acid-derived nonselective HDAC inhibitor in mouse models of HD.
  
  
  
  The efficacy of LBH589 is tested in two HD mouse models using various biochemical, behavioral and neuropathological outcome measures.
  
  
  
  We show that LBH589 crosses the blood brain barrier; induces histone hyperacetylation and prevents striatal neuronal shrinkage in R6/2 HD mice. In full-length knock-in HD mice LBH589-treatment improves motor performance and reduces neuronal atrophy.
  
  
  
  Our efficacious results of LBH589 in fragment and full-length mouse models of HD suggest that LBH589 is a promising candidate for clinical assessment in HD patients and provides confirmation that non-selective HDAC inhibitors can be viable clinical candidates.
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Vanita
authors.initials: V
authors.lastname: Chopra
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Luisa
authors.initials: L
authors.lastname: Quinti
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Prarthana
authors.initials: P
authors.lastname: Khanna
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Paganetti
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kuhn
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Anne B
authors.initials: AB
authors.lastname: Young
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Aleksey G
authors.initials: AG
authors.lastname: Kazantsev
authors.affiliation: Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Hersch
mesh_terms: D000818:Animals; D001284:Atrophy / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D006877:Hydroxamic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D007211:Indoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000077767:Panobinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D007211:Indoles; D018696:Neuroprotective Agents; D000077767:Panobinostat
keywords: HDAC inhibitor; huntington; neuroprotection; panobinostat