Traumatic brain injury (TBI) induces a profound inflammatory response that contributes to brain edema, neuronal cell death, and adverse outcome [55] [56] [57] . Posttraumatic activation of the complement cascade has been shown to play a pivotal role in the development of secondary brain injury (Table 1) [10, 12, 23, 24, 58, 59] . Multiple experimental Table 1 Insights from experimental complement inhibition based on genetically engineered mice and pharmacological approaches in models of traumatic brain injury (TBI). and clinical studies have revealed elevated levels of complement components and complement activation fragments in serum, cerebrospinal fluid (CSF), and brain parenchyma after head injury [12, 23, 60, 61] . Intracerebral complement deposition after TBI derives either from an altered permeability of a dysfunctional blood-brain barrier (BBB), or from posttraumatic biosynthesis of complement components by resident and infiltrating cells of the central nervous system (CNS) [12, [62] [63] [64] . Most studies have focused on the central complement component C3, and on the potential neuroprotective effects of inhibiting C3 convertases, the level at which the three main activation pathways merge, thus inhibiting downstream complement activation. Clinical studies revealed elevated C3 levels in the CSF of patients with severe TBI [65] . Experimental brain injury models described intracerebral PMNL infiltration and concomitant accumulation of complement C3 in cortical and hippocampal brain sections after experimental TBI in rats [66] . In those studies, C3 accumulation was significantly related to places of intracerebral cell death and to increased intracerebral myeloperoxidase activity [66] . In accordance with these findings, C3-deficient mice were found to have lower neutrophil extravasation and cerebral lesion volumes in a freeze model of brain injury [67] . In light of the central role of C3 and downstream complement activation fragments in the pathophysiology of TBI, much emphasis has been recently devoted to elucidating therapeutic aspects of C3 convertase inhibition, in various experimental model systems [68] [69] [70] [71] [72] . Genetically engineered mice, either deficient in the C3 gene, or with transgenic CNS-restricted overexpression of Crry -a soluble inhibitor of C3 convertases in mice-showed a significant extent of neuroprotection after brain injury, compared to wild-type animals [67, 70] . The GFAP-sCrry transgenic mice showed a significantly improved neurological outcome and an attenuated extent of posttraumatic BBB dysfunction in a model of closed head injury [70] . Based on these insights, the concept of Crry-mediated neuroprotection was extrapolated to a pharmacological approach, by posttraumatic injection of a recombinant chimeric Crry-Ig molecule in the same model of closed head injury [71] . The systemic injection of Crry-Ig during an early therapeutic "window of opportunity" within one hour to 24 hours after trauma resulted in a significant neurological improvement and reduced extent of neuronal cell death, compared to vehicle-injected control mice [71] .