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Updated: Jun 21, 2026
Measuring Motor Coordination in Mice
Published on: May 29, 2013
Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice
Mei Li1, Yong Huang, Aye Aye K Ma
1Department of Neurology, University of California, San Francisco, CA 94143, USA.
Insights
The Rho-associated kinase (ROCK) inhibitor Y-27632 showed limited benefits in a mouse model of Huntington disease (HD). While it improved motor function and reduced huntingtin protein levels, it did not extend lifespan or prevent neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Huntington disease (HD) is an inherited neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (Htt) gene.
- Current treatments for HD are limited, necessitating the exploration of novel therapeutic targets.
- Y-27632, a Rho-associated kinase (ROCK) inhibitor, has shown promise in preclinical models for reducing Htt aggregation and neurodegeneration.
Purpose of the Study:
- To evaluate the efficacy of Y-27632 in a mouse model of Huntington disease.
- To determine if Y-27632 can mitigate Htt-induced neurodegeneration and improve motor deficits in vivo.
- To assess the bioavailability and brain penetration of Y-27632 in mice.
Main Methods:
- Y-27632 bioavailability and half-life in mouse brain were determined.
- R6/2 HD model mice received daily Y-27632 (100 mg/kg/day) in drinking water.
- Neurological, behavioral, and biochemical assessments were performed, including rotarod tests, brain weight, inclusion body counts, neuron counts, and soluble Htt levels.
Main Results:
- Y-27632 demonstrated bioavailability in the brain with a half-life of 60-90 minutes.
- No significant improvements were observed in brain weight, inclusion number/size, medium spiny neuron number, clasping behavior, or lifespan.
- Significant improvements in rotarod performance and reductions in soluble brain Htt levels were observed in Y-27632 treated mice.
Conclusions:
- ROCK signaling remains a potential therapeutic target for Huntington disease.
- While Y-27632 showed some benefits in a mouse model, more potent ROCK inhibitors may be required for significant therapeutic impact.
- Further research into ROCK pathway modulation is warranted for HD treatment development.
Abstract:
Huntington disease (HD) is a devastating, untreatable, dominantly inherited neurodegenerative disease. It is caused by an expanded CAG codon repeat that leads to an elongated polyglutamine tract in the N-terminus of the huntingtin (Htt) protein. Few mechanism-based therapeutic leads have been developed. Y-27632, an inhibitor of the Rho-associated kinase ROCK, reduces Htt aggregation in cultured cells and Htt-induced neurodegeneration in Drosophila, but its effect in mice is unknown. We determined that Y-27632 is bioavailable in brain, with a half-life of 60-90 min. We then initiated a trial in R6/2 mice, which express Htt exon 1, administering 100 mg/kg/day of Y-27632 in drinking water. We did not observe a significant effect on brain weight, inclusion number or size, striatal medium spiny neuron number, clasping behavior, or lifespan. However, Y-27632 treatment improved rotarod performance significantly, and also reduced soluble brain Htt levels. The ROCK signaling pathway thus remains a promising therapeutic target for HD, and more potent inhibitors may prove useful.
