Woodruff Trent M, Costantini Kerina J, Crane James W, Atkin Julie D, Monk Peter N, Taylor Stephen M, Noakes Peter G
School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
J Immunol. 2008 Dec 15;181(12):8727-34. doi: 10.4049/jimmunol.181.12.8727.
Complement activation products are elevated in the cerebrospinal fluid and spinal cord of patients with amyotrophic lateral sclerosis (ALS). In this study, we demonstrate complement system involvement in a rodent model of ALS (human SOD1(G93A) transgenic rats). With end-stage disease, SOD1(G93A) rats displayed marked deposition of C3/C3b, and a significant up-regulation of the C5aR in the lumbar spinal cord. This was associated with increased numbers of C5aR-positive astrocytes. However, expression of C5L2, the alternative receptor for C5a, was highest on motor neurons early in the disease process. To determine the contribution of C5a to the pathology displayed by this model of ALS, rats were administered an orally active, selective C5aR antagonist (PMX205; 1 mg/kg/day, oral). Animals treated with PMX205 displayed a significant extension of survival time and a reduction in end-stage motor scores, as compared with vehicle-treated rats. PMX205-treated animals also displayed reduced levels of astroglial proliferation in the lumbar spinal cord. This study provides the first demonstration of an involvement of C5a in an ALS model and suggests that inhibitors of complement activation could be beneficial in the treatment of this neurodegenerative disease.
补体激活产物在肌萎缩侧索硬化症（ALS）患者的脑脊液和脊髓中升高。在本研究中，我们证明补体系统参与了ALS的啮齿动物模型（人SOD1(G93A)转基因大鼠）。在疾病终末期，SOD1(G93A)大鼠在腰脊髓中显示出C3/C3b的明显沉积以及C5aR的显著上调。这与C5aR阳性星形胶质细胞数量增加有关。然而，C5a的替代受体C5L2的表达在疾病早期在运动神经元上最高。为了确定C5a对该ALS模型所表现出的病理学的贡献，给大鼠施用口服活性的选择性C5aR拮抗剂（PMX205；1mg/kg/天，口服）。与用赋形剂处理的大鼠相比，用PMX205处理的动物显示出生存时间显著延长和终末期运动评分降低。用PMX205处理的动物在腰脊髓中的星形胶质细胞增殖水平也降低。本研究首次证明C5a参与了ALS模型，并表明补体激活抑制剂可能对治疗这种神经退行性疾病有益。
