Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction
Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction
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DOI：
10.1097/00006123-200106000-00051
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发表时间：
2001-06-01
期刊：
影响因子：
4.8
通讯作者：
Friedlander, RM
中科院分区：
文献类型：
--
作者：
Mejia, ROS;Ona, VO;Friedlander, RM
目的：Caspase-1在小鼠实验性创伤性脑损伤（TBI）后介导神经元细胞死亡和功能障碍中起重要作用。米诺环素，一种抗生素四环素的衍生物，抑制半胱天冬酶-1的表达。本研究探讨二甲胺四环素是否可以改善TBI介导的损伤mice.METHODS：从小鼠脑创伤性脑损伤进行免疫组化分析caspase-1，caspase-3，和神经元特异性标记物（NeuN）。米诺环素和盐水治疗的小鼠创伤性脑损伤进行了比较，就神经功能，病变体积，和白细胞介素-LP production.Results：免疫组化分析显示，激活caspase-1和caspase-3是存在于神经元TBI后24小时。与给予盐水对照的小鼠相比，在TBI之前12小时或之后30分钟在小鼠中腹膜内给予米诺环素导致神经功能改善，如通过TBI之后1至4天的旋转棒性能所评估的。与盐水治疗的小鼠相比，创伤后4天评估的损伤体积在创伤前或创伤后接受米诺环素治疗的小鼠中显着减少。Caspase-1的活性，通过测量成熟的白细胞介素-1 β的生产酶联免疫吸附试验，定量，在小鼠进行TBI，这一增加显着减少米诺环素治疗mice.CONCLUSION：我们首次表明，caspase-1和caspase-3的活动定位在实验性脑外伤后的神经元内。此外，这些结果表明，米诺环素是一种有效的药理学试剂，用于减少由实验性TBI引起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。这些结果为米诺环素在人类创伤患者中的评价提供了实验依据。
OBJECTIVE: 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.METHODS: 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-lp production.RESULTS: 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-1 beta production by enzyme-linked immunosorbent assay, was considerably increased in mice that underwent TBI, and this increase was significantly diminished in minocycline-treated mice.CONCLUSION: 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.