hirudin and Encephalitis

Intracerebral hemorrhage (ICH) is a severe type of stroke without effective treatment. The coagulation cascade is activated after blood flows into the brain parenchyma. The conversion of fibrinogen to fibrin is an essential step of coagulation processes, but its influences on neuroinflammation and long-term outcome after ICH have not been adequately studied. Hirudin binds to thrombin and inhibits the conversion of fibrinogen to fibrin. We therefore investigated the impact of hirudin treatment on brain inflammation and long-term outcome of ICH in mice.. Fibrinogen levels were measured in plasma samples from patients with ICH. In mice subjected to collagenase injection, fibrinogen levels were measured in the plasma and brain. The impact of hirudin on neuroinflammation and long-term neurological outcome was determined in ICH mice.. Circulating fibrinogen level was increased in patients with ICH at day 1 and day 4 after onset. In ICH mice, fibrinogen levels in the blood and brain were increased at day 7. Delayed daily administration of hirudin from day 7 to day 28 significantly improved long-term outcome in ICH mice. Hirudin treatment reduced leukocyte accumulation in the brain and shifted microglia toward an anti-inflammatory phenotype. In addition, depletion of microglia in ICH mice diminished the benefit of hirudin in ICH mice.. These results suggest that inhibition of fibrin formation alleviates brain inflammation and improves long-term outcome after ICH.

Topics: Animals; Brain; Cerebral Hemorrhage; Encephalitis; Female; Fibrin; Fibrinogen; Hirudin Therapy; Hirudins; Humans; Male; Mice, Inbred C57BL

Hirudin is a specific and direct-acting thrombin inhibitor superior to heparin as an anticoagulant. Thrombin is a multifunctional molecule that acts as a serine protease locally generated from prothrombin during blood coagulation related to injury and/or inflammation. We previously reported that thrombin might be involved in the inflammatory response, glial reaction, and scar formation that occurred in central nervous system (CNS). Here we studied the suppressive effects of hirudin on the inflammation, vimentin-positive astrocytes, and glial fibrillary acidic protein (GFAP)-positive astrocytes using rat cerebral ablation models. Hirudin and vehicle solution soaked in Gelform were administered to the cavity of the traumatic brain defect. Brains were examined by conventional histologic and immunohistologic technique. Antibodies for monocytes/macrophages, GFAP, and vimentin were used to assess the infiltration of inflammatory cells and reaction of astrocytes. The number of the inflammatory cells, vimentin-positive astrocytes, and GFAP-positive astrocytes were quantitatively analyzed. Hirudin suppressed the infiltration of inflammatory cells and the increase in vimentin-positive astrocytes, but had no effects on the increase in GFAP-positive astrocytes. These data suggest that thrombin may play an important role in inflammatory and glial responses to CNS injury, and that hirudin can be a candidate for the therapeutic agent that minimizes the secondary brain damage following the inflammation, and the glial reaction mediated by vimentin-positive astrocytes near the lesion site.

Topics: Animals; Antithrombins; Astrocytes; Brain Injuries; Encephalitis; Hirudins; Immunohistochemistry; Male; Rats; Rats, Wistar; Recombinant Proteins; Vimentin