title: A New VMAT-2 Inhibitor NBI-641449 in the Treatment of Huntington Disease.
abstract: OBJECTIVE
  To evaluate the effectiveness of a new VMAT-2 inhibitor NBI-641449 in controlling hyperkinetic movements of Huntington disease (HD) and to investigate its possible therapeutic effects.
  
  
  METHODS
  We applied three different doses of NBI-641449 (1, 10, 100 mg/kg/day) for 2 weeks in 4-month-old YAC128 mice and wild-type (WT) mice. Rotarod performance and locomotive activities were tested during the administration of the drug. The concentration of dopamine (DA) and its metabolites was quantified in the striatal tissues by high-performance liquid chromatography (HPLC). Neuron survival in striatum and huntingtin protein aggregates were assessed with immunostaining. Expression levels of endoplasmic reticulum (ER) stress proteins were detected by immunoblotting.
  
  
  RESULTS
  Rotarod performance was significantly improved after treatment with low or middle dose of NBI-641449 in YAC128 mice. Open field test showed that NBI-641449 treatment could attenuate the increased horizontal activity (HACTV), total vertical movement, moving time, and moving distance in YAC128 mice. High dose of NBI-641449 might cause sedative effects in WT and YAC128 mice. HPLC showed that NBI-641449 caused a dose-dependent decrease of DA, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels in the striatum. NeuN and DARPP-32 immunostaining revealed that NBI-641449 had no significant effect on the neuron survival in the striatum. However, NBI-641449 treatment reduced the huntingtin protein aggregates in the cortex of YAC128 mice. In addition, the levels of ER stress proteins were increased in YAC128 mice, which can be suppressed by NBI-641449.
  
  
  CONCLUSIONS
  These findings suggest that this new VMAT-2 inhibitor NBI-641449 may have therapeutic potential for the treatment of HD.
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Department of Neurology, Baylor College of medicine, Houston, TX, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xiao-Jie
authors.initials: XJ
authors.lastname: Zhang
authors.affiliation: Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA.
authors.forename: Wen-Jie
authors.initials: WJ
authors.lastname: Xie
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hong-Yan
authors.initials: HY
authors.lastname: Qiu
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.|Center for Translational Research of Neurology Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Le
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; C497929:Ppp1r1b protein, mouse; D050486:Serotonin Plasma Membrane Transport Proteins; C493453:Slc18a2 protein, mouse; C493231:Slc6a4 protein, mouse; D050493:Vesicular Monoamine Transport Proteins; D015102:3,4-Dihydroxyphenylacetic Acid; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine; D006719:Homovanillic Acid
keywords: Endoplasmic reticulum stress; Huntington disease; NBI-641449; Therapeutics effects; VMAT-2 inhibitor