Dantrolene is neuroprotective in Huntington's disease transgenic mouse model

Xi Chen, Jun Wu, Svetlana Lvovskaya, Emily Herndon, Charlene Supnet, Ilya Bezprozvanny

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number81
JournalMolecular Neurodegeneration
Volume6
Issue number1
DOIs
StatePublished - 2011

Fingerprint

Dantrolene
Huntington Disease
Transgenic Mice
Neurons
Corpus Striatum
Glutamic Acid
Walking
Machado-Joseph Disease
Yeast Artificial Chromosomes
Spinocerebellar Ataxias
Ryanodine Receptor Calcium Release Channel
Caffeine
Gait
Neurodegenerative Diseases
Pathology
Calcium

Keywords

  • neuroprotection

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Dantrolene is neuroprotective in Huntington's disease transgenic mouse model. / Chen, Xi; Wu, Jun; Lvovskaya, Svetlana; Herndon, Emily; Supnet, Charlene; Bezprozvanny, Ilya.

In: Molecular Neurodegeneration, Vol. 6, No. 1, 81, 2011.

Research output: Contribution to journalArticle

@article{a57ed1cb66ab45db8a573345cea89288,
title = "Dantrolene is neuroprotective in Huntington's disease transgenic mouse model",
abstract = "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.",
keywords = "neuroprotection",
author = "Xi Chen and Jun Wu and Svetlana Lvovskaya and Emily Herndon and Charlene Supnet and Ilya Bezprozvanny",
year = "2011",
doi = "10.1186/1750-1326-6-81",
language = "English (US)",
volume = "6",
journal = "Molecular Neurodegeneration",
issn = "1750-1326",
publisher = "BioMed Central",
number = "1",

}

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

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

UR - http://www.scopus.com/inward/citedby.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

VL - 6

JO - Molecular Neurodegeneration

JF - Molecular Neurodegeneration

SN - 1750-1326

IS - 1

M1 - 81

ER -