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 (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 Httexp 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.
authors: Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390, USA.
authors: Xi
authors: X
authors: Chen
authors: Jun
authors: J
authors: Wu
authors: Svetlana
authors: S
authors: Lvovskaya
authors: Emily
authors: E
authors: Herndon
authors: Charlene
authors: C
authors: Supnet
authors: Ilya
authors: I
authors: Bezprozvanny
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology; D003620:Dantrolene / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000633:toxicity; D006816:Huntington Disease / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009125:Muscle Relaxants, Central / Q000494:pharmacology / Q000627:therapeutic use; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000697:Central Nervous System Stimulants; D009125:Muscle Relaxants, Central; D018696:Neuroprotective Agents; D002110:Caffeine; D018698:Glutamic Acid; D003620:Dantrolene; D002118:Calcium