Mocco J, Mack William J, Ducruet Andrew F, King Ryan G, Sughrue Michael E, Coon Alexander L, Sosunov Sergei A, Sciacca Robert R, Zhang Yuan, Marsh Henry C, Pinsky David J, Connolly E Sander
Department of Neurological Surgery, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
J Neurosurg. 2006 Oct;105(4):595-601. doi: 10.3171/jns.2006.105.4.595.
Postischemic cerebral inflammatory injury has been extensively investigated in an effort to develop effective neuroprotective agents. The complement cascade has emerged as an important contributor to postischemic neuronal injury. Soluble complement receptor Type 1 (sCR1), a potent inhibitor of complement activation, has been shown to reduce infarct volume and improve functional outcome after murine stroke. Given numerous high-profile failures to translate promising antiinflammatory strategies from the laboratory to the clinic and given the known species-specificity of the complement cascade, the authors sought to evaluate the neuroprotective effect of sCR1 in a nonhuman primate model of stroke.
A total of 48 adult male baboons (Papio anubis) were randomly assigned to receive 15 mg/kg of sCR1 or vehicle. The animals were subjected to 75 minutes of middle cerebral artery occlusion/reperfusion. Perioperative blood samples were analyzed for total complement activity by using a CH50 assay. Infarct volume and neurological scores were assessed at the time the animals were killed, and immunohistochemistry was used to determine cerebral drug penetration and C1q deposition. An interim futility analysis led to termination of the trial after study of 12 animals. Total serum complement activity was significantly depressed in the sCR1-treated animals compared with the controls. Immunostaining also demonstrated sCR1 deposition in the ischemic hemispheres of treated animals. Despite these findings, there were no significant differences in infarct volume or neurological score between the sCR1--and vehicle-treated cohorts.
A preischemic bolus infusion of sCR1, the most effective means of administration in mice, was not neuroprotective in a primate model. This study illustrates the utility of a translational primate model of stroke in the assessment of promising antiischemic agents prior to implementation of large-scale clinical trials.
为了研发有效的神经保护剂，人们对缺血后脑炎性损伤进行了广泛研究。补体级联反应已成为缺血后神经元损伤的一个重要因素。可溶性补体1型受体（sCR1）是一种有效的补体激活抑制剂，已被证明可减少小鼠中风后的梗死体积并改善功能结局。鉴于众多将有前景的抗炎策略从实验室转化到临床的尝试均告失败，且已知补体级联反应具有物种特异性，作者试图在非人类灵长类动物中风模型中评估sCR1的神经保护作用。
总共48只成年雄性狒狒（埃及狒狒）被随机分配接受15mg/kg的sCR1或赋形剂。动物接受75分钟的大脑中动脉闭塞/再灌注。通过CH50试验分析围手术期血样中的总补体活性。在处死动物时评估梗死体积和神经学评分，并使用免疫组织化学来确定脑内药物渗透和C1q沉积。一项中期无效性分析导致在研究12只动物后终止试验。与对照组相比，sCR1治疗组动物的总血清补体活性显著降低。免疫染色也显示sCR1在治疗动物的缺血半球中沉积。尽管有这些发现，但sCR1治疗组和赋形剂治疗组在梗死体积或神经学评分方面没有显著差异。
在小鼠中最有效的给药方式——缺血前推注sCR1，在灵长类动物模型中并无神经保护作用。本研究说明了在开展大规模临床试验之前，中风转化灵长类动物模型在评估有前景的抗缺血药物方面的作用。
