Nicole Forgione1, Michael G Fehlings2. 1. Division of Genetics and Development, Toronto Western Research Institute, Toronto, Ontario, Canada. 2. Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada. Electronic address: Michael.Fehlings@uhn.on.ca.
Abstract
BACKGROUND: The Rho pathway has been shown to have a role in the pathophysiology of spinal cord injury (SCI). Upregulation of the Rho signaling pathway occurs as a result of SCI. Activation of Rho and its downstream effector kinases triggers growth cone collapse and represents a significant barrier to axon regeneration. Furthermore, there is evidence that Rho-ROCK signaling mediates the inhibitory effects of chondroitin sulfate proteoglycans on neurons, and that inhibition of Rho and ROCK can reverse chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth. Work building on these findings suggests that inhibition of this pathway may boost neuroprotection and axonal regeneration after SCI. METHODS: A narrative review. RESULTS: Investigators have identified a C3 transferase, which selectively inhibits Rho without affecting other guanine triphosphatases. This has been shown to promote axonal sprouting and recovery of locomotor function after hemisection of the thoracic spinal cord in a mouse model of SCI. The neuroprotective properties of Rho inhibitors in animal models of SCI have been reinforced by studies carried out in vitro using retinal ganglion cells. In light of this, a Rho inhibitor known as Cethrin has been evaluated as a therapeutic intervention for SCI in a phase I/IIa clinical trial with promising results. CONCLUSIONS: The Rho pathway has been shown to have a role in the pathophysiology of SCI and preclinical and clinical work and is currently a promising target for the treatment of patients with SCI.
BACKGROUND: The Rho pathway has been shown to have a role in the pathophysiology of spinal cord injury (SCI). Upregulation of the Rho signaling pathway occurs as a result of SCI. Activation of Rho and its downstream effector kinases triggers growth cone collapse and represents a significant barrier to axon regeneration. Furthermore, there is evidence that Rho-ROCK signaling mediates the inhibitory effects of chondroitin sulfate proteoglycans on neurons, and that inhibition of Rho and ROCK can reverse chondroitin sulfate proteoglycan-mediated inhibition of neurite outgrowth. Work building on these findings suggests that inhibition of this pathway may boost neuroprotection and axonal regeneration after SCI. METHODS: A narrative review. RESULTS: Investigators have identified a C3 transferase, which selectively inhibits Rho without affecting other guanine triphosphatases. This has been shown to promote axonal sprouting and recovery of locomotor function after hemisection of the thoracic spinal cord in a mouse model of SCI. The neuroprotective properties of Rho inhibitors in animal models of SCI have been reinforced by studies carried out in vitro using retinal ganglion cells. In light of this, a Rho inhibitor known as Cethrin has been evaluated as a therapeutic intervention for SCI in a phase I/IIa clinical trial with promising results. CONCLUSIONS: The Rho pathway has been shown to have a role in the pathophysiology of SCI and preclinical and clinical work and is currently a promising target for the treatment of patients with SCI.
Authors: Nureddin Ashammakhi; Han-Jun Kim; Arshia Ehsanipour; Rebecca D Bierman; Outi Kaarela; Chengbin Xue; Ali Khademhosseini; Stephanie K Seidlits Journal: Tissue Eng Part B Rev Date: 2019-10-23 Impact factor: 6.389