Recombinant human soluble thrombomodulin ameliorates cerebral ischemic injury through a high-mobility group box 1 inhibitory mechanism without hemorrhagic complications in mice.

ABSTRACT

BACKGROUND: It has been reported that recombinant human soluble thrombomodulin (rhsTM) has a high-mobility group box (HMGB)1 inhibitory effect. Some investigators reported that HMGB1 is associated with ischemic stroke. However, there have been no previous studies to determine whether rhsTM can ameliorate cerebral ischemic injury through its HMGB1 inhibitory mechanism in ischemic stroke. We investigated the effects of rhsTM on cerebral ischemic injury in a 4-h middle cerebral artery occlusion (MCAO) murine model. METHODS: rhsTM (1 or 5mg/kg, i.v.) was administered immediately after 4-h MCAO. Infarct volume, motor coordination, plasma HMGB1 level, and hemorrhage volume were evaluated 24h after 4-h MCAO. RESULTS: The infarct volume (P<0.05) was reduced by rhsTM in mice subjected to 4-h MCAO in a dose-dependent manner. Moreover, rhsTM (5mg/kg) significantly improved motor coordination determined by the rotarod test (P<0.05), and significantly decreased plasma HMGB1 level compared with vehicle-treated controls (P<0.001). In addition, there was no difference in hemorrhage volume between vehicle-treated controls and the rhsTM treatment group. CONCLUSIONS: This represents the first report that rhsTM ameliorates cerebral ischemic injury through an HMGB1 inhibitory mechanism without hemorrhagic complications in mice. Taken together, these observations indicate a palliative effect of rhsTM and suggest new therapeutic possibilities for treatment of ischemic stroke via inhibition of HMGB1.