Microglial activation and brain injury after intracerebral hemorrhage

Abstract

SummaryMicroglial activation and thrombin formation contribute to brain injury after intracerebral hemorrhage (ICH). Tumor necrosis factor-alpha (TNF-) and interleukin-1 beta (IL-1) are 2 major proinflammatory cytokines. In this study, we investigated whether thrombin stimulates TNF-and IL-1 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 10 U=mL), or thrombin plus tuftsin (0.05 mg=mL), an inhibitor of microglia activation. Levels of TNF-and IL-1 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 mL autologous whole blood with or without 25 mg 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-and IL-1 levels in the culture medium were increased after thrombin treatment. Tuftsin reduced thrombin-induced upregulation of TNF-and IL-1. In vivo, microglia were activated after ICH, and intracerebral injection of tuftsin reduced brain edema in the ipsilateral basal ganglia (81.1 AE 0.7% vs. 82.7 AE 1.3% in vehicle-treated group; p < 0.05) after ICH.These results suggest a critical role of microglia activation in ICHrelated brain injury.

Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage–induced secondary brain injury and as potential targets for intervention

“…6 Thrombin also stimulates microglia to secrete IL-1b, resulting in similar damaging effects as TNF-α, such as neurotoxicity, opening of the BBB, and induction of apoptosis. 142 The role of this mechanism in ICH-mediated injury is supported by studies showing attenuation of brain edema by the overexpression of IL-1b receptor antagonists.…”

Xenon Enhances LPS-Induced IL-1β Expression in Microglia via the Extracellular Signal-Regulated Kinase 1/2 Pathway

“…Microglia, the resident immune cells of the central nervous system (CNS; Gehrmann et al 1995), play a central role in the CNS inflammatory response to an injury (Koshinaga et al 2000;Wu et al 2008;Jin et al 2010). The modulation of microglial activation has been shown to exert protective properties (Bye et al 2007;Liu et al 2010;Wilms et al 2010).…”

Neuronal tumour necrosis factor-α and interleukin-1β expression in a porcine model of intracerebral haemorrhage: Modulation by U-74389G

“…IL-1β has been related to oedema formation in ICH (Wagner et al, 2006;Wagner and Dwyer, 2004), inflammation, as well as apoptosis and vasogenic oedema in several brain pathologies (Holmin and Mathiesen, 2000) and central nervous system injury (Allan and Rothwell, 2003). Wagner et al (2006) report upregulation of IL-1β gene expression the first hours after haematoma induction in ICH, while Wu et al (2008) showed that IL-1β levels were increased after thrombin treatment in the culture medium. A reduction of IL-1β has been observed after administration of Curmucin (King et al, 2011) or deferoxamine (Miao et al, 2012), in mice and rat models of ICH respectively, with final reduced neurological deficiency.…”