Quinic acid derivative KZ-41 exhibits radiomitigating activity in preclinical models of radiation injury.
Quinic acid derivative KZ-41 exhibits radiomitigating activity in preclinical models of radiation injury.
复制标题
奎尼酸衍生物 KZ-41 在放射损伤的临床前模型中表现出放射缓解活性。
DOI：
10.1002/ddr.21164
复制
发表时间：
2014
影响因子：
3.8
通讯作者：
Yates,CharlesR
中科院分区：
文献类型：
--
作者：
Thompson,KarinE;Zeng,Kui;Wilson,ChristyM;Gaber,MostafaW;Miller,DuaneD;Yates,CharlesR
临床前研究急性辐射综合征是诱发时，身体的重要部分接受高剂量，以及高剂量率，辐射。我们之前已经确定了一种奎尼酸衍生物KZ-41，可以防止辐射损伤。进行了进一步的临床前有效性研究，以确定KZ-41的放射性激动活性。C57 BL/6小鼠接受全身照射（TBI-LD 80/30，137 Cs; 102 min），然后接受生理盐水或KZ-41（TBI后26 h，100 mg/kg sc）。与溶剂对照相比，KZ-41使30天存活率增加约45%（P< 0.05）。为了进一步研究KZ-41的潜在放射调节机制，我们开发了一种联合放射和血管损伤模型。通过手术固定背窗进行真皮血管成像的C57 BL/6小鼠接受假手术或TBI（137 Cs; 6格雷）。诱导毛细血管后小静脉损伤（TBI后24、48、72和96 h），然后在5 min和24 h进行成像，以评估凝块形成和血流。早在48和72 h分别观察到血流受损（P<0.05）和血凝块形成（P< 0.05）。因此，TBI后72小时的血管损伤用于评价干预（KZ-41; 100 mg/kg，在TBI后12、36和60小时腹腔注射）对放射诱导的血流和凝块形成变化的影响。KZ-41虽然没有改善血流，但增加了凝块形成（P< 0.05）。两组血小板计数均低于假手术对照组（P< 0.05）。总之，KZ-41在致死剂量照射的小鼠中发挥放射性刺激活性。成像结果表明，KZ-41通过促进初始凝块形成和血管血流恢复等机制发挥放射性激动活性。本文所述的成像模型可用于进一步检查辐射诱导的血管损伤修复机制。
Preclinical ResearchAcute radiation syndrome is induced when a significant portion of the body receives high‐dose, as well as high‐dose rate, radiation. We have previously identified a quinic acid‐based derivative, KZ‐41, that protects from radiation injury. Further preclinical efficacy studies were conducted to determine the radiomitigating activity of KZ‐41. C57BL/6 mice received total body irradiation (TBI—LD80/30,137Cs; ∼2 min) followed by either normal saline or KZ‐41 (100 mg/kg sc ∼26 h post‐TBI). KZ‐41 increased 30‐day survival by approximately 45% compared with vehicle controls (P< 0.05). To further investigate the potential radiomodulating mechanisms of KZ‐41, we developed a combined radiation and vascular injury model. C57BL/6 mice surgically fixed with dorsal windows for dermal vasculature imaging received either sham or TBI (137Cs; 6 Gray). Postcapillary venule injury was induced (24, 48, 72, and 96 h post‐TBI) followed by imaging at 5 min and 24 h to assess clot formation and blood flow. Impairment in flow (P< 0.05) and clot formation (P< 0.05) were observed as early as 48 and 72 h, respectively. Thus, vascular injury 72 h post‐TBI was used to evaluate intervention (KZ‐41; 100 mg/kg i.p. at 12, 36, and 60 h post‐TBI) on radiation‐induced changes in both flow and clot formation. KZ‐41, although not improving flow, increased clot formation (P< 0.05). Platelet counts were lower in both irradiated groups compared with sham controls (P< 0.05). In summary, KZ‐41 exerts radiomitigating activity in lethally irradiated mice. Imaging results suggest KZ‐41 exerts radiomitigating activity through mechanisms involving promotion of initial clot formation and vascular flow restoration. The imaging model described herein is useful for further examination of radiation‐induced vascular injury repair mechanisms.