TY - JOUR
T1 - Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice
AU - Li, Mei
AU - Huang, Yong
AU - Ma, Aye Aye K
AU - Lin, Emil
AU - Diamond, Marc I.
N1 - Funding Information:
We thank Mitsubishi Pharma for generously providing the Y-27632 used for this study. We thank Stanley Prusiner, M.D. for the help in obtaining Y-27632; Samuel Pleasure, M.D., Ph.D. for use of his cryostat; Clifford Bryant, Ph.D. for detecting Y-27632 stability; Kurt Thorn, Ph.D.; Amie Lee, M.D.; and the Nikon Imaging Center at UCSF for use of the Nikon C1s1 spectral confocal microscope and Nikon 6D microscope. We also thank Jieya Shao, Ph.D.; Zhaolin Hua, M.D., Ph.D.; Guangnan Li, Ph.D.; and Brian Feldman, M.D., Ph.D. for advice, reagents and technical support. ML was supported by a grant from the Muscular Dystrophy Association. MID was supported by grants from the Muscular Dystrophy Association, the NIH:NINDS, and the Taube Family Foundation Program in Huntington's Disease Research.
PY - 2009/12
Y1 - 2009/12
N2 - 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.
AB - 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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U2 - 10.1016/j.nbd.2009.06.011
DO - 10.1016/j.nbd.2009.06.011
M3 - Article
C2 - 19591939
AN - SCOPUS:70350348368
SN - 0969-9961
VL - 36
SP - 413
EP - 420
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 3
ER -