Matthew C Culkin, Priyanka Bele, Anastasia P Georges, Patricia Santos, Grace Niziolek, Lewis J Kaplan, Douglas H Smith, Jose L Pascual
{"title":"剂量依赖性氨甲环酸阻碍创伤性脑损伤后脑干白细胞动员和血脑屏障通透性:体内小鼠研究","authors":"Matthew C Culkin, Priyanka Bele, Anastasia P Georges, Patricia Santos, Grace Niziolek, Lewis J Kaplan, Douglas H Smith, Jose L Pascual","doi":"10.1007/s12028-024-01952-0","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Early posttraumatic brain injury (TBI) tranexamic acid (TXA) may reduce blood-brain barrier (BBB) permeability, but it is unclear if this effect is fixed regardless of dose. We hypothesized that post-TBI TXA demonstrates a dose-dependent reduction of in vivo penumbral leukocyte mobilization, BBB microvascular permeability, and enhancement of neuroclinical recovery.</p><p><strong>Methods: </strong>CD1 male mice (n = 40) were randomly assigned to TBI by controlled cortical impact (injury [I]) or sham TBI (S), followed by intravenous bolus of either saline (placebo [P]) or TXA (15, 30, or 60 mg/kg). At 48 h, in vivo pial intravital microscopy visualized live penumbral BBB microvascular leukocytes and albumin leakage. Neuroclinical recovery was assessed by Garcia Neurological Test scores and animal weight changes at 24 h and 48 h after injury.</p><p><strong>Results: </strong>I + TXA60 reduced live penumbral leukocyte rolling compared with I + P (p < 0.001) and both lower TXA doses (p = 0.017 vs. I + TXA15, p = 0.012 vs. I + TXA30). Leukocyte adhesion was infrequent and similar across groups. Only I + TXA60 significantly reduced BBB permeability compared with that in the I + P (p = 0.004) group. All TXA doses improved Garcia Test scores relative to I + P at both 24 h and 48 h (p < 0.001 vs. I + P for all at both time points). Mean 24-h body weight loss was greatest in the I + P (- 8.7 ± 1.3%) group and lowest in the I + TXA15 (- 4.4 ± 1.0%, p = 0.051 vs. I + P) group.</p><p><strong>Conclusions: </strong>Only higher TXA dosing definitively abrogates penumbral leukocyte mobilization, preserving BBB integrity post TBI. Some neuroclinical recovery is observed, even with lower TXA dosing. Better outcomes with higher dose TXA after TBI may occur secondary to blunting of leukocyte-mediated penumbral cerebrovascular inflammation.</p>","PeriodicalId":19118,"journal":{"name":"Neurocritical Care","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dose-Dependent Tranexamic Acid Blunting of Penumbral Leukocyte Mobilization and Blood-Brain Barrier Permeability Following Traumatic Brain Injury: An In Vivo Murine Study.\",\"authors\":\"Matthew C Culkin, Priyanka Bele, Anastasia P Georges, Patricia Santos, Grace Niziolek, Lewis J Kaplan, Douglas H Smith, Jose L Pascual\",\"doi\":\"10.1007/s12028-024-01952-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Early posttraumatic brain injury (TBI) tranexamic acid (TXA) may reduce blood-brain barrier (BBB) permeability, but it is unclear if this effect is fixed regardless of dose. We hypothesized that post-TBI TXA demonstrates a dose-dependent reduction of in vivo penumbral leukocyte mobilization, BBB microvascular permeability, and enhancement of neuroclinical recovery.</p><p><strong>Methods: </strong>CD1 male mice (n = 40) were randomly assigned to TBI by controlled cortical impact (injury [I]) or sham TBI (S), followed by intravenous bolus of either saline (placebo [P]) or TXA (15, 30, or 60 mg/kg). At 48 h, in vivo pial intravital microscopy visualized live penumbral BBB microvascular leukocytes and albumin leakage. Neuroclinical recovery was assessed by Garcia Neurological Test scores and animal weight changes at 24 h and 48 h after injury.</p><p><strong>Results: </strong>I + TXA60 reduced live penumbral leukocyte rolling compared with I + P (p < 0.001) and both lower TXA doses (p = 0.017 vs. I + TXA15, p = 0.012 vs. I + TXA30). Leukocyte adhesion was infrequent and similar across groups. Only I + TXA60 significantly reduced BBB permeability compared with that in the I + P (p = 0.004) group. All TXA doses improved Garcia Test scores relative to I + P at both 24 h and 48 h (p < 0.001 vs. I + P for all at both time points). Mean 24-h body weight loss was greatest in the I + P (- 8.7 ± 1.3%) group and lowest in the I + TXA15 (- 4.4 ± 1.0%, p = 0.051 vs. I + P) group.</p><p><strong>Conclusions: </strong>Only higher TXA dosing definitively abrogates penumbral leukocyte mobilization, preserving BBB integrity post TBI. Some neuroclinical recovery is observed, even with lower TXA dosing. 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引用次数: 0
摘要
背景:创伤性脑损伤(TBI)后早期氨甲环酸(TXA)可降低血脑屏障(BBB)的通透性,但目前尚不清楚这种效应是否与剂量无关。我们假设,创伤性脑损伤后氨甲环酸可剂量依赖性地降低体内半球白细胞动员、BBB微血管通透性,并促进神经临床恢复:方法:CD1雄性小鼠(n = 40)被随机分配到受控皮层冲击(损伤 [I])或假性创伤性脑损伤(S),然后静脉注射生理盐水(安慰剂 [P])或TXA(15、30或60 mg/kg)。48 小时后,体内髓内观察显微镜可观察到活的半月板 BBB 微血管白细胞和白蛋白渗漏。根据加西亚神经测试评分和损伤后24小时和48小时动物体重变化评估神经临床恢复情况:结果:与 I + P 相比,I + TXA60 减少了活的半球白细胞滚动(p 结论:I + TXA60 减少了活的半球白细胞滚动,而 I + P 减少了活的半球白细胞滚动:只有较高剂量的TXA才能明确消除半球白细胞移动,保护创伤性脑损伤后BBB的完整性。即使使用较低剂量的 TXA,也能观察到一些神经临床恢复。创伤性脑损伤后使用较高剂量的 TXA 会有更好的疗效,这可能是由于白细胞介导的半球脑血管炎症变得迟钝。
Dose-Dependent Tranexamic Acid Blunting of Penumbral Leukocyte Mobilization and Blood-Brain Barrier Permeability Following Traumatic Brain Injury: An In Vivo Murine Study.
Background: Early posttraumatic brain injury (TBI) tranexamic acid (TXA) may reduce blood-brain barrier (BBB) permeability, but it is unclear if this effect is fixed regardless of dose. We hypothesized that post-TBI TXA demonstrates a dose-dependent reduction of in vivo penumbral leukocyte mobilization, BBB microvascular permeability, and enhancement of neuroclinical recovery.
Methods: CD1 male mice (n = 40) were randomly assigned to TBI by controlled cortical impact (injury [I]) or sham TBI (S), followed by intravenous bolus of either saline (placebo [P]) or TXA (15, 30, or 60 mg/kg). At 48 h, in vivo pial intravital microscopy visualized live penumbral BBB microvascular leukocytes and albumin leakage. Neuroclinical recovery was assessed by Garcia Neurological Test scores and animal weight changes at 24 h and 48 h after injury.
Results: I + TXA60 reduced live penumbral leukocyte rolling compared with I + P (p < 0.001) and both lower TXA doses (p = 0.017 vs. I + TXA15, p = 0.012 vs. I + TXA30). Leukocyte adhesion was infrequent and similar across groups. Only I + TXA60 significantly reduced BBB permeability compared with that in the I + P (p = 0.004) group. All TXA doses improved Garcia Test scores relative to I + P at both 24 h and 48 h (p < 0.001 vs. I + P for all at both time points). Mean 24-h body weight loss was greatest in the I + P (- 8.7 ± 1.3%) group and lowest in the I + TXA15 (- 4.4 ± 1.0%, p = 0.051 vs. I + P) group.
Conclusions: Only higher TXA dosing definitively abrogates penumbral leukocyte mobilization, preserving BBB integrity post TBI. Some neuroclinical recovery is observed, even with lower TXA dosing. Better outcomes with higher dose TXA after TBI may occur secondary to blunting of leukocyte-mediated penumbral cerebrovascular inflammation.
期刊介绍:
Neurocritical Care is a peer reviewed scientific publication whose major goal is to disseminate new knowledge on all aspects of acute neurological care. It is directed towards neurosurgeons, neuro-intensivists, neurologists, anesthesiologists, emergency physicians, and critical care nurses treating patients with urgent neurologic disorders. These are conditions that may potentially evolve rapidly and could need immediate medical or surgical intervention. Neurocritical Care provides a comprehensive overview of current developments in intensive care neurology, neurosurgery and neuroanesthesia and includes information about new therapeutic avenues and technological innovations. Neurocritical Care is the official journal of the Neurocritical Care Society.