Department of Medicine (Neurology), Multidisciplinary Neuroprotection Laboratories, Duke University, Durham, NC, USA>
Neurocrit Care. 2012 Apr;16(2):316-26. doi: 10.1007/s12028-011-9641-5.
Apolipoprotein E has previously been demonstrated to modulate acute brain injury responses, and administration of COG1410, an apoE-mimetic peptide derived from the receptor-binding region of apoE, improves outcome in preclinical models of acute neurological injury. In the current study, we sought to establish the optimal dose and timing of peptide administration associated with improved functional outcome in a murine model of intracerebral hemorrhage (ICH).
Ten to twelve-week-old C57/BL6 male mice were injured by collagenase-induced ICH and randomly selected to receive either vehicle or one of four doses of COG1410 (0.5, 1, 2, or 4 mg/kg) via tail vein injection at 30 min after injury and then daily for 5 days. The injured mice were euthanized at various time points to assess inflammatory mediators, cerebral edema, and hematoma volume. Over the first 5 days following injury, vestibulomotor function was tested via Rotorod (RR) latency. After an optimal dose was demonstrated, a final cohort of animals was injured with ICH and randomly assigned to receive the first dose of COG1410 or vehicle at increasingly longer treatment initiation times after injury. The mice were then assessed for functional deficit via RR testing over the first 5 days following injury.
The mice receiving 2 mg/kg of COG1410 after injury demonstrated reduced functional deficit, decreased brain concentrations of inflammatory proteins, and less cerebral edema, although hematoma volume did not vary. The improved RR performance was maintained when peptide administration was delayed for up to 2 h after ICH.
COG1410 administered at a dose of 2 mg/kg within 2 h after injury improves functional recovery in a murine model of ICH.
载脂蛋白 E 先前已被证明可调节急性脑损伤反应，而给予源自载脂蛋白 E 受体结合区的载脂蛋白 E 模拟肽 COG1410 可改善急性神经损伤的临床前模型中的预后。在本研究中，我们试图确定与改善脑出血（ICH）小鼠模型的功能结果相关的肽给药的最佳剂量和时间。
10 至 12 周龄的 C57/BL6 雄性小鼠通过胶原酶诱导的 ICH 受伤，并随机选择接受载体或 COG1410 的四种剂量（0.5、1、2 或 4mg/kg）之一通过尾静脉注射，在受伤后 30 分钟内注射，然后每天注射 5 天。受伤的小鼠在不同时间点被安乐死，以评估炎症介质、脑水肿和血肿体积。在受伤后的头 5 天内，通过转棒（RR）潜伏期测试前庭运动功能。在证明最佳剂量后，最后一组动物用 ICH 受伤，并随机分配接受 COG1410 或载体的第一剂，在受伤后越来越长的治疗起始时间。然后，通过 RR 测试在受伤后的头 5 天内评估小鼠的功能缺陷。
受伤后给予 2mg/kg COG1410 的小鼠表现出功能缺陷减少、大脑中炎症蛋白浓度降低和脑水肿减少，尽管血肿体积没有变化。当肽给药延迟到 ICH 后 2 小时内时，RR 性能的改善得以维持。
在受伤后 2 小时内给予 2mg/kg 剂量的 COG1410 可改善 ICH 小鼠模型的功能恢复。
