Abstract
Rho-Rho kinase (Rho-ROCK) triggers an intracellular signalling cascade that regulates cell survival, death, adhesion, migration, neurite outgrowth and retraction and influences the generation and development of several neurological disorders. Although Fasudil, a ROCK inhibitor, effectively suppressed encephalomyelitis (EAE), certain side effects may limit its clinical use. A novel and efficient ROCK inhibitor, FSD-C10, has been explored. In the present study, we present chemical synthesis and structure of FSD-C10, as well as the relationship between compound concentration and ROCK inhibition. We compared the inhibitory efficiency of ROCKI and ROCK II, the cell cytotoxicity, neurite outgrowth and dendritic formation, neurotrophic factors and vasodilation between Fasudil and FSD-C10. The results demonstrated that FSD-C10, like Fasudil, induced neurite outgrowth of neurons and dendritic formation of BV-2 microglia and enhanced the production of neurotrophic factor brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3). However, the cell cytotoxicity and vasodilation of FSD-C10 were relatively small compared with Fasudil. Although Fasudil inhibited both ROCK I and ROCK II, FSD-C10 more selectively suppressed ROCK II, but not ROCK I, which may be related to vasodilation insensitivity and animal mortality. Thus, FSD-C10 may be a safer and more promising novel ROCK inhibitor than Fasudil for the treatment of several neurological disorders.
Highlights
Rho kinase (ROCK), a serine/threonine kinase, is activated by binding to the active GTP-bound form of the small GTPase Rho
A series of studies have demonstrated that the blockade of Rho/ROCK is considered to be beneficial for inflammatory demyelination and degeneration in the central nervous system (CNS) and has proved to be efficacious in animal models of stroke [2], multiple sclerosis (MS) [3,4,5,6], amyotrophic lateral sclerosis (ALS) [7], Alzheimer’s disease (AD) [8] and Parkinson’s disease (PD) [9,10]
The results showed that an obvious vasodilation after 30 and 60 min on the foot of mice was observed in mice that were i.p. injected with Fasudil (800 μg/mouse) compared with mice injected with FSD-C10 at the same dose (Figure 8a), revealing that FSD-C10 has a relatively weak vasodilator effect in mice
Summary
Rho kinase (ROCK), a serine/threonine kinase, is activated by binding to the active GTP-bound form of the small GTPase Rho. A series of studies have demonstrated that the blockade of Rho/ROCK is considered to be beneficial for inflammatory demyelination and degeneration in the central nervous system (CNS) and has proved to be efficacious in animal models of stroke [2], multiple sclerosis (MS) [3,4,5,6], amyotrophic lateral sclerosis (ALS) [7], Alzheimer’s disease (AD) [8] and Parkinson’s disease (PD) [9,10]. Rho/ROCK pathway is a promising therapeutic target in neurodegenerative and neurotraumatic diseases and ROCK inhibitor should be a promising drug for preventing neurodegeneration and stimulating neuroregeneration in several neurological diseases [11].
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