Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury
Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury
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DOI：
10.1111/j.1471-4159.2006.03799.x
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发表时间：
2006-06-01
影响因子：
4.7
通讯作者：
Citron, Bruce A.
中科院分区：
文献类型：
--
作者：
Festoff, Barry W.;Ameenuddin, Syed;Citron, Bruce A.
米诺环素是一种临床使用超过40年的四环素，可穿过血脑屏障并阻止半胱天冬酶上调。在亨廷顿氏病和家族性肌萎缩侧索硬化症（ALS）小鼠模型中，它可以减少细胞凋亡，并且正在进行散发性ALS的临床试验。由于脑和脊髓（SCI）损伤后也会发生细胞凋亡，因此预防细胞凋亡可能有助于改善恢复。我们分析了米诺环素在挫伤SCI后28天内的神经保护作用，发现与四环素相比，米诺环素具有显著的功能恢复。组织学、免疫细胞化学和图像分析表明，组织保留具有统计学意义，细胞凋亡和小胶质细胞增生减少，活化的半胱天冬酶-3和底物裂解减少。自从我们最初以摘要形式报道以来，其他人已经发表了米诺环素在各种SCI啮齿动物模型中的积极和消极作用以及各种给药途径。此后，我们发现肿瘤坏死因子-α以及半胱天冬酶-3 mRNA表达降低，这可能是米诺环素改善作用的作用机制。这些结果支持了调节细胞凋亡、半胱天冬酶和小胶质细胞为预防和/或限制CNS创伤后功能丧失程度提供了有前景的治疗靶点的报道。米诺环素和更有效的化学合成四环素类药物，可能会在治疗药物库中找到一个位置，以促进人类SCI后的早期恢复。
Minocycline, a clinically used tetracycline for over 40 years, crosses the blood-brain barrier and prevents caspase up-regulation. It reduces apoptosis in mouse models of Huntington's disease and familial amyotrophic lateral sclerosis (ALS) and is in clinical trial for sporadic ALS. Because apoptosis also occurs after brain and spinal cord (SCI) injury, its prevention may be useful in improving recovery. We analyzed minocycline's neuroprotective effects over 28 days following contusion SCI and found significant functional recovery compared to tetracycline. Histology, immunocytochemistry, and image analysis indicated statistically significant tissue sparing, reduced apoptosis and microgliosis, and less activated caspase-3 and substrate cleavage. Since our original report in abstract form, others have published both positive and negative effects of minocycline in various rodent models of SCI and with various routes of administration. We have since found decreased tumor necrosis factor-alpha, as well as caspase-3 mRNA expression, as possible mechanisms of action for minocycline's ameliorative action. These results support reports that modulating apoptosis, caspases, and microglia provide promising therapeutic targets for prevention and/or limiting the degree of functional loss after CNS trauma. Minocycline, and more potent chemically synthesized tetracyclines, may find a place in the therapeutic arsenal to promote recovery early after SCI in humans.