Wang Xin, Zhu Shan, Drozda Martin, Zhang Wenhua, Stavrovskaya Irina G, Cattaneo Elena, Ferrante Robert J, Kristal Bruce S, Friedlander Robert M
Neuroapoptosis Laboratory, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10483-7. doi: 10.1073/pnas.1832501100. Epub 2003 Aug 20.
Minocycline is broadly protective in neurologic disease models featuring cell death and is being evaluated in clinical trials. We previously demonstrated that minocycline-mediated protection against caspase-dependent cell death related to its ability to prevent mitochondrial cytochrome c release. These results do not explain whether or how minocycline protects against caspase-independent cell death. Furthermore, there is no information on whether Smac/Diablo or apoptosis-inducing factor might play a role in chronic neurodegeneration. In a striatal cell model of Huntington's disease and in R6/2 mice, we demonstrate the association of cell death/disease progression with the recruitment of mitochondrial caspase-independent (apoptosis-inducing factor) and caspase-dependent (Smac/Diablo and cytochrome c) triggers. We show that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways. Furthermore, this report demonstrates recruitment of Smac/Diablo and apoptosis-inducing factor in chronic neurodegeneration. Our results further delineate the mechanism by which minocycline mediates its remarkably broad neuroprotective effects.
米诺环素在以细胞死亡为特征的神经疾病模型中具有广泛的保护作用，目前正在进行临床试验评估。我们之前证明，米诺环素介导的针对半胱天冬酶依赖性细胞死亡的保护作用与其预防线粒体细胞色素c释放的能力有关。这些结果并未解释米诺环素是否以及如何预防半胱天冬酶非依赖性细胞死亡。此外，关于Smac/Diablo或凋亡诱导因子是否可能在慢性神经退行性变中发挥作用尚无相关信息。在亨廷顿舞蹈病的纹状体细胞模型和R6/2小鼠中，我们证明了细胞死亡/疾病进展与线粒体半胱天冬酶非依赖性（凋亡诱导因子）和半胱天冬酶依赖性（Smac/Diablo和细胞色素c）触发因素的募集有关。我们表明，米诺环素是一种直接抑制半胱天冬酶非依赖性和依赖性线粒体细胞死亡途径的药物。此外，本报告证明了Smac/Diablo和凋亡诱导因子在慢性神经退行性变中的募集。我们的结果进一步阐明了米诺环素介导其显著广泛的神经保护作用的机制。
