Riluzole prolongs survival time and alters nuclear inclusion formation in a transgenic mouse model of Huntington's disease.
Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of Huntington's disease (HD). Riluzole is a substance with glutamate antagonistic properties that is used for neuroprotective treatment in amyotrophic lateral sclerosis and which is currently tested in clinical trials for treatment of HD. R6/2 transgenic mice, which express exon 1 of the human HD gene with an expanded CAG triplet repeat, serve as a well-characterized mouse model for HD with progressing neurological abnormalities and limited survival. We treated R6/2 HD transgenic mice with riluzole orally beginning at a presymptomatic stage until death to investigate its potential neuroprotective effects in this mouse model and found that survival time in the riluzole group was significantly increased in comparison to placebo-treated transgenic controls. Additionally, the progressive weight loss was delayed and significantly reduced by riluzole treatment; behavioral testing of motor coordination and spontaneous locomotor activity, however, showed no statistically significant differences. We also examined the formation of the HD characteristic neuronal intranuclear inclusions (NII) immunohistologically. At a late disease stage, striatal NII from riluzole-treated transgenic mice showed profound changes in ubiquitination, i.e., NII were less ubiquitinated and surrounded by ubiquitinated micro-aggregates. Staining with antibodies directed against the mutated huntingtin revealed no significant difference in this component of NII. Taken together, these data suggest that riluzole is a promising candidate for neuroprotective treatment in human HD.
Schiefer
Johannes
J
University Hospital RWTH Aachen, Department of Neurology, Aachen, Germany.
Landwehrmeyer
G Bernhard
GB
Lüesse
Hans-Gerd
HG
Sprünken
Arne
A
Puls
Christiane
C
Milkereit
Anna
A
Milkereit
Eva
E
Kosinski
Christoph M
CM
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000473:pathology* / Q000502:physiology; D002540:Cerebral Cortex / Q000473:pathology / Q000503:physiopathology; D003342:Corpus Striatum / Q000473:pathology / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005091:Exons; D018698:Glutamic Acid / Q000502:physiology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007124:Immunoenzyme Techniques; D051379:Mice; D008822:Mice, Transgenic; D009048:Motor Skills / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics; D019782:Riluzole / Q000494:pharmacology*; D016019:Survival Analysis; D018911:Trinucleotide Repeats
D018691:Excitatory Amino Acid Antagonists; C086055:HTT protein, human; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009687:Nuclear Proteins; D018698:Glutamic Acid; D019782:Riluzole