Abstract
Traumatic brain injury (TBI) induces a strong inflammatory response which includes blood-brain barrier damage, edema formation and infiltration of different immune cell subsets. More recently, microvascular thrombosis has been identified as another pathophysiological feature of TBI. The contact-kinin system represents an interface between inflammatory and thrombotic circuits and is activated in different neurological diseases. C1-Inhibitor counteracts activation of the contact-kinin system at multiple levels. We investigated the therapeutic potential of C1-Inhibitor in a model of TBI. Male and female C57BL/6 mice were subjected to cortical cryolesion and treated with C1-Inhibitor after 1 h. Lesion volumes were assessed between day 1 and day 5 and blood-brain barrier damage, thrombus formation as well as the local inflammatory response were determined post TBI. Treatment of male mice with 15.0 IU C1-Inhibitor, but not 7.5 IU, 1 h after cryolesion reduced lesion volumes by ~75% on day 1. This protective effect was preserved in female mice and at later stages of trauma. Mechanistically, C1-Inhibitor stabilized the blood-brain barrier and decreased the invasion of immune cells into the brain parenchyma. Moreover, C1-Inhibitor had strong antithrombotic effects. C1-Inhibitor represents a multifaceted anti-inflammatory and antithrombotic compound that prevents traumatic neurodegeneration in clinically meaningful settings.
Highlights
Traumatic brain injury (TBI) accounts for more than 10 million fatalities worldwide and is a leading cause of permanent disability (Hyder et al, 2007; Roozenbeek et al, 2013)
We investigated the therapeutic potential of C1-Inhibitor in a model of TBI
After trauma the brain endothelium upregulates cellular adhesion molecules and this activation step enables trafficking of inflammatory cells from the blood stream to the sites of tissue damage (Schwarzmaier et al, 2013). Those peripheral cells together with resident cell populations produce myriads of highly active mediators such as cytokines and chemokines that perpetuate the inflammatory response (Schmidt et al, 2005). Another characteristic of severe brain trauma is structural disintegration of the blood-brain barrier, which in consequence leads to the formation of brain edema (Shlosberg et al, 2010)
Summary
Traumatic brain injury (TBI) accounts for more than 10 million fatalities worldwide and is a leading cause of permanent disability (Hyder et al, 2007; Roozenbeek et al, 2013). After trauma the brain endothelium upregulates cellular adhesion molecules and this activation step enables trafficking of inflammatory cells (neutrophils, macrophages) from the blood stream to the sites of tissue damage (Schwarzmaier et al, 2013). Those peripheral cells together with resident cell populations (endothelial cells, microglia, astrocytes) produce myriads of highly active mediators such as cytokines and chemokines that perpetuate the inflammatory response (Schmidt et al, 2005). Pharmaceuticals able to substantially influence inflammation or edema formation in TBI are not available and decompressive surgery, which is a highly invasive procedure, failed to prove efficacy in trauma patients in a recent phase III trial (Cooper et al, 2011)
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