Antithrombin reduces compression-induced spinal cord injury in rats.
Antithrombin (AT), a natural anticoagulant, has been shown to exert anti-inflammatory activity by promoting the endothelial production of prostaglandin I2 (PGI2), thereby reducing tissue injury. To examine whether AT prevents post-traumatic spinal cord injury (SCI), a pathologic condition in which activated neutrophils are critically involved, we tested the effect of AT on SCI induced by compression trauma in rats. Intravenous administration of AT, either before or after the induction of SCI, significantly reduced SCI-related motor disturbances in these animals. AT also significantly inhibited both intramedullary hemorrhage and the decrease in the number of motor neurons following SCI, and inhibited the accumulation of neutrophils in the damaged segment of the spinal cord by inhibiting the increase in transcription of tumor necrosis factor-alpha (TNF-alpha). AT significantly enhanced the increase in the tissue level of 6-keto-PGF1alpha, a stable metabolite of PGI2, at the injured segment of the cord. These therapeutic effects of AT may not depend on its anticoagulant effect. AT did not show any effects in animals pretreated with indomethacin, a potent inhibitor of prostaglandin synthesis, and iloprost, a stable PGI2 analog, produced effects similar to those of AT. Furthermore, intravenously administered AT accumulated selectively at the injured segment of the spinal cord, where thrombin generation might be increased. These findings suggest that AT may reduce the effects of compression trauma-induced SCI by inhibiting neutrophil activation as a consequence of the AT-mediated inhibition of TNF-alpha production. Such therapeutic effects of AT might be mediated by its promoting the endothelial release of PGI2. These findings strongly suggest AT as a potential agent for treating SCI in the clinical setting.
Taoka
Yuji
Y
Department of Diagnostic Medicine, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
Okajima
Kenji
K
Uchiba
Mitsuhiro
M
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology*; D000818:Animals; D000991:Antithrombins / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D011464:Epoprostenol / Q000037:antagonists & inhibitors / Q000502:physiology*; D015951:Factor Xa / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000502:physiology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013117:Spinal Cord Compression / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013917:Thrombin / Q000037:antagonists & inhibitors*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D000991:Antithrombins; D010446:Peptide Fragments; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C097736:dansyl-glutamyl-glycyl-arginyl chloromethyl ketone-treated factor Xa; C072032:thrombin receptor peptide (42-55); D015121:6-Ketoprostaglandin F1 alpha; D011464:Epoprostenol; D009195:Peroxidase; D013917:Thrombin; D015951:Factor Xa; D007213:Indomethacin