Precision Effects of Glibenclamide on MRI Endophenotypes in Clinically Relevant Murine Traumatic Brain Injury.
Precision Effects of Glibenclamide on MRI Endophenotypes in Clinically Relevant Murine Traumatic Brain Injury.
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DOI：
10.1097/ccm.0000000000005749
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发表时间：
2023-02-01
影响因子：
8.8
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中科院分区：
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鉴于临床试验失败的悠久历史，解决创伤性脑损伤 (TBI) 异质性越来越被认为对于治疗转化至关重要。我们根据剂量、TBI 类型（患者选择）和影像内表型（结果选择）评估了一种有前途的治疗方法（格列本脲）的差异效应。鉴于正在进行的格列本脲治疗脑挫伤的 2 期/计划 3 期试验，我们向 TBI 精准医学提供信息的目标是及时的。在两种已建立的严重 TBI 模型中，格列本脲对 MRI 内表型进行盲法随机对照临床前试验：受控皮质冲击（CCI，孤立性脑挫伤）和 CCI+失血性休克（HS，临床常见的第二次损伤）。临床前实验室。成年雄性 C57BL/6J 小鼠 (n = 54)。小鼠被随机分配至初始 CCI±HS 组和媒介物/低剂量（20 μg/kg）/高剂量格列本脲（10 μg/小鼠）。继续皮下输注（0.4μg/小时）7天。连续 MRI（3 小时、6 小时、24 小时和 7 天）测量血肿和水肿体积、T2 松弛（血管源性水肿）、表观扩散系数（ADC、细胞/细胞毒性水肿）和 7 天 T1 后钆值（血脑屏障 [BBB] 完整性）。线性混合模型评估时间变化。在产生的不同 MRI 水肿内表型方面，CCI 与 CCI+HS 之间观察到明显的异质性（所有 p < 0.05）。格列本脲具有不同的影响。与媒介物相比，高剂量格列本脲在 CCI (p = 0.0001) 后减少了约 60% 的血肿量，在 CCI+HS (p = 4.1 × 10–6) 后减少了约 48% 的血肿量。抗水肿益处主要体现在 CCI 中：高剂量格列本脲使同侧皮层的几种 MRI 内表型正常化（血肿体积、T2、ADC 和 T1 对比后所有 p < 0.05）。急性效应（3小时）针对血肿（p = 0.001）和细胞毒性水肿减少（p = 0.0045）。高剂量格列本脲可减少 TBI 后伴有 HS 的血肿量，但抗水肿作用并不强。小剂量格列本脲没有益处。高剂量格列本脲有利于孤立性脑挫伤后的血肿量、血管源性水肿、细胞毒性水肿和血脑屏障完整性。血肿和细胞毒性水肿的影响是急性的；血管源性水肿可能需要更长的治疗时间。我们的研究结果提供了新的见解，可以为正在进行的试验的解释以及格列本脲未来 TBI 试验的精确设计（剂量、样本量估计、患者选择、结果选择和贝叶斯分析）提供信息。
Addressing traumatic brain injury (TBI) heterogeneity is increasingly recognized as essential for therapy translation given the long history of failed clinical trials. We evaluated differential effects of a promising treatment (glibenclamide) based on dose, TBI type (patient selection), and imaging endophenotype (outcome selection). Our goal to inform TBI precision medicine is contextually timely given ongoing phase 2/planned phase 3 trials of glibenclamide in brain contusion. Blinded randomized controlled preclinical trial of glibenclamide on MRI endophenotypes in two established severe TBI models: controlled cortical impact (CCI, isolated brain contusion) and CCI+hemorrhagic shock (HS, clinically common second insult). Preclinical laboratory. Adult male C57BL/6J mice (n = 54). Mice were randomized to naïve, CCI±HS with vehicle/low-dose (20 μg/kg)/high-dose glibenclamide (10 μg/mouse). Seven-day subcutaneous infusions (0.4 μg/hr) were continued. Serial MRI (3 hr, 6 hr, 24 hr, and 7 d) measured hematoma and edema volumes, T2 relaxation (vasogenic edema), apparent diffusion coefficient (ADC, cellular/cytotoxic edema), and 7-day T1-post gadolinium values (blood-brain-barrier [BBB] integrity). Linear mixed models assessed temporal changes. Marked heterogeneity was observed between CCI versus CCI+HS in terms of different MRI edema endophenotypes generated (all p < 0.05). Glibenclamide had variable impact. High-dose glibenclamide reduced hematoma volume ~60% after CCI (p = 0.0001) and ~48% after CCI+HS (p = 4.1 × 10–6) versus vehicle. Antiedema benefits were primarily in CCI: high-dose glibenclamide normalized several MRI endophenotypes in ipsilateral cortex (all p < 0.05, hematoma volume, T2, ADC, and T1-post contrast). Acute effects (3 hr) were specific to hematoma (p = 0.001) and cytotoxic edema reduction (p = 0.0045). High-dose glibenclamide reduced hematoma volume after TBI with concomitant HS, but antiedema effects were not robust. Low-dose glibenclamide was not beneficial. High-dose glibenclamide benefitted hematoma volume, vasogenic edema, cytotoxic edema, and BBB integrity after isolated brain contusion. Hematoma and cytotoxic edema effects were acute; longer treatment windows may be possible for vasogenic edema. Our findings provide new insights to inform interpretation of ongoing trials as well as precision design (dose, sample size estimation, patient selection, outcome selection, and Bayesian analysis) of future TBI trials of glibenclamide.