Neuroprotection by recombinant thrombomodulin

We examined whether recombinant human soluble thrombomodulin (rhs-TM) reduc es compression trauma-induced spinal cord injury through protein C activati on in rats. Administration of Ihs-TM, either before or after the induction of spinal cord injury (SCI), markedly reduced the resulting motor disturban ces. However. neither rhs-TM pretreated with an anti-rhs-TM monoclonal anti body (MAb) F2H5, which inhibits thrombin binding to rhs-TM, nor those pretr eated with MAb R5G12, which selectively inhibits protein C activation by rh s-TM, prevented the motor disturbances. Intramedullary hemorrhages, observe d 24 h after trauma, were significantly reduced in animals given rhs-TM. Th e increase in the tissue levels of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha mRNA expression, and the accumulation of leukocytes in the damag ed segment of the spinal cord were significantly inhibited in animals recei ving rhs-TM, but these effects were not observed following administration o f rhs-TM pretreated with MAb R5G12 or MAb F2H5. Leukocytopenia and activate d 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-alph a mRNA and such therapeutic effects of rhs-TM could be dependent on its pro tein C activation capacity. Findings further suggest that thrombomodulin ca n be implicated not only in the coagulation system but in regulation of the inflammatory response.