Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

Molecular Neurodegeneration

Ilya Bezprozvanny³  Charlene Supnet³  Emily Herndon¹  Svetlana Lvovskaya³  Jun Wu²  Xi Chen² 

[1] Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA;Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA;Department of Medical Physics and Bioengineering, St Petersburg State Polytechnical University, St. Petersburg, Russia

关键词: neuroprotection;    aggregation;    ryanodine receptor;    dantrolene;    cell death;    calcium imaging;    calcium signaling;    Huntington's disease;   

Others  :  864008
DOI  :  10.1186/1750-1326-6-81

 received in 2011-08-05, accepted in 2011-11-25,  发布年份 2011

【 摘 要 】

Background

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Our group has previously demonstrated that calcium (Ca²⁺) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca²⁺ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca²⁺ signaling in neurons from spinocerebellar ataxia 2 (SCA2) and spinocerebellar ataxia 3 (SCA3) mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca²⁺ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model.

Results

The application of caffeine and glutamate resulted in increased Ca²⁺ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Htt^exp nuclear aggregates.

Conclusions

Our results support the hypothesis that deranged Ca²⁺ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that RyanR inhibitors and Ca²⁺ signaling stabilizers such as dantrolene should be considered as potential therapeutics for the treatment of HD and other polyQ-expansion disorders.

【 授权许可】

   
2011 Chen et al; licensee BioMed Central Ltd.

【 图 表 】

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