Inhibition of the Membrane Attack Complex of the Complement System Reduces Secondary Neuroaxonal Loss and Promotes Neurologic Recovery after Traumatic Brain Injury in Mice

Abstract

Traumatic brain injury (TBI) is the leading cause of disability and death in young adults. The secondary neuroinflammation and neuronal damage that follows the primary mechanical injury is an important cause of disability in affected people. The membrane attack complex (MAC) of the complement system is detected in the traumatized brain early after TBI; however, its role in the pathology and neurologic outcome of TBI has not yet been investigated. We generated a C6 antisense oligonucleotide that blocks MAC formation by inhibiting C6, and we compared its therapeutic effect to that of Ornithodoros moubata complement inhibitor (OmCI), a known inhibitor of C5 activation that blocks generation of the anaphylatoxin C5a and C5b, an essential component of MAC. Severe closed head injury in mice induced abundant MAC deposition in the brain. Treatment with C6 antisense reduced C6 synthesis (85%) and serum levels (90%), and inhibited MAC deposition in the injured brain (91–96%). Treatment also reduced accumulation of microglia/macrophages (50–88%), neuronal apoptosis, axonal loss and weight loss (54–93%), and enhanced neurologic performance (84–92%) compared with placebo-treated controls after injury. These data provide the first evidence, to our knowledge, that inhibition of MAC formation in otherwise complement-sufficient animals reduces neuropathology and promotes neurologic recovery after TBI. Given the importance of maintaining a functional complement opsonization system to fight infections, a critical complication in TBI patients, inhibition of the MAC should be considered to reduce posttraumatic neurologic damage. This work identifies a novel therapeutic target for TBI and will guide the development of new therapy for patients.

An anticomplement agent that homes to the damaged brain and promotes recovery after traumatic brain injury in mice

“…The C3 activation fragment (C3b/ iC3b/C3dg) deposition colocalized with CD59-2a-CRIg (Fig. 3B), but immunostaining for MAC (14,(19)(20)(21)(22) was negative in corresponding areas (Fig. 3C); in contrast, brain tissue from PBStreated TBI controls showed C3 fragments ( Fig.…”

“…S2). Anti-C5 therapies that blocked both C5a and MAC were previously shown to be effective when delivered up to 15 min postinjury (14). To test whether this therapeutic window could be expanded, mice were treated with CD59-2a-CRIg 30 min post-TBI and with a second dose 24 h later.…”

“…To determine whether CD59-2a-CRIg blocked MAC deposition and reduced brain inflammation, sagittal sections from treated and control mice were stained for C9, a marker of MAC deposition (14,(19)(20)(21)(22) (Fig. 5 A-C), and Iba-1, a marker of microglia/macrophages (14) (Fig.…”

“…We recently demonstrated that inhibition of the most downstream complement activation product, the membrane attack complex (MAC), effectively prevents secondary neurologic damage and deficit in experimental TBI (14). MAC inhibition was achieved using an antisense oligonucleotide targeting C6, an essential MAC component, administered for 1 wk before injury (14).…”

“…MAC inhibition was achieved using an antisense oligonucleotide targeting C6, an essential MAC component, administered for 1 wk before injury (14). A clinically relevant anticomplement therapy in TBI must rapidly block complement activation when administered postinjury and be targeted to the activation site to minimize infection risk.…”