Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration

Abstract

The complement system consists of Ͼ30 proteins that interact in a carefully regulated manner to destroy invading bacteria and prevent the deposition of immune complexes in normal tissue. This complex system can be activated by diverse mechanisms proceeding through distinct pathways, yet all converge on a final common pathway in which five proteins assemble into a multimolecular complex, the membrane attack complex (MAC). The MAC inserts into cell membranes to form a functional pore, resulting in ion flux and ultimately osmotic lysis. Immunohistochemical evidence of the MAC decorating neurons in cortical gray matter has been identified in multiple CNS diseases, yet the deleterious consequences, if any, of MAC deposition in the cortex of mammalian brain in vivo are unknown. Here we demonstrate that the sequential infusion of individual proteins of the membrane attack pathway (C5b6, C7, C8, and C9) into the hippocampus of awake, freely moving rats induced both behavioral and electrographic seizures as well as cytotoxicity. The onset of seizures occurred during or shortly after the infusion of C8/C9. Neither seizures nor cytotoxicity resulted from the simultaneous infusion of all five proteins premixed in vitro. The requirement for the sequential infusion of all five proteins together with the temporal relationship of seizure onset to infusions of C8/C9 implies that the MAC was formed in vivo and triggered both seizures and cytotoxicity. Deposition of the complement MAC in cortical gray matter may contribute to epileptic seizures and cell death in diverse diseases of the human brain.

Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy

“…However, an overactivation of the complement system can also have damaging effects through the activation of microglia and proinflammatory cytokines. Interestingly, sequential infusion of individual proteins of the membrane attack pathway into the hippocampus of freely moving rats induces seizures as well as cytotoxicity (Xiong et al, 2003). A recent microarray study on entorhinal cortex material of MTLE patients also has pointed to the involvement of complement activation (Jamali et al, 2006).…”

Immunity and Inflammation in Epilepsy

“…This effect was mediated by prostaglandin E2 (PGE2)-induced activation of the E-prostanoid 2 (EP2) receptors (Rojas et al 2014). A role in cell loss has also been ascribed to the activation of the complement cascade in neurons and glia (also eliciting seizures) (Xiong et al 2003) and to neurotrophils that may enter the brain Figure 1. Pathophysiological consequences of glia activation in epilepsy.…”

Complement-Dependent Apoptosis and Inflammatory Gene Changes in Murine Lupus Cerebritis

“…In addition to anaphylatoxin receptors on inflammatory cells, there is increasing evidence of a role for these receptors on fixed tissue cells. C3b binds to immune complexes, whereas C5b initiates the assembly of the C5b-9 membrane attack complex (MAC) that can result in cellular death or activation after membrane insertion (5,6). To prevent injury of host tissue, regulatory proteins strictly control the spontaneous and immune complex-induced activation of the complement system (7).…”