Rho-kinase inhibition enhances axonal regeneration after peripheral nerve injury.
In injured adult neurons, the process of axonal regrowth and reestablishment of the neuronal function have to be activated. We assessed in this study whether RhoA, a key regulator of neurite elongation, is activated after injury to the peripheral nervous system. RhoA is activated in motoneurons but not in Schwann cells after mouse sciatic nerve injury. To examine whether the activation of RhoA and its effector, Rho-kinase, retards axon regeneration of injured motoneurons, we employed a Rho-kinase inhibitor, fasudil. Amplitudes of distally evoked compound muscle action potentials are increased significantly faster after axonal injury in mice treated with fasudil compared with controls. Histological analysis shows that fasudil treatment increases the number of regenerating axons with large diameter, suggesting that axon maturation is facilitated by Rho-kinase inhibition. In addition, fasudil does not suppress the myelination of regenerating axons. These findings suggest that RhoA/Rho-kinase may be a practical molecular target to enhance axonal regeneration in human peripheral neuropathies.
Hiraga
Akiyuki
A
Department of Neurobiology, Chiba University Graduate School of Medicine, Chiba, Japan.
Kuwabara
Satoshi
S
Doya
Hideo
H
Kanai
Kazuaki
K
Fujitani
Masashi
M
Taniguchi
Junko
J
Arai
Kimihito
K
Mori
Masahiro
M
Hattori
Takamichi
T
Yamashita
Toshihide
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009046:Motor Neurons / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009431:Neural Conduction / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D013997:Time Factors; D014048:Tolonium Chloride; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D014048:Tolonium Chloride; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; C049347:fasudil