Neuroprotection by recombinant thrombomodulin.
We examined whether recombinant human soluble thrombomodulin (rhs-TM) reduces compression trauma-induced spinal cord injury through protein C activation in rats. Administration of rhs-TM, either before or after the induction of spinal cord injury (SCI), markedly reduced the resulting motor disturbances. However, neither rhs-TM pretreated with an anti-rhs-TM monoclonal antibody (MAb) F2H5, which inhibits thrombin binding to rhs-TM, nor those pretreated with MAb R5G12, which selectively inhibits protein C activation by rhs-TM, prevented the motor disturbances. Intramedullary hemorrhages, observed 24 h after trauma, were significantly reduced in animals given rhs-TM. The increase in the tissue levels of tumor necrosis factor-alpha (TNF-alpha), TNF-alpha mRNA expression, and the accumulation of leukocytes in the damaged segment of the spinal cord were significantly inhibited in animals receiving rhs-TM, but these effects were not observed following administration of rhs-TM pretreated with MAb R5G12 or MAb F2H5. Leukocytopenia and activated protein C all produced effects similar to those of rhs-TM. These findings suggest that rhs-TM prevents compression trauma-induced SCI by inhibiting leukocyte accumulation by reducing the expression of TNF-alpha mRNA and such therapeutic effects of rhs-TM could be dependent on its protein C activation capacity. Findings further suggest that thrombomodulin can be implicated not only in the coagulation system but in regulation of the inflammatory response.
Taoka
Y
Y
Department of Laboratory Medicine, Kumamoto University School of Medicine, Japan.
Okajima
K
K
Uchiba
M
M
Johno
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D006801:Humans; D007970:Leukopenia / Q000503:physiopathology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D018180:Thrombomodulin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018696:Neuroprotective Agents; D011486:Protein C; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase