Inhibition of Rho kinase (ROCK) increases neurite outgrowth on chondroitin sulphate proteoglycan in vitro and axonal regeneration in the adult optic nerve in vivo

J Neurochem. 2007 Oct;103(1):181-9. doi: 10.1111/j.1471-4159.2007.04756.x. Epub 2007 Jul 2.

Abstract

Inhibitory molecules derived from CNS myelin and glial scar tissue are major causes for insufficient functional regeneration in the mammalian CNS. A multitude of these molecules signal through the Rho/Rho kinase (ROCK) pathway. We evaluated three inhibitors of ROCK, Y- 27632, Fasudil (HA-1077), and Dimethylfasudil (H-1152), in models of neurite outgrowth in vitro. We show, that all three ROCK inhibitors partially restore neurite outgrowth of Ntera-2 neurons on the inhibitory chondroitin sulphate proteoglycan substrate. In the rat optic nerve crush model Y-27632 dose-dependently increased regeneration of retinal ganglion cell axons in vivo. Application of Dimethylfasudil showed a trend towards increased axonal regeneration in an intermediate concentration. We demonstrate that inhibition of ROCK can be an effective therapeutic approach to increase regeneration of CNS neurons. The selection of a suitable inhibitor with a broad therapeutic window, however, is crucial in order to minimize unwanted side effects and to avoid deleterious effects on nerve fiber growth.

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • Amides / pharmacology
  • Animals
  • Axons / drug effects
  • Axons / pathology
  • Cell Line
  • Chondroitin Sulfate Proteoglycans / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Nerve Crush
  • Nerve Regeneration / drug effects*
  • Neurites / drug effects*
  • Neurites / physiology
  • Neurons / drug effects
  • Neurons / pathology
  • Optic Nerve / drug effects
  • Optic Nerve / enzymology
  • Optic Nerve / pathology
  • Optic Nerve Injuries / drug therapy*
  • Optic Nerve Injuries / enzymology
  • Optic Nerve Injuries / pathology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Pyridines / pharmacology
  • Rats
  • Rats, Wistar
  • rho-Associated Kinases

Substances

  • 2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
  • Amides
  • Chondroitin Sulfate Proteoglycans
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Pyridines
  • Y 27632
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • Protein Serine-Threonine Kinases
  • rho-Associated Kinases
  • fasudil