Sanchez Mejia R O, Ona V O, Li M, Friedlander R M
Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Neurosurgery. 2001 Jun;48(6):1393-9; discussion 1399-401. doi: 10.1097/00006123-200106000-00051.
Caspase-1 plays an important functional role mediating neuronal cell death and dysfunction after experimental traumatic brain injury (TBI) in mice. Minocycline, a derivative of the antibiotic tetracycline, inhibits caspase-1 expression. This study investigates whether minocycline can ameliorate TBI-mediated injury in mice.
Brains from mice subjected to traumatic brain injury underwent immunohistochemical analyses for caspase-1, caspase-3, and a neuronal specific marker (NeuN). Minocycline- and saline-treated mice subjected to traumatic brain injury were compared with respect to neurological function, lesion volume, and interleukin-1beta production.
Immunohistochemical analysis revealed that activated caspase-1 and caspase-3 are present in neurons 24 hours after TBI. Intraperitoneal administration of minocycline 12 hours before or 30 minutes after TBI in mice resulted in improved neurological function when compared with mice given saline control, as assessed by Rotarod performance 1 to 4 days after TBI. The lesion volume, assessed 4 days after trauma, was significantly decreased in mice treated with minocycline before or after trauma when compared with saline-treated mice. Caspase-1 activity, quantified by measuring mature interleukin-1beta production by enzyme-linked immunosorbent assay, was considerably increased in mice that underwent TBI, and this increase was significantly diminished in minocycline-treated mice.
We show for the first time that caspase-1 and caspase-3 activities localize specifically within neurons after experimental brain trauma. Further, these results indicate that minocycline is an effective pharmacological agent for reducing tissue injury and neurological deficits that result from experimental TBI, likely through a caspase-1-dependent mechanism. These results provide an experimental rationale for the evaluation of minocycline in human trauma patients.
在小鼠实验性创伤性脑损伤（TBI）后，半胱天冬酶 -1在介导神经元细胞死亡和功能障碍中发挥重要作用。米诺环素是抗生素四环素的衍生物，可抑制半胱天冬酶 -1的表达。本研究旨在探讨米诺环素是否能改善小鼠TBI介导的损伤。
对遭受创伤性脑损伤的小鼠大脑进行半胱天冬酶 -1、半胱天冬酶 -3和神经元特异性标志物（NeuN）的免疫组织化学分析。比较米诺环素和生理盐水处理的创伤性脑损伤小鼠的神经功能、损伤体积和白细胞介素 -1β的产生。
免疫组织化学分析显示，TBI后24小时神经元中存在活化的半胱天冬酶 -1和半胱天冬酶 -3。与给予生理盐水对照的小鼠相比，在TBI前12小时或后30分钟腹腔注射米诺环素的小鼠，在TBI后1至4天通过转棒试验评估，其神经功能得到改善。与生理盐水处理的小鼠相比，创伤后4天评估的损伤体积在创伤前后用米诺环素处理的小鼠中显著减小。通过酶联免疫吸附测定法测量成熟白细胞介素 -1β的产生来定量半胱天冬酶 -1活性，在遭受TBI的小鼠中显著增加，而在米诺环素处理的小鼠中这种增加显著减少。
我们首次表明，实验性脑创伤后半胱天冬酶 -1和半胱天冬酶 -3活性特异性定位于神经元内。此外，这些结果表明，米诺环素是一种有效的药物，可减少实验性TBI导致的组织损伤和神经功能缺损，可能是通过半胱天冬酶 -1依赖性机制。这些结果为评估米诺环素在人类创伤患者中的应用提供了实验依据。
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