Abstract
Rho kinase (ROCK) is a serine/threonine kinase and a downstream target of the small GTPase Rho. The RhoA/ROCK pathway is associated with various neuronal functions such as migration, dendrite development, and axonal extension. Evidence from animal studies reveals that RhoA/ROCK signaling is involved in various central nervous system (CNS) diseases, including optic nerve and spinal cord injuries, stroke, and neurodegenerative diseases. Given that RhoA/ROCK plays a critical role in the pathophysiology of CNS diseases, the development of therapeutic agents targeting this pathway is expected to contribute to the treatment of CNS diseases. The RhoA/ROCK pathway mediates the effects of myelin-associated axon growth inhibitors—Nogo, myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp), and repulsive guidance molecule (RGM). Blocking RhoA/ROCK signaling can reverse the inhibitory effects of these molecules on axon outgrowth, and promotes axonal sprouting and functional recovery in animal models of CNS injury. To date, several RhoA/ROCK inhibitors have been under development or in clinical trials as therapeutic agents for neurological disorders. In this review, we focus on the RhoA/ROCK signaling pathway in neurological disorders. We also discuss the potential therapeutic approaches of RhoA/ROCK inhibitors for various neurological disorders.
Highlights
Because of the complexity of the central nervous system (CNS) and its limited capacity to regenerate on its own, the CNS is one of the most difficult organs to repair after an injury
Inhibition of myosin IIA prevents neurite outgrowth inhibition induced by RGMa (Kubo et al, 2008). These results indicate that ROCK induces phosphorylation of myosin light chain (MLC), leading to myosin IIA activation, and that this effect is essential for neurite outgrowth inhibition induced by RGMa
The evidence obtained from animal models and clinical trials implicate that inhibition of the RhoA/ROCK pathway would be an effective therapeutic approach for CNS disorders
Summary
Because of the complexity of the CNS and its limited capacity to regenerate on its own, the CNS is one of the most difficult organs to repair after an injury. It is evident that lesions to the adult CNS in animals activates RhoA/ROCK signaling pathway and this pathway inhibits axon growth and sprouting. This pathway is considered to be a potential therapeutic target for CNS diseases. It has been considered that multiple factors, including the weakness of intrinsic growth capacity, the inhibitory extrinsic environment, and neuronal vulnerability after lesion, cause regenerative failure in the adult CNS. When myelinated fibers are damaged after injury, injured CNS axons are exposed to myelin debris that contains inhibitory molecules for axonal regrowth These inhibitory molecules induce the activation of RhoA/ROCK in neurons.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
