Long-Term Treatment with Thrombomodulin Improves Functional Outcomes after Cerebral Ischemia Even if Administration is Delayed.

Our previous study indicated that recombinant human soluble thrombomodulin (rhsTM) could attenuate brain damage when administered as a bolus in the cerebral ischaemic early phase. Then, we considered that treatment with rhsTM may show therapeutic effects even when administered in the ischaemic delayed phase, because rhsTM has an action of inhibiting high-mobility group box 1 (HMGB1) as a late mediator of lethal systemic inflammation. This study was performed to investigate the effects of delayed treatment with rhsTM on ischaemic brain damage induced by high HMGB1 level in mice subjected to 4-hour middle cerebral artery occlusion (MCAO). One day after MCAO, rhsTM was administered intraperitoneally at a dose of 1 or 5 mg/kg once a day for 7 days. Neurological score, motor coordination and HMGB1 levels were measured 1, 3 and 7 days after MCAO. The presence of activated microglia was evaluated 7 days after MCAO. Systemic HMGB1 levels increased 1 to 7 days after MCAO and were higher at 7 days compared with day 1. At the same time, survival rate decreased, and activated microglia increased in the infarct area. Treatment with rhsTM improved neurological score, motor coordination, survival and prevented brain damage. Moreover, rhsTM decreased both HMGB1 level and number of activated M1 microglia. The results of this study indicated that rhsTM improved functional outcomes via inhibition of HMGB1 up-regulation and M1 microglial activation in the cerebral ischaemic delayed phase. rhsTM may become a new therapeutic agent with a wide therapeutic time window in patients with cerebral ischaemia.