Complement in Neurotrauma
Central nervous system (CNS) injury is classified as a diverse group of disorders that can include spinal cord injury (SCI) and traumatic brain injury (TBI). Once either an SCI or TBI occurs there is an inflammatory response, which includes the activation of the complement pathway. Activation of this pathway leads to the formation of opsonic fragments (C3b and C4b), anaphylactic fragments (C3a and C5a), and the formation of the membrane attack complex (MAC) also known as C5b-9. Studies on complement’s effect after SCI or TBI have concluded that complement activation impairs recovery. However, recent studies have suggested that there is a dual role for complement that can be both beneficial as well as detrimental in the CNS. Interestingly, many studies utilizing animal models for the inflammatory response of the complement system have been utilizing an animal model we show here is a poor indicator of mechanism.
Previous data from the laboratory has shown that C6 deficiency in PVG rats was beneficial for recovery after SCI. However, this data was in conflict with other data from our laboratory experiments utilizing a more complement sufficient BUB/BnJ mouse that was also C6 deficient, which was, in this case detrimental for recovery. Due to this inconsistency littermate PVG C6-D and C6 WT rats were generated to ask the question if C6 deficiency would improve fully complement sufficient rodent model. Investigation has revealed that littermate controls of PVG C6-D rats had results similar to our BUB C6-D mice, that C6 was beneficial for recovery as shown through motor recovery and lesion volume. Critically, investigations of inhibiting the classical, alternative, and lectin pathway demonstrated that a BUB C3 knockout had increased hippocampal sparing, neuronal sparing, synaptic sparing, and decreased activated microglial response. BUB C3 knockouts also exhibited increased motor recovery after TBI and less hyperactivity. In conclusion these studies suggest that MAC is beneficial for recovery after a SCI in a correct rodent model and that C3 knockout is beneficial for recovery after a TBI.