Gabexate mesilate, a synthetic protease inhibitor, prevents compression-induced spinal cord injury by inhibiting activation of leukocytes in rats.
OBJECTIVE
Gabexate mesilate is a synthetic protease inhibitor capable of inhibiting both coagulation and cytokine production by monocytes. To investigate whether gabexate mesilate is useful for the prevention of posttraumatic spinal cord injury, we examined its effect on compression trauma-induced spinal cord injury in rats.


METHODS
Prospective, randomized, blinded, controlled study.


METHODS
Research laboratory at a university medical center.


METHODS
Male Wistar rats weighing 300 to 350 g.


METHODS
Spinal cord injury was induced by applying a 20-g weight extradurally to the spinal cord at the level of the 12th thoracic vertebra for 20 mins. Spinal cord injury was evaluated by assessing the motor function of the rats 24 hrs posttrauma. The accumulation of leukocytes and histologic changes in the injured spinal cord tissue also were examined. Rats received gabexate mesilate (10 or 20 mg/kg i.p.) 30 mins before or after the compressive trauma. The effects of heparin or an inactive derivative of activated factor X (a selective inhibitor of thrombin generation) on compressive trauma-induced spinal cord injury also were examined. Leukocytopenia was induced by the administration of nitrogen mustard.


RESULTS
The motor disturbances observed following traumatic spinal cord compression, evaluated by Tarlov's score, and the accumulation of leukocytes in the injured tissue, evaluated by measuring tissue myeloperoxidase activity, were markedly reduced by leukocyte depletion induced by nitrogen mustard and by pre- or posttreatment of animals with gabexate mesilate. Neither heparin nor the inactive derivative of activated factor X prevented the motor disturbances and the accumulation of leukocytes. Histologic examination demonstrated that intramedullary hemorrhages observed 24 hrs after trauma at the 12th thoracic vertebra were significantly attenuated by nitrogen mustard-induced leukocytopenia and the administration of gabexate mesilate.


CONCLUSIONS
The compression trauma-induced spinal cord injury demonstrated by this model was mainly mediated by leukocytes. Gabexate mesilate prevented spinal cord injury not by inhibiting coagulation, but by inhibiting the activation of leukocytes.
Taoka
Y
Y
Department of Laboratory Medicine, Kumamoto University Medical School, Japan.
Okajima
K
K
Uchiba
M
M
Murakami
K
K
Kushimoto
S
S
Johno
M
M
Naruo
M
M
Okabe
H
H
Takatsuki
K
K
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology; D015951:Factor Xa / Q000494:pharmacology; D016670:Gabexate / Q000494:pharmacology / Q000627:therapeutic use*; D006493:Heparin / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000201:enzymology; D008297:Male; D008466:Mechlorethamine / Q000633:toxicity; D009043:Motor Activity / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013117:Spinal Cord Compression / Q000150:complications* / Q000473:pathology; D013119:Spinal Cord Injuries / Q000209:etiology / Q000517:prevention & control*
D000590:Amino Acid Chloromethyl Ketones; D000925:Anticoagulants; D000991:Antithrombins; D015842:Serine Proteinase Inhibitors; C097736:dansyl-glutamyl-glycyl-arginyl chloromethyl ketone-treated factor Xa; D016670:Gabexate; D008466:Mechlorethamine; D006493:Heparin; D009195:Peroxidase; D015951:Factor Xa