Rho kinase inhibitor improves motor dysfunction and hypoalgesia in a rat model of lumbar spinal canal stenosis.
METHODS
Immunohistochemical and behavioral study using a rat cauda equina compression model.


OBJECTIVE
To investigate, after cauda equina compression by spinal canal stenosis (SCS), Rho activation in the spinal cord and cauda equina, and the effect of intrathecal administration of a Rho kinase inhibitor on hypoalgesia and motor dysfunction.


BACKGROUND
Compression of the cauda equina caused by SCS is a common clinical disorder associated with sensory disturbance and intermittent claudication. Cauda equina compression is thought to reduce blood flow and result in nerve degeneration caused by various cytokines. Rho, a member of the small GTPases, is a signal transmitter. It promotes Wallerian degeneration, decreases blood flow in the spinal cord and brain, and increases expression of several cytokines. Currently, Rho kinase inhibitor is used clinically to treat progressive nerve damage due to cerebrovascular disorders. However, its effect for SCS has not been evaluated.


METHODS
Forty-two 6-week-old male Sprague-Dawley rats (200-250 g) were used. For the SCS model (n = 27), a small piece of silicon was placed under the lamina of the fourth lumbar vertebra. In the sham-operated group, laminectomies were performed at L5 only (n = 15). We examined mechanical sensitivity and motor function using von Frey hairs and a treadmill, and immunohistochemically localized Rho in the spinal ventral neurons, axons, and Schwann cells in the cauda equina. We also examined the effects of intrathecally administered Rho kinase inhibitor for hypoalgesia or motor dysfunction caused by SCS.


RESULTS
We observed motor dysfunction and hypoalgesia and activated Rho-immunoreactive cells in spinal ventral neuroreported to induce neurite and axonal outgrowth in the spinal cord and brain after nervous system injury. In addition, 1 report showed that Rho kinase was involved in Wallerian degeneration that was rescued by Rho kinase inhibitor. Furthermore, it is thought that Rho is involved in TNF-alpha and interleukin (IL) production in the central nervous system, and the production was inhibited by administering Rho kinase inhibitor in the central nervous system. Regardns, axons, and Schwann cells in the cauda equina. Intrathecal administration of Rho kinase inhibitor improved mechanical hypoalgesia and motor dysfunction caused by SCS.


CONCLUSIONS
Activated Rho may play an important role in nerve damage in the cauda equina in SCS. Rho kinase inhibitor may be a useful tool in determining the pathomechanism of cauda equina syndrome caused by SCS.
Ito
Toshinori
T
Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
Ohtori
Seiji
S
Hata
Katsuhiko
K
Inoue
Gen
G
Moriya
Hideshige
H
Takahashi
Kazuhisa
K
Yamashita
Toshihide
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000870:Anterior Horn Cells / Q000187:drug effects / Q000201:enzymology; D001369:Axons / Q000187:drug effects / Q000201:enzymology; D001522:Behavior, Animal / Q000187:drug effects; D002420:Cauda Equina / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D006987:Hypesthesia / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D007278:Injections, Spinal; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008159:Lumbar Vertebrae; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D019957:Motor Skills Disorders / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017288:Pain Threshold / Q000187:drug effects; D011128:Polyradiculopathy / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012107:Research Design; D012583:Schwann Cells / Q000187:drug effects / Q000201:enzymology; D013130:Spinal Stenosis / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D013997:Time Factors; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases
D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; C049347:fasudil