Loss of plasmalemmal integrity may mediate cell death after traumatic brain injury (TBI). Prior studies in controlled cortical impact (CCI) indicated that the membrane resealing agent Kollidon VA64 improved histopathological and functional outcomes. Kollidon VA64 was therefore selected as the seventh therapy tested by the Operation Brain Trauma Therapy consortium, across three pre-clinical TBI rat models: parasagittal fluid percussion injury (FPI), CCI, and penetrating ballistic-like brain injury (PBBI). In each model, rats were randomized to one of four exposures (7–15/group): (1) sham; (2) TBI+vehicle; (3) TBI+Kollidon VA64 low-dose (0.4 g/kg); and (4) TBI+Kollidon VA64 high-dose (0.8 g/kg). A single intravenous VA64 bolus was given 15 min post-injury. Behavioral, histopathological, and serum biomarker outcomes were assessed over 21 days generating a 22-point scoring matrix per model. In FPI, low-dose VA64 produced zero points across behavior and histopathology. High-dose VA64 worsened motor performance compared with TBI-vehicle, producing -2.5 points. In CCI, low-dose VA64 produced intermediate benefit on beam balance and the Morris water maze (MWM), generating +3.5 points, whereas high-dose VA64 showed no effects on behavior or histopathology. In PBBI, neither dose altered behavior or histopathology. Regarding biomarkers, significant increases in glial fibrillary acidic protein (GFAP) levels were seen in TBI versus sham at 4 h and 24 h across models. Benefit of low-dose VA64 on GFAP was seen at 24 h only in FPI. Ubiquitin C-terminal hydrolase-L1 (UCH-L1) was increased in TBI compared with vehicle across models at 4 h but not at 24 h, without treatment effects. Overall, low dose VA64 generated +4.5 points (+3.5 in CCI) whereas high dose generated -2.0 points. The modest/inconsistent benefit observed reduced enthusiasm to pursue further testing.

中文翻译：

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Kollidon VA64 治疗创伤性脑损伤：手术脑创伤治疗

质膜完整性的丧失可能会介导创伤性脑损伤（TBI）后的细胞死亡。先前对受控皮质冲击 (CCI) 的研究表明，膜重新密封剂 Kollidon VA64 改善了组织病理学和功能结果。因此，Kollidon VA64 被选为脑外伤手术治疗联盟测试的第七种疗法，涵盖三种临床前 TBI 大鼠模型：矢状旁液体冲击损伤 (FPI)、CCI 和穿透性弹道样脑损伤 (PBBI)。在每个模型中，大鼠被随机分配到四种暴露中的一种（7-15/组）：（1）假手术；(2) TBI+车辆；(3)TBI+Kollidon VA64低剂量(0.4g/kg)；(4)TBI+Kollidon VA64高剂量(0.8g/kg)。受伤后 15 分钟给予单次静脉注射 VA64。行为学、组织病理学、在 21 天内评估血清生物标志物结果，为每个模型生成 22 点评分矩阵。在 FPI 中，低剂量 VA64 在行为和组织病理学方面产生零分。与 TBI 车辆相比，高剂量 VA64 的运动性能恶化，产生 -2.5 分。在 CCI 中，低剂量 VA64 对平衡木平衡和莫里斯水迷宫 (MWM) 产生中等益处，产生 +3.5 分，而高剂量 VA64 对行为或组织病理学没有影响。在 PBBI 中，剂量均不会改变行为或组织病理学。关于生物标志物，在模型中 4 小时和 24 小时，TBI 组与假手术组相比，胶质纤维酸性蛋白 (GFAP) 水平显着增加。仅在 FPI 中 24 小时时才观察到低剂量 VA64 对 GFAP 的益处。与媒介物相比，TBI 模型中泛素 C 末端水解酶 L1 (UCH-L1) 在 4 小时内增加，但在 24 小时内没有增加，且无治疗效果。总体而言，低剂量 VA64 产生 +4.5 分（CCI 中 +3.5），而高剂量产生 -2.0 分。观察到的适度/不一致的好处降低了进行进一步测试的热情。