Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice.
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.
Li
Mei
M
Department of Neurology, University of California, San Francisco, CA 94143, USA.
Huang
Yong
Y
Ma
Aye Aye K
AA
Lin
Emil
E
Diamond
Marc I
MI
D000577:Amides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy*; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011897:Random Allocation; D013997:Time Factors; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D000577:Amides; D004791:Enzyme Inhibitors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011725:Pyridines; C108830:Y 27632; D054460:rho-Associated Kinases