title: Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  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 Alzheimer'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.
  
  
  METHODS
  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.
  
  
  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 Akt in SOD1(G93A) mice.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Takata
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Kimura
authors.forename: Y
authors.initials: Y
authors.lastname: Nagahara
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: M
authors.initials: M
authors.lastname: Seto
authors.forename: K
authors.initials: K
authors.lastname: Tsuruma
authors.forename: M
authors.initials: M
authors.lastname: Shimazawa
authors.forename: H
authors.initials: H
authors.lastname: Hara
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D008297:Male; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D015996:Survival Rate; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; C431085:hydroxyfasudil; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; C049347:fasudil
keywords: PTEN/Akt pathway; amyotrophic lateral sclerosis; fasudil hydrochloride; motor neuron degeneration; rho kinase (ROCK)