Rho Kinase Inhibition Enhances Axonal Regeneration in the Injured CNS

By A. Fournier, B. Takizawa, S. Strittmatter. Journal of Neuroscience, 2003

678 citations recorded by the source corpus.

Myelin-associated inhibitors limit axonal regeneration in the injured brain and spinal cord. A common target of many neurite outgrowth inhibitors is the Rho family of small GTPases. Activation of Rho and a downstream effector of Rho, p160ROCK, inhibits neurite outgrowth. Here, we demonstrate that Rho is directly activated by the myelin-associated inhibitor Nogo-66. Using a binding assay to measure Rho activity, we detected increased levels of GTP Rho in PC12 and dorsal root ganglion (DRG) cell lysates after Nogo-66 stimulation. Rho activity levels were not affected by Amino–Nogo stimulation. Rho inactivation with C3 transferase promotes neurite outgrowth of chick DRG neurons in vitro, but with the delivery method used here, it fails to promote neurite outgrowth after corticospinal tract (CST) lesions in the adult rat. Inhibition of p160ROCK with Y-27632 also promotes neurite outgrowth on myelin-associated inhibitors in vitro. Furthermore, Y-27632 enhances sprouting of CST fibers in vivo and accelerates locomotor recovery after CST lesions in adult rats.

Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience

View Paper: https://www.semanticscholar.org/paper/f13d1587adc74451fa1fb97b9d7ea6de7d872a5f

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Guo-li Ming
2. Martin E. Schwab
3. A. Tran
4. G. Ferraro
5. L. Mckerracher
6. P. Warren
7. J. Silver
8. A. Fournier

In Developmental Neuroscience

1. Guo-li Ming
2. Martin E. Schwab
3. G. Ferraro
4. L. Mckerracher
5. A. Fournier
6. J. Silver
7. Glenn Yiu
8. Zhigang He

Citations in the corpus

• The Biology of Regeneration Failure and Success After Spinal Cord Injury. (2018, background): “Indeed, use of the specific inhibitors C3 coenzyme or Y-27632 in vivo facilitates axonal growth following SCI (90, 120, 268, 316).”
• Nogo and axon regeneration. (2004, background): “The Rho-inactivating enzyme C3 transferase has been applied to optic nerve and spinal cord lesion sites [31,37,49], resulting in enhanced regenerative sprouting of retinal axons and CST fibres, and in more axons located distally from the lesion.”
• Glial inhibition of CNS axon regeneration (2006, background): “Inhibiting RhoA using C3 transferase or a dominant-negative approach also promotes axon outgrowth on inhibitory substrates, as can pharmacological inhibition of ROC”
• The role of the Rho GTPases in neuronal development. (2005, background): “…substrate (Da Silva et al. 2003; Schwamborn and Puschel 2004), and neurite outgrowth is promoted by Rho inhibition using C3 exoenzyme in chick dorsal root ganglia (DRG) and cultured rat hippocampal neurons (Jin and Strittmatter 1997; Sarner et al. 2000; Da Silva et al. 2003; Fournier et al. 2003).”
• New directions in neuroregeneration (2006, background): “Several intracellular molecules have been identified as important in inhibitory pathways (reviewed in [1-4]), including intracellular Ca2+ [16,17], cAMP [18] and Rho GTPases [19,20].”
• Rho signaling and axon regeneration. (2012, methodology): “These results contrast with an earlier study of BBB scores in rats where 500 mg of C3 transferase without a transport sequence was applied by Alzet minipump (Fournier et al., 2003).”