Serine Protease Inhibitor Attenuates Intracerebral Hemorrhage-Induced Brain Injury and Edema Formation in Rat
Our previous studies have demonstrated that thrombin plays an important role in intracerebral hemorrhage (ICH)-induced brain injury and edema formation. We, therefore, examined whether nafamostat mesilate (FUT), a serine protease inhibitor, can reduce ICH
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Abstract Our previous studies have demonstrated that thrombin plays an important role in intracerebral hemorrhage (ICH)-induced brain injury and edema formation. We, therefore, examined whether nafamostat mesilate (FUT), a serine protease inhibitor, can reduce ICH-induced brain injury. Anesthetized male Sprague-Dawley rats received an infusion of autologous whole blood (100 µL), thrombin (5U/50 µL) or type VII collagenase (0.4 U/2 µL) into the right basal ganglia, the three ICH models used in the present study. FUT (10 mg/kg) or vehicle was administered intraperitoneally 6 h after ICH (or immediately
T. Nakamura (*) Department of Neurobiology and Neurological Surgery, Kagawa University Faculty of Medicine, 1750-1, IkenobeMiki, Kita, Kagawa 761-0173, Japan e-mail: [email protected] Y. Kuroda Department of Emergency and Critical Care Medicine, Kagawa University Faculty of Medicine, 1750-1, IkenobeMiki, Kita, Kagawa, 761-0173, Japan N. Hosomi Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, 1750-1, IkenobeMiki, Kita, Kagawa 761-0173, Japan N. Okabe Department of Neurobiology, Kagawa University Faculty of Medicine, 1750-1, IkenobeMiki, Kita, Kagawa 761-0173, Japan N. Kawai and T. Tamiya Department of Neurological Surgery, Kagawa University Faculty of Medicine, 1750-1, IkenobeMiki, Kita, Kagawa, 761-0173, Japan G. Xi and R.F. Keep R5018 Biomedical Science Research Building Department of Neurosurgery University of Michigan 109 Zina Pitcher Place Ann Arbor, MI 48109-2200, USA T. Itano Department of Neurobiology, Kagawa University Faculty of Medicine, 1750-1, IkenobeMiki, Kita, Kagawa 761-0173, Japan
after thrombin infusion) and then at 12-h intervals (six treatments in total, n = 5 in each group). All rats were sacrificed 72 h later. We also examined whether FUT promotes rebleeding in a model in which ICH was induced by intracerebral injection of collagenase. Systemic administration of FUT starting 6 h after ICH reduced brain water content in the ipsilateral basal ganglia 72 h after ICH compared with vehicle. FUT attenuated ICH-induced changes in 8-OHdG and thrombin-reduced brain edema. FUT did not increase collagenase-induced hematoma volume. FUT attenuates ICH-induced brain edema and DNA injury suggesting that serine protease inhibitor may be potential therapeutic agent for ICH. Keywords Intracerebral hemorrhage • thrombin • serine protease inhibitor • brain edema • rat
Introduction Intracerebral hemorrhage (ICH) is a subtype of stroke with high morbidity. Our previous studies have demonstrated that toxic factors, including iron and thrombin, released from a blood clot may account for the formation of perihematomal edema in ICH (1,8). Thrombin is a serine protease and an essential component in the coagulation cascade. Previous study showed that nafamostat mesilate (FUT) inhibits complement factors thrombin and plasmin and suppresses the protease-based inflammation (2). FUT is a competitive serine protease inhibitor, widely used in Japan in the treatment of acute pancre
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