From the Department of General Surgery, University of Cincinnati, Cincinnati Ohio.
J Trauma Acute Care Surg. 2021 Aug 1;91(2S Suppl 2):S89-S98. doi: 10.1097/TA.0000000000003259.
Traumatic brain injury (TBI) is common in civilians and military personnel. No potential therapeutics have been evaluated to prevent secondary injury induced by the hypobaric hypoxia (HH) environment integral to postinjury aeromedical evacuation (AE). We examined the role of allopurinol, propranolol, adenosine/lidocaine/magnesium (ALM), or amitriptyline administration prior to simulated flight following murine TBI.
Mice underwent TBI and were given allopurinol, propranolol, amitriptyline, or ALM prior to simulated AE or normobaric normoxia (NN) control. Heart rate (HR), respiratory rate, and oxygen saturation (Spo2) were recorded throughout simulated AE. Mice were sacrificed at 24 hours, 7 days, or 30 days. Serum and cerebral cytokines were assessed by enzyme-linked immunosorbent assay. Motor function testing was performed with Rotarod ambulation. Immunohistochemistry was conducted to examine phosphorylated tau (p-tau) accumulation in the hippocampus at 30 days.
While all treatments improved oxygen saturation, propranolol, amitriptyline, and allopurinol improved AE-induced tachycardia. At 24 hours, both propranolol and amitriptyline reduced tumor necrosis factor alpha levels while allopurinol and ALM reduced tumor necrosis factor alpha levels only in NN mice. Propranolol, amitriptyline, and ALM demonstrated lower serum monocyte chemoattractant protein-1 7 days after AE. Both amitriptyline and allopurinol improved Rotarod times for AE mice while only allopurinol improved Rotarod times for NN mice. Propranolol was able to reduce p-tau accumulation under both HH and NN conditions while ALM only reduced p-tau in hypobaric hypoxic conditions.
Propranolol lowered post-TBI HR with reduced proinflammatory effects, including p-tau reduction. Amitriptyline-induced lower post-TBI HR and improved functional outcomes without affecting inflammatory response. Allopurinol did not affect vital signs but improved late post-TBI systemic inflammation and functional outcomes. Adenosine/lidocaine/magnesium provided no short-term improvements but reduced p-tau accumulation at 30 days in the HH cohort. Allopurinol may be the best of the four treatments to help prevent short-term functional deficits while propranolol may address long-term effects.
Basic science article.
颅脑创伤（TBI）在平民和军人中很常见。在与伤后航空医疗后送（AE）相关的低压低氧（HH）环境中，尚未评估任何潜在的治疗方法来预防继发性损伤。我们在模拟飞行后检查了别嘌呤醇、普萘洛尔、腺嘌呤/利多卡因/镁（ALM）或阿米替林在模拟 TBI 后给药对 HH 环境下的治疗作用。
在模拟 AE 或常压低氧（NN）对照前，小鼠接受 TBI 并给予别嘌呤醇、普萘洛尔、阿米替林或 ALM。在模拟 AE 期间记录心率（HR）、呼吸频率和血氧饱和度（Spo2）。24 小时、7 天或 30 天后处死小鼠。通过酶联免疫吸附试验评估血清和脑内细胞因子。采用旋转轮步行运动测试进行运动功能测试。30 天时通过免疫组化检查海马中磷酸化 tau（p-tau）的积累。
虽然所有治疗都改善了氧饱和度，但普萘洛尔、阿米替林和别嘌呤醇改善了 AE 引起的心动过速。在 24 小时时，普萘洛尔和阿米替林降低了肿瘤坏死因子-α水平，而别嘌呤醇和 ALM 仅在 NN 小鼠中降低了肿瘤坏死因子-α水平。AE 后 7 天，普萘洛尔、阿米替林和 ALM 均降低了血清单核细胞趋化蛋白-1 水平。AE 后，阿米替林和别嘌呤醇均改善了 AE 小鼠的旋转轮时间，而仅别嘌呤醇改善了 NN 小鼠的旋转轮时间。普萘洛尔可降低 HH 和 NN 条件下的 TBI 后 HR，降低促炎作用，包括减少 p-tau 积累。阿米替林诱导的 TBI 后 HR 降低和功能结果改善而不影响炎症反应。别嘌呤醇不影响生命体征，但改善了晚期 TBI 后的全身炎症和功能结果。腺嘌呤/利多卡因/镁没有提供短期改善，但在 HH 队列中 30 天时减少了 p-tau 的积累。别嘌呤醇可能是四种治疗方法中最适合帮助预防短期功能缺陷的方法，而普萘洛尔可能解决长期影响。
基础科学文章。
