Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice
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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.
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In the R6/2 HD mouse model, Y27632-mediated ROCK inhibition improves rotarod performance and reduces soluble Htt, but has no effect on Htt aggregation, cellular atrophy in the striatum, or survival, possibly due to suboptimal dosing as no significant reduction of ROCK effector protein phosphorylation was seen.
“In the R6/2 HD mouse model, Y27632-mediated ROCK inhibition improved rotarod performance and reduced soluble Htt, but it had no effect on Htt aggregation, cellular atrophy in the striatum, or survival, possibly due to suboptimal dosing as no significant reduction of ROCK effector protein phosphorylation was seen [199].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [199]
Cites
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RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
- Authors
- Li, M., Huang, Y., Ma, A. A. K., Lin, E., & Diamond, M. I.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Diamond, Marc I.
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 36
- Issue
- 3
- Pages
- 413-420
- ISSN
- 0969-9961 (ISSN-L)
- OpenAlex
- W2062059213
- Cited by
- 68
- References
- 3
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 3 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 6 · 2017: 5 · 2016: 6 · 2015: 9 · 2014: 3 · 2013: 7 · 2012: 7
- FWCI
- 2.22
- Type
- journal article
- Language
- en
- Open access
- green
- doaj.org
- Licence
- Locations
- Neurobiology of Disease (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Huntington's disease, Y-27632, ROCK inhibitor, huntingtin, R6/2 mice, rotarod performance, motor coordination, striatal degeneration, huntingtin aggregation, therapeutic target
- MeSH terms
- Huntingtin Protein, Amides, Animals, Brain, Cell Count, Disease Models, Animal, Enzyme Inhibitors, Female, Half-Life, Huntington Disease, Longevity, Mice, Transgenic, Motor Activity, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Pyridines, Random Allocation, Time Factors, Dyskinesias, Mice, rho-Associated Kinases
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