Medusa's Head: The Complement System in Traumatic Brain and Spinal Cord Injury.

Traumatic brain injury (TBI) and spinal cord injury (SCI) are critical medical conditions and a public health problem for which limited therapeutic options are available. The complement cascade is activated after TBI and SCI, and the resulting effects have been investigated in gene-knockout and pharmacological models. Multiple experimental studies support a net detrimental role of C3 and C5 activation in the early stages of TBI and SCI. Less firm experimental evidence suggests that, downstream of C3/C5, effector mechanisms, including the generation of membrane-activated complex and direct damage to membranes and neutrophils infiltration, may bring about the direct damage of central nervous system tissue and enhancement of neuroinflammation. The role of upstream classical, alternative, or extrinsic complement activation cascades remains unclear. Although several issues remain to be investigated, current evidence supports the investigation of a number of complement-targeting agents targeting C3 or C5, such as eculizumab, for repurposing in TBI and SCI treatment.