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

Abstract

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 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. 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 (SOD1G93A) 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 SOD1G93A. 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 SOD1G93A. 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 SOD1G93A mice. Fasudil also attenuated the increase in ROCK activity and PTEN, and the reduction in Akt in SOD1G93A 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.

Rho Kinases in Health and Disease: From Basic Science to Translational Research

“…This neuroprotection also supports the beneficial effect of pharmacologic ROCK inhibition in the R6/2 HD mouse model of Huntington disease (Li et al, 2009). In the mouse model of amyotrophic lateral sclerosis (hSOD1 G93A ), neuron loss has been attributed to ROCKmediated inhibition of Akt signaling, and inhibition of this pathway by fasudil slows disease progression and prolongs survival time (Takata et al, 2013). In an experimental autoimmune encephalomyelitis animal model of multiple sclerosis, RhoA-ROCK signaling in autoreactive Th1/Th17 helper T cells has been identified as a potential target for treatment of multiple sclerosis and related neurodegenerative disorders (Paintlia et al, 2012).…”

Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

“…This underlines that ROCK is considerably involved in the modulation of microglial cell function. In line with this, SOD1.G93A mice were shown to exhibit enhanced ROCK activity leading to increased levels of phosphorylated adducin, elevated PTEN activation and decreased Akt activity (Takata et al, 2013). In patients with sporadic ALS, increases of ROCK2 protein have also been shown and were most prominent in skeletal muscle tissue (Conti et al, 2014).…”

Reversal of Bone Marrow Mobilopathy and Enhanced Vascular Repair by Angiotensin-(1-7) in Diabetes

“…Where applicable, A779, a MasR antagonist, was administered at the rate of 0.5 µg/kg/min s.c. (osmotic pumps for 4 weeks) (27), or fasudil, a ρ-kinase (ROCK) inhibitor, at a dose of 30 mg/kg i.p. for 14 days (28). …”