Open AccessA New VMAT ‐2 Inhibitor NBI ‐641449 in the Treatment of Huntington Disease
Author(s) -
Chen Sheng,
Zhang XiaoJie,
Xie WenJie,
Qiu HongYan,
Liu Hui,
Le WeiDong
Publication year - 2015
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12425
Subject(s) - striatum , huntingtin , immunostaining , homovanillic acid , open field , endoplasmic reticulum , dopamine , chemistry , pharmacology , nucleus accumbens , huntington's disease , endocrinology , medicine , immunohistochemistry , biochemistry , disease , receptor , serotonin
Summary Aims 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 YAC 128 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 YAC 128 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 YAC 128 mice. High dose of NBI ‐641449 might cause sedative effects in WT and YAC 128 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 YAC 128 mice. In addition, the levels of ER stress proteins were increased in YAC 128 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 .