Abstract

Axonal injury in the adult human central nervous system often results in loss of sensation and motor functions. Promoting regeneration of severed axons requires the inactivation of growth inhibitory influences from the tissue environment and stimulation of the neuron intrinsic growth potential. Especially glial cell derived factors, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, and myelin in general, prevent axon regeneration. Most of the glial growth inhibiting factors converge onto the Rho/ROCK signaling pathway in neurons. Although conditions in the injured nervous system are clearly different from those during neurite outgrowth in vitro, here we use a chemical approach to manipulate Rho/ROCK signalling with small-molecule agents to encourage neurite outgrowth in cell culture. The development of therapeutic treatments requires drug testing not only on neurons of experimental animals, but also on human neurons. Using human NT2 model neurons, we demonstrate that the pain reliever Ibuprofen decreases RhoA (Ras homolog gene family, member A GTPase) activation and promotes neurite growth. Inhibition of the downstream effector Rho kinase by the drug Y-27632 results in a strong increase in neurite outgrowth. Conversely, activation of the Rho pathway by lysophosphatidic acid results in growth cone collapse and eventually to neurite retraction. Finally, we show that blocking of Rho kinase, but not RhoA results in an increase in neurons bearing neurites. Due to its anti-inflammatory and neurite growth promoting action, the use of a pharmacological treatment of damaged neural tissue with Ibuprofen should be explored.

Highlights

  • The adult mammalian central nervous system (CNS) cannot regenerate injured axons

  • Even low concentrations of 1 μM of the ROCK inhibitor Y-27632 caused an elongation to 129% of control (Fig. 2A), the level reached by application of 500 μM Ibuprofen (Fig. 1A and C)

  • In spinal cord injury (SCI) the formation of the glial scar requires several weeks. This would enable at least a theoretical time window for axonal regeneration beyond the forming glial scar [24], if the growth-inhibitory environment of the myelin could be neutralized

Read more

Summary

Introduction

The adult mammalian central nervous system (CNS) cannot regenerate injured axons. Inhibitors of Rho/ROCK Signaling Enhance Neurite Growth proteoglycans (CSPGs) forming scar tissue [2,3] and myelin-producing oligodendrocytes that expose myelin associated glycoprotein (MAG), Nogo-A [4] and oligodendrocyte myelin glycoprotein (OMgp) as growth-inhibitory factors [5,6,7,8] to the axons. These two broad classes of molecules are upregulated after neuronal injury and prevent regeneration beyond the lesion site. The activation of RhoA causes cytoskeletal changes eventually leading to a growth cone collapse which in turn suppresses axonal re-extension [9]

Methods
Results
Conclusion

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 call

Disclaimer: 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.