Departments of Pediatrics, Neurosurgery, and Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA.
J Neurosci. 2010 Feb 10;30(6):2077-87. doi: 10.1523/JNEUROSCI.5249-09.2010.
Hypoxic-ischemic (HI) brain injury in infants is a leading cause of lifelong disability. We report a novel pathway mediating oxidative brain injury after hypoxia-ischemia in which C1q plays a central role. Neonatal mice incapable of classical or terminal complement activation because of C1q or C6 deficiency or pharmacologically inhibited assembly of membrane attack complex were subjected to hypoxia-ischemia. Only C1q(-/-) mice exhibited neuroprotection coupled with attenuated oxidative brain injury. This was associated with reduced production of reactive oxygen species (ROS) in C1q(-/-) brain mitochondria and preserved activity of the respiratory chain. Compared with C1q(+/+) neurons, cortical C1q(-/-) neurons exhibited resistance to oxygen-glucose deprivation. However, postischemic exposure to exogenous C1q increased both mitochondrial ROS production and mortality of C1q(-/-) neurons. This C1q toxicity was abolished by coexposure to antioxidant Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid). Thus, the C1q component of complement, accelerating mitochondrial ROS emission, exacerbates oxidative injury in the developing HI brain. The terminal complement complex is activated in the HI neonatal brain but appeared to be nonpathogenic. These findings have important implications for design of the proper therapeutic interventions against HI neonatal brain injury by highlighting a pathogenic priority of C1q-mediated mitochondrial oxidative stress over the C1q deposition-triggered terminal complement activation.
缺氧缺血（HI）性脑损伤是婴儿终身残疾的主要原因。我们报告了一种新的途径，该途径介导缺氧缺血后的氧化脑损伤，其中 C1q 起核心作用。由于 C1q 或 C6 缺乏或药物抑制膜攻击复合物的组装，不能进行经典或终末补体激活的新生小鼠会发生缺氧缺血。只有 C1q(-/-) 小鼠表现出神经保护作用，同时伴有氧化脑损伤减轻。这与 C1q(-/-) 脑线粒体中活性氧（ROS）的产生减少以及呼吸链活性的保持有关。与 C1q(+/+) 神经元相比，皮质 C1q(-/-) 神经元对氧葡萄糖剥夺具有抗性。然而，缺血后暴露于外源性 C1q 会增加 C1q(-/-) 神经元的线粒体 ROS 产生和死亡率。这种 C1q 毒性可通过同时暴露于抗氧化剂 Trolox（6-羟基-2,5,7,8-四甲基色满-2-羧酸）而消除。因此，补体的 C1q 成分加速了线粒体 ROS 的释放，加重了发育中 HI 脑的氧化损伤。末端补体复合物在 HI 新生脑中被激活，但似乎没有致病性。这些发现对于通过强调 C1q 介导的线粒体氧化应激相对于 C1q 沉积触发的末端补体激活的致病性优先级，为 HI 新生儿脑损伤的适当治疗干预措施的设计提供了重要意义。
