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
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Amides / pharmacology
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Animals
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Axons / drug effects
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Axons / pathology
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Cell Line
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Chondroitin Sulfate Proteoglycans / pharmacology*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology*
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Female
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Humans
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Nerve Crush
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Nerve Regeneration / drug effects*
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Neurites / drug effects*
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Neurites / physiology
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Neurons / drug effects
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Neurons / pathology
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Optic Nerve / drug effects
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Optic Nerve / enzymology
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Optic Nerve / pathology
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Optic Nerve Injuries / drug therapy*
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Optic Nerve Injuries / enzymology
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Optic Nerve Injuries / pathology
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Pyridines / pharmacology
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Rats
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Rats, Wistar
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rho-Associated Kinases
Substances
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2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
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Amides
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Chondroitin Sulfate Proteoglycans
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Enzyme Inhibitors
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Intracellular Signaling Peptides and Proteins
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Pyridines
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Y 27632
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Protein Serine-Threonine Kinases
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rho-Associated Kinases
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fasudil