Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats.
OBJECTIVE
In Japan fasudil hydrochloride (HA1077), a protein kinase inhibitor, is widely administered to prevent vasospasm in patients after subarachnoid hemorrhage. The effects of fasudil on experimental spinal cord injury (SCI) were investigated and compared with those obtained using methylprednisolone.


METHODS
Spinal cord contusion was induced in rats by applying an aneurysm clip extradurally to the spinal cord at T-3 for 1 minute. After injury three groups of rats were treated with intravenously administered saline (control), intraperitoneally administered fasudil (10 mg/kg), or intravenously administered methylprednisolone (four 30 mg/kg injections). Neurological recovery was evaluated periodically over 1 month by using a modified combined behavioral scale and histopathological examination. Leukocyte infiltration near the injury site was evaluated by measuring myeloperoxidase (MPO) activity at 24 hours. Spinal cord blood flow was measured at intervals up to 3 hours after injury by using laser Doppler flowmetry. In rats in the fasudil-treated group significant improvement in modified combined behavioral score was demonstrated at each time point, whereas in the methylprednisolone-treated rats no beneficial effects were shown. In the fasudil-treated group, reduction of traumatic spinal cord damage was evident histologically in the caudal portion of the injured areas, and tissue MPO activity in tissue samples was reduced. Spinal cord blood flow was not significantly different between fasudil-treated and control group rats.


CONCLUSIONS
Fasudil hydrochloride showed promise of effectiveness in promoting neurological recovery after traumatic SCI. Possible mechanisms of this effect include protein kinase inhibition and decreased infiltration by neutrophils.
Hara
M
M
Department of Neurosurgery, Nagoya University School of Medicine, Aichi, Japan.
Takayasu
M
M
Watanabe
K
K
Noda
A
A
Takagi
T
T
Suzuki
Y
Y
Yoshida
J
J
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003288:Contusions / Q000188:drug therapy / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D017078:Laser-Doppler Flowmetry; D007962:Leukocytes / Q000201:enzymology / Q000473:pathology; D008775:Methylprednisolone / Q000008:administration & dosage / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D009504:Neutrophils / Q000473:pathology; D009195:Peroxidase / Q000032:analysis; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D012018:Reflex / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D013116:Spinal Cord / Q000098:blood supply; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000473:pathology; D018709:Statistics, Nonparametric
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D009195:Peroxidase; C049347:fasudil; D008775:Methylprednisolone