Lack of neuroprotective effects of simvastatin and minocycline in a model of cervical spinal cord injury
Lack of neuroprotective effects of simvastatin and minocycline in a model of cervical spinal cord injury
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DOI：
10.1016/j.expneurol.2010.06.018
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发表时间：
2010-09-01
影响因子：
5.3
通讯作者：
Kwon, Brian K.
中科院分区：
文献类型：
--
作者：
Lee, Jae H. T.;Tigchelaar, Seth;Kwon, Brian K.
米诺环素是一种常用的四环素类抗生素，在许多神经系统疾病如肌萎缩侧索硬化症、多发性硬化症、帕金森病、亨廷顿病、中风和脊髓损伤（SCI）的动物模型中显示出作为潜在治疗剂的前景。辛伐他汀是一种用于降低胆固醇的羟甲基戊二酰辅酶A还原酶抑制剂。这些药物也被称为减少炎症和氧化应激，改善内皮功能，并调节中风，创伤性脑损伤和SCI中的免疫系统。由于这两种药物都具有转化潜力，我们在临床相关的挫伤性颈脊髓损伤模型中评估了它们的神经保护特性。米诺环素90 mg/kg x 3天，2.辛伐他汀20 mg/kg x 7天，3.辛伐他汀20 mg/kg x 7天，然后5 mg/kg x 35天，或4.生理盐水（对照）。使用水平梯测试、圆柱体直立测试、改良的Montoya楼梯测试和梳理测试在6周内评估行为恢复，还使用电子von Frey触觉计评估前爪敏感性。损伤后7周追踪皮质脊髓束和红核脊髓束，并收集脊髓。在脊髓的横截面上评价了灰质和白色物质保留以及皮质脊髓和红核脊髓束发芽的程度。最后，与生理盐水对照组相比，米诺环素和辛伐他汀治疗均与行为测试的表现改善相关。所有组的水平梯试验、圆柱体直立试验和von Frey感觉试验的表现相似。与其他组相比，用辛伐他汀治疗42天的动物在梳理评分中得分显著更高，但在改良的Montoya楼梯试验中回收的颗粒显著少于对照和米诺环素治疗的动物。组织学上，四组之间的白色和灰质保留以及皮质脊髓和红核脊髓发芽的程度没有显著差异。总之，米诺环素和辛伐他汀都不能改善我们的挫伤性颈脊髓损伤模型的功能和组织学恢复。(C)2010年爱思唯尔公司All rights reserved.
Minocycline, a commonly prescribed tetracycline antibiotic, has shown promise as a potential therapeutic agent in animal models of numerous neurologic disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Huntington's disease, stroke, and spinal cord injury (SCI). Simvastatin is one of many hydroxymethylglutaryl-coenzyme-A reductase inhibitors prescribed to lower cholesterol. These drugs are also known to reduce inflammation and oxidative stress, improve endothelial function, and modulate the immune system in stroke, traumatic brain injury, and SCI. As both drugs have translational potential, we evaluated their neuroprotective properties here in a clinically relevant model of contusive cervical spinal cord injury.Sprague-Dawley rats underwent a unilateral cervical contusion SCI at C5 and were randomized to receive: 1. Minocycline 90 mg/kg x 3 days, 2. Simvastatin 20 mg/kg x 7 days, 3. Simvastatin 20 mg/kg x 7 days then 5 mg/kg x 35 days, or 4. Saline (Control). Behavioral recovery was assessed over 6 weeks using the horizontal ladder test, cylinder rearing test, modified Montoya staircase test and grooming test Forepaw sensitivity was also assessed using the electronic von Frey Aesthesiometer. The corticospinal and rubrospinal tracts were traced and the spinal cords were harvested 7 weeks after injury. The extent of gray matter and white matter sparing and corticospinal and rubrospinal tract sprouting were evaluated in cross sections of the spinal cord.In the end, neither minocycline nor simvastatin treatment was associated with improved performance on the behavioral tests, as compared to saline controls. Performance on the horizontal ladder test, cylinder rearing test, and von Frey sensory test were similar among all groups. Animals treated for 42 days with simvastatin scored significantly higher in the grooming score compared to other groups, but retrieved significantly fewer pellets on the modified Montoya staircase test than control and minocycline treated animals. Histologically, there were no significant differences in white and gray matter sparing and in the extent of corticospinal and rubrospinal sprouting between the four groups. In conclusion, both minocycline and simvastatin failed to improve functional and histological recovery in our model of contusive cervical spinal cord injury. (C) 2010 Elsevier Inc. All rights reserved.