TY - JOUR
T1 - Dantrolene is neuroprotective in Huntington's disease transgenic mouse model
AU - Chen, Xi
AU - Wu, Jun
AU - Lvovskaya, Svetlana
AU - Herndon, Emily
AU - Supnet, Charlene
AU - Bezprozvanny, Ilya
N1 - Funding Information:
We thank Xia Liang for help with maintaining the YAC128 mouse colony and help with behavioral experiments, Leah Benson for administrative assistance. IB is a holder of the Carl J. and Hortense M. Thomsen Chair in Alzheimer’s Disease Research. This project was supported by the CHDI foundation, NINDS R01 NS056224 and R01 NS074376 and by the contracts with the Russian Ministry of Science and Education 14.740.11.0924 and 11. G34.31.0056.
PY - 2011
Y1 - 2011
N2 - 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 (Ca 2+) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca 2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ signaling stabilizers such as dantrolene should be considered as potential therapeutics for the treatment of HD and other polyQ-expansion disorders.
AB - 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 (Ca 2+) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca 2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Ca 2+ signaling stabilizers such as dantrolene should be considered as potential therapeutics for the treatment of HD and other polyQ-expansion disorders.
KW - neuroprotection
UR - http://www.scopus.com/inward/record.url?scp=82055164052&partnerID=8YFLogxK
U2 - 10.1186/1750-1326-6-81
DO - 10.1186/1750-1326-6-81
M3 - Article
C2 - 22118545
AN - SCOPUS:82055164052
SN - 1750-1326
VL - 6
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 81
ER -