Y-27632 improves rotarod performance and reduces huntingtin levels in R6/2 mice

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.