Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage.
Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage.
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DOI：
10.1016/j.brainres.2009.04.047
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发表时间：
2009-11-17
期刊：
影响因子：
2.9
通讯作者：
Connolly ES
中科院分区：
文献类型：
--
作者：
Garrett MC;Otten ML;Starke RM;Komotar RJ;Magotti P;Lambris JD;Rynkowski MA;Connolly ES
脑出血(ICH)与神经损伤有关，这种损伤可以通过针对补体级联的神经保护策略来改善。我们研究了C5a受体拮抗剂(C5aRA)单独及与C3a受体拮抗剂(C3aRA)合用在小鼠脑出血后的作用。成年雄性C57BL/6J小鼠随机分为溶媒组、单纯C5aRA组和C3aRA+C5aRA组，分别于脑出血后6h、12h及以后每12h给药一次。采用双注射技术，向右侧纹状体内注入30μL自体全血。最后一组小鼠接受了仅由针头插入和车辆注射组成的假手术。于脑出血后第3天检测双侧大脑半球脑组织含水量及白细胞、小胶质细胞的浸润和活化情况。分别于脑出血后6、12、24、48、72h用Morris水迷宫(MWM)、28分量表和角点试验评定神经功能。脑出血后6h，三组患者均出现神经功能障碍，且有可比性。接受C5aRA治疗的动物和C3aRA/C5aRA联合治疗的动物在24、48和72小时的转弯试验和28分神经功能评分中显示出与赋形剂治疗组相比的显著改善。同样，在Morris水迷宫实验中，C5aRA和C3aRA/C5aRA组小鼠的空间记忆保持能力明显好于赋形剂组小鼠(C3aRA/C5aRA组：23.4±2.0 S p≤0.0001 vs赋形剂组：10.0±1.7 S)。与赋形剂对照组相比，C3aRA/C5aRA组小鼠同侧皮质和同侧纹状体的脑含水量显著降低(同侧皮质：C3aRA/C5aRA：0.755403±0.008比0.773327±0.003 p=0.01纹状体：0.752273±0.007比0.771163±0.0036 p=0.02)。C5aRA治疗组和C3aRA/C5aRA治疗组小鼠出血侧与非出血侧脑内粒细胞比例(CD45+/CD11b+/Ly-6G+)均低于赋形剂对照组(C5aRA：1.78±0.36p=0.02C3aRA/C5aRA：1.59±0.22p=0.005)。虽然C5aRA单独应用提供了神经保护，但C3aRA/C5aRA联合治疗可协同改善神经功能结局，同时减少炎细胞渗透和脑水肿。本研究结果表明，同时阻断C3a和C5a受体是治疗出血性卒中的一种有前途的神经保护策略。
Intracerebral hemorrhage (ICH) is associated with neurological injury that may be ameliorated by a neuroprotective strategy targeting the complement cascade. We investigated the role of C5a-receptor antagonist (C5aRA) solely and in combination with C3a-receptor antagonist (C3aRA) following ICH in mice. Adult male C57BL/6J mice were randomized to receive vehicle, C5aRA alone or C3aRA and C5aRA 6 and 12 h after ICH, and every 12 h thereafter. A double injection technique was used to infuse 30 μL of autologous whole blood into the right striatum. A final group of mice received a sham procedure consisting only of needle insertion followed by vehicle injections. Brain water content and flow cytometry analysis for leukocyte and microglia infiltration and activation in both hemispheres were measured on day 3 post ICH. Neurological dysfunction was assessed using a Morris water-maze (MWM), a 28-point scale, and a corner test at 6, 12, 24, 48 and 72 h after ICH induction. Neurological deficits were present and comparable in all three cohorts 6 h after ICH. Animals treated with C5aRA and animals treated with combined C3aRA/C5aRA demonstrated significant improvements in neurological function assessed by both the corner turn test and a 28-point neurological scale at 24, 48 and 72 h relative to vehicle-treated animals. Similarly, C5aRA and C3aRA/C5aRA-treated mice demonstrated better spatial memory retention in the Morris water-maze test compared with vehicle-treated animals (C3aRA/C5aRA: 23.4 ± 2.0 s p ≤ 0.0001 versus vehicle: 10.0 ± 1.7 s). Relative to vehicle-treated mice, the brain water content in C3aRA/C5aRA-treated mice was significantly decreased in the ipsilateral cortex and ipsilateral striatum (ipsilateral cortex: C3aRA/C5aRA: 0.755403 ± 0.008 versus 0.773327 ± 0.003 p = 0.01 striatum: 0.752273 ± 0.007 versus 0.771163 ± 0.0036 p = 0.02). C5aRA-treated mice and C3aRA/C5aRA-treated mice had a decreased ratio of granulocytes (CD45+/CD11b+/Ly-6G+) in the hemorrhagic versus non-hemorrhagic hemispheres relative to vehicle-treated animals (C5aRA: 1.78 ± 0.36 p = 0.02 C3aRA/C5aRA: 1.59 ± 0.22 p = 0.005 versus vehicle: 3.01). While administration of C5aRA alone provided neuroprotection, combined C3aRA/C5aRA therapy led to synergistic improvements in neurofunctional outcome while reducing inflammatory cell infiltration and brain edema. The results of this study indicate that simultaneous blockade of the C3a and C5a receptors represents a promising neuroprotective strategy in hemorrhagic stroke.
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