Formation of complement membrane attack complex in mammalian cerebral cortex evokes seizures and neurodegeneration.
The complement system consists of >30 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.
Xiong
Zhi-Qi
ZQ
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Qian
Weihua
W
Suzuki
Katsuaki
K
McNamara
James O
JO
D000818:Animals; D002404:Catheterization; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D003184:Complement C7 / Q000008:administration & dosage / Q000378:metabolism; D003185:Complement C8 / Q000008:administration & dosage / Q000378:metabolism; D003186:Complement C9 / Q000008:administration & dosage / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000096:biosynthesis / Q000633:toxicity*; D003165:Complement System Proteins / Q000008:administration & dosage / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004567:Electrodes, Implanted; D004569:Electroencephalography; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D019636:Neurodegenerative Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced* / Q000503:physiopathology; D014851:Wakefulness
D003184:Complement C7; D003185:Complement C8; D003186:Complement C9; D015938:Complement Membrane Attack Complex; D005456:Fluorescent Dyes; C050974:complement C5b-6 complex; D003165:Complement System Proteins