From the Department of Surgery, Texas A&M Health Science Center, (A.J.M., B.D.R., C.L.I.), Research Regulatory Affairs (A.R.H.), Department of Biostatistics (C.N.S.), Baylor Scott & White Research Institute, Temple, Texas; and Department of Surgery (B.T.), Morehouse School of Medicine, Atlanta, Georgia.
J Trauma Acute Care Surg. 2020 Sep;89(3):435-440. doi: 10.1097/TA.0000000000002801.
Traumatic brain injury (TBI) has significant morbidity and cost implications. Primary treatment modalities aim to decrease intracranial pressure; however, therapies targeting the underlying pathophysiology of a TBI are limited. The TBI-induced microvascular leak and secondary injury are largely due to proteolysis of the blood-brain barrier (BBB) by matrix metalloproteinase-9. We previously observed doxycycline's inhibitory affinity on matrix metalloproteinase-9 resulting in preserved BBB integrity in nonsurvival murine studies. This study sought to determine the effect of doxycycline on functional motor and behavioral outcomes in the setting of a TBI murine survival model.
C57BL/6J mice were assigned to a sham, TBI, or TBI with doxycycline arm. A moderate TBI was induced utilizing a controlled cortical impactor. The TBI with doxycycline cohort received a dose of doxycycline (20 mg/kg) 2 hours after injury and every 12 hours until postoperative day (POD) 6. All mice underwent preoperative testing for weight, modified neurological severity score, wire grip, and ataxia analysis (DigiGait). Postoperative testing was performed on POD 1, POD 3, and POD 6 for the same measures. SAS 9.4 was used for comparative analysis.
Fifteen sham mice, 15 TBI mice, and 10 TBI with doxycycline mice were studied. Mice treated with doxycycline had significantly improved modified neurological severity score and wire grip scores at POD 1 (all p < 0.05). Mice treated with doxycycline had significantly improved ataxia scores by POD 3 and POD 6 (all p < 0.05). There was no significant difference in rate of weight change between the three groups.
Mice treated with doxycycline following TBI demonstrated improved behavioral and motor function suggesting doxycycline's role in preserving murine BBB integrity. Examining the role of doxycycline in human TBIs is warranted given the relative universal accessibility, affordability, and safety profile of doxycycline.
创伤性脑损伤 (TBI) 具有显著的发病率和成本影响。主要治疗方法旨在降低颅内压；然而，针对 TBI 潜在病理生理学的治疗方法有限。TBI 引起的微血管渗漏和继发性损伤主要是由于基质金属蛋白酶-9 对血脑屏障 (BBB) 的蛋白水解作用。我们之前观察到强力霉素对基质金属蛋白酶-9 的抑制亲和力导致非存活小鼠研究中 BBB 完整性得以保留。本研究旨在确定强力霉素对 TBI 存活小鼠模型中功能性运动和行为结果的影响。
C57BL/6J 小鼠分为假手术、TBI 或 TBI 加强力霉素组。使用皮质撞击器诱导中度 TBI。强力霉素组在损伤后 2 小时给予强力霉素（20mg/kg），并在术后第 6 天（POD）前每 12 小时给予一次。所有小鼠在术前进行体重、改良神经严重程度评分、线夹和共济失调分析（DigiGait）测试。术后第 1、3 和 6 天进行相同的测试。使用 SAS 9.4 进行比较分析。
研究了 15 只假手术小鼠、15 只 TBI 小鼠和 10 只 TBI 加强力霉素组。强力霉素治疗的小鼠在 POD1 时改良神经严重程度评分和线夹评分明显改善（均 p < 0.05）。强力霉素治疗的小鼠在 POD3 和 POD6 时共济失调评分明显改善（均 p < 0.05）。三组之间体重变化率无显著差异。
TBI 后用强力霉素治疗的小鼠表现出改善的行为和运动功能，表明强力霉素在保持小鼠 BBB 完整性方面的作用。鉴于强力霉素相对普遍的可及性、可负担性和安全性，检查强力霉素在人类 TBI 中的作用是合理的。
