Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis

Background and Purpose Amyotrophic lateral sclerosis ( ALS ) is a fatal neurodegenerative disorder with no effective treatment. Fasudil hydrochloride (fasudil), a potent rho kinase ( ROCK ) inhibitor, is useful for the treatment of ischaemic diseases. In previous reports, fasudil improved pathology in mouse models of A lzheimer's disease and spinal muscular atrophy, but there is no evidence in that it can affect ALS . We therefore investigated its effects on experimental models of ALS . Experimental Approach In mice motor neuron ( NSC34 ) cells, the neuroprotective effect of hydroxyfasudil ( M3 ), an active metabolite of fasudil, and its mechanism were evaluated. Moreover, the effects of fasudil, 30 and 100 mg·kg −1 , administered via drinking water to mutant superoxide dismutase 1 ( SOD1 G93A ) mice were tested by measuring motor performance, survival time and histological changes, and its mechanism investigated. Key Results M3 prevented motor neuron cell death induced by SOD1 G93A . Furthermore, M3 suppressed both the increase in ROCK activity and phosphorylated phosphatase and tensin homologue deleted on chromosome 10 ( PTEN ), and the reduction in phosphorylated Akt induced by SOD1 G93A . These effects of M3 were attenuated by treatment with a PI3K inhibitor ( LY294002 ). Moreover, fasudil slowed disease progression, increased survival time and reduced motor neuron loss, in SOD1 G93A mice. Fasudil also attenuated the increase in ROCK activity and PTEN , and the reduction in A kt in SOD1 G93A mice. Conclusions and Implications These findings indicate that fasudil may be effective at suppressing motor neuron degeneration and symptom progression in ALS . Hence, fasudil may have potential as a therapeutic agent for ALS treatment.