title: Microglial activation and brain injury after intracerebral hemorrhage.
abstract: Microglial activation and thrombin formation contribute to brain injury after intracerebral hemorrhage (ICH). Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) are 2 major proinflammatory cytokines. In this study, we investigated whether thrombin stimulates TNF-alpha and IL-1beta secretion in vitro, and whether microglial inhibition reduces ICH-induced brain injury in vivo. There were 2 parts to this study. In the first part, cultured rat microglial cells were treated with vehicle, thrombin (5 and 10U/mL), or thrombin plus tuftsin (0.05 microg/mL), an inhibitor of microglia activation. Levels of TNF-alpha and IL-1beta in culture medium were measured by ELISA at 4, 8, and 24 h after thrombin treatment. In the second part of the study, rats received an intracerebral infusion of 100 microL autologous whole blood with or without 25 microg of tuftsin 1-3 fragment. Rats were killed at day 1 or day 3 for immunohistochemistry and brain water content measurement. We found that thrombin receptors were expressed in cultured microglia cells, and TNF-alpha and IL-1beta levels in the culture medium were increased after thrombin treatment. Tuftsin reduced thrombin-induced upregulation of TNF-alpha and IL-1beta. In vivo, microglia were activated after ICH, and intracerebral injection of tuftsin reduced brain edema in the ipsilateral basal ganglia (81.1 +/- 0.7% vs. 82.7 +/- 1.3% in vehicle-treated group; p < 0.05) after ICH. These results suggest a critical role of microglia activation in ICH-related brain injury.
authors.affiliation: Medical School, Zhejiang University, Hangzhou, China.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.forename: S
authors.initials: S
authors.lastname: Yang
authors.forename: G
authors.initials: G
authors.lastname: Xi
authors.forename: S
authors.initials: S
authors.lastname: Song
authors.forename: G
authors.initials: G
authors.lastname: Fu
authors.forename: R F
authors.initials: RF
authors.lastname: Keep
authors.forename: Y
authors.initials: Y
authors.lastname: Hua
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001929:Brain Edema / Q000378:metabolism / Q000473:pathology; D001930:Brain Injuries / Q000209:etiology* / Q000473:pathology*; D039481:CD11b Antigen / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002543:Cerebral Hemorrhage / Q000150:complications*; D004195:Disease Models, Animal; D007155:Immunologic Factors / Q000494:pharmacology; D053583:Interleukin-1beta / Q000378:metabolism; D007477:Ions / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors; D014405:Tuftsin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D039481:CD11b Antigen; D007155:Immunologic Factors; D053583:Interleukin-1beta; D007477:Ions; D014409:Tumor Necrosis Factor-alpha; D013917:Thrombin; D014405:Tuftsin