PDF(Pubmed)
Abstract：
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. There are no effective therapies available for TBI patients. Vepoloxamer is an amphiphilic polyethylene-polypropylene-polyethylene tri-block copolymer that seals membranes and restores plasma membrane integrity in damaged cells. We previously demonstrated that treatment of TBI rats with Vepoloxamer improves functional recovery. However, additional studies are needed to potentially translate Vepoloxamer treatment from preclinical studies into clinical applications. We thus conducted a study to investigate dose-response and therapeutic window of Vepoloxamer on functional recovery of adult rats after TBI. To identify the most effective dose of Vepoloxamer, male Wistar adult rats with controlled cortical impact (CCI) injury were randomly treated with 0 (vehicle), 100, 300, or 600 mg/kg of Vepoloxamer, administered intravenously (IV) at 2 h after TBI. We then performed a therapeutic window study in which the rats were treated IV with the most effective single dose of Vepoloxamer at different time points of 2 h, 4 h, 1 day, or 3 days after TBI. A battery of cognitive and neurological tests was performed. Animals were killed 35 days after TBI for histopathological analysis. Dose-response experiments showed that Vepoloxamer at all three tested doses (100, 300, 600 mg/kg) administered 2 h post injury significantly improved cognitive functional recovery, whereas Vepoloxamer at doses of 300 and 600 mg/kg, but not the 100 mg/kg dose, significantly reduced lesion volume compared to saline treatment. However, Vepoloxamer at 300 mg/kg showed significantly improved neurological and cognitive outcomes than treatment with a dose of 600 mg/kg. In addition, our data demonstrated that the dose of 300 mg/kg of Vepoloxamer administered at 2 h, 4 h, 1 day, or 3 days post injury significantly improved neurological function compared with vehicle, whereas Vepoloxamer administered at 2 h or 4 h post injury significantly improved cognitive function compared with the 1-day and 3-day treatments, with the most robust effect administered at 2 h post injury. The present study demonstrated that Vepoloxamer improves functional recovery in a dose-and time-dependent manner, with therapeutic efficacy compared with vehicle evident even when the treatment is initiated 3 days post TBI in the rat.
摘要：
创伤性脑损伤（TBI）是全球范围内死亡和残疾的主要原因。对于TBI患者没有有效的治疗方法。维泊洛沙姆是一种两亲聚乙烯-聚丙烯-聚乙烯三嵌段共聚物，可密封膜并恢复受损细胞中的质膜完整性。我们先前证明了用Vepoloxamer治疗TBI大鼠可改善功能恢复。然而,还需要更多的研究将维泊洛沙姆治疗从临床前研究转化为临床应用.因此，我们进行了一项研究，以研究维泊洛沙姆对TBI后成年大鼠功能恢复的剂量反应和治疗窗。为了确定维泊洛沙姆的最有效剂量，雄性Wistar成年大鼠控制性皮质冲击（CCI）损伤随机治疗0（媒介物），100、300或600mg/kg的维泊洛沙姆，在TBI后2小时静脉内（IV）给药。然后，我们进行了治疗窗口研究，其中在2小时的不同时间点用最有效的单剂量的维泊洛沙姆对大鼠进行IV治疗。4h,1天,或TBI后3天。进行了一系列认知和神经学测试。在TBI后35天处死动物用于组织病理学分析。剂量反应实验表明，维泊洛沙姆在所有三个测试剂量（100，300，600mg/kg）在损伤后2小时给予显着改善认知功能恢复，而维泊洛沙姆的剂量为300和600毫克/千克，但不是100毫克/千克的剂量，与盐水治疗相比，病变体积显着减少。然而,与使用600mg/kg剂量的治疗相比,300mg/kg的维泊洛沙姆显示出显著改善的神经和认知结果。此外,我们的数据表明，剂量为300毫克/千克的维泊洛沙姆在2小时给药，4h,1天,或损伤后3天显着改善神经功能与车辆相比，与1天和3天治疗相比，在损伤后2小时或4小时给予Vepoloxamer显着改善了认知功能，在受伤后2小时给予最强烈的效果。本研究表明，维泊洛沙姆以剂量和时间依赖性方式改善功能恢复，甚至当在大鼠TBI后3天开始治疗时,与媒介物相比具有明显的治疗功效。
