Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration
Formation of Complement Membrane Attack Complex in Mammalian Cerebral Cortex Evokes Seizures and Neurodegeneration
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DOI：
10.1523/jneurosci.23-03-00955.2003
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发表时间：
2003-02
期刊：
影响因子：
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通讯作者：
Z. Xiong;Weihua Qian;Katsuaki Suzuki;J. McNamara
中科院分区：
文献类型：
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作者：
Z. Xiong;Weihua Qian;Katsuaki Suzuki;J. McNamara
补体系统由>；30蛋白质组成，它们以一种仔细调节的方式相互作用，以摧毁入侵的细菌，并防止免疫复合体在正常组织中沉积。这个复杂的系统可以通过不同的途径被不同的机制激活，但所有的机制都会聚在最终的共同途径上，在这个途径中，五种蛋白质组装成一个多分子复合体，即膜攻击复合体(MAC)。MAC插入细胞膜形成功能孔，导致离子流动和最终的渗透溶解。在多种中枢神经系统疾病中，已发现大脑皮质灰质中存在MAC修饰神经元的免疫组织化学证据，但在活体哺乳动物大脑皮层中MAC沉积的有害后果尚不清楚。在这里，我们证明了将膜攻击途径的单个蛋白(C5b6、C7、C8和C9)顺序地注入清醒的自由活动大鼠的海马区，引起了行为和电信号的癫痫发作以及细胞毒性。癫痫发作发生在注射C8/C9期间或之后不久。在体外同时输注所有五种预混蛋白既不会引起癫痫发作，也不会产生细胞毒性。连续输注所有五种蛋白质的要求以及癫痫发作与输注C8/C9的时间关系表明，MAC是在体内形成的，并触发了癫痫发作和细胞毒性。大脑皮质灰质中补体MAC的沉积可能与癫痫发作和人类大脑各种疾病的细胞死亡有关。
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 premixedinvitro. 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.