Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses.
Antithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI(2)) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGFIalpha, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-alpha, rat interleukin-8 and myeloperoxidase. In contrast,Trp(49) -modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT. An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI. Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI(2). These findings also suggested that AT might be a potential neuroprotective agent.
Hirose
Koji
K
Department Surgery, Graduate School of Medical Science, Kumamoto University, Honjo 1-1-1, Kumamoto 860-0811, Japan.
Okajima
Kenji
K
Uchiba
Mitsuhiro
M
Nakano
Kan-yu
KY
Utoh
Junichi
J
Kitamura
Nobuo
N
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D000991:Antithrombins / Q000502:physiology*; D004396:Coloring Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D011464:Epoprostenol / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D016209:Interleukin-8 / Q000378:metabolism; D007511:Ischemia; D008297:Male; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy*; D013116:Spinal Cord / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013997:Time Factors; D014364:Tryptophan / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000991:Antithrombins; D004396:Coloring Agents; D016209:Interleukin-8; D013778:Tetrazolium Salts; D014409:Tumor Necrosis Factor-alpha; D015121:6-Ketoprostaglandin F1 alpha; C009591:triphenyltetrazolium; D014364:Tryptophan; D011464:Epoprostenol; D009195:Peroxidase; D015951:Factor Xa