McCollum Adrian T, Nasr Payman, Estus Steven
Department of Physiology, Sanders-Brown Center on Aging, University of Kentucky, Lexington, USA.
J Neurochem. 2002 Sep;82(5):1208-20. doi: 10.1046/j.1471-4159.2002.01057.x.
While caspases have been strongly implicated in delayed neuronal death in a variety of experimental paradigms, other proteases such as calpain can also contribute to neuronal death. To evaluate the relative roles of caspase and calpain, we used a model system wherein UV treatment induced moderate or severe delayed cortical neuronal death, as quantified by propidium iodide and calcein AM. UV treatment led to increases in both caspase and calpain activation. Calpain inhibitor III (MDL-28170) reduced caspase activation, suggesting that caspase activation was mediated by calpain. Calpain contributed to neuronal death, as indicated by strong neuroprotection provided by calpain inhibitor III, calpeptin, or Ca2+-free medium. In contrast, caspase inhibitors were not neuroprotective. These results suggest that UV neurotoxicity is mediated by a loss of Ca2+ homeostasis which leads to a calpain-dependent, caspase-independent cell death. That calpain, but not caspase, may mediate death in instances involving the activation of both proteases may have relevance to other neuronal death models.
虽然在各种实验模型中，半胱天冬酶与延迟性神经元死亡密切相关，但其他蛋白酶如钙蛋白酶也可能导致神经元死亡。为了评估半胱天冬酶和钙蛋白酶的相对作用，我们使用了一个模型系统，其中紫外线处理可诱导中度或重度延迟性皮质神经元死亡，通过碘化丙啶和钙黄绿素 AM 进行定量分析。紫外线处理导致半胱天冬酶和钙蛋白酶的激活均增加。钙蛋白酶抑制剂 III（MDL - 28170）可降低半胱天冬酶的激活，这表明半胱天冬酶的激活是由钙蛋白酶介导的。钙蛋白酶抑制剂 III、钙蛋白酶抑制肽或无钙培养基提供的强大神经保护作用表明，钙蛋白酶导致了神经元死亡。相比之下，半胱天冬酶抑制剂没有神经保护作用。这些结果表明，紫外线神经毒性是由钙离子稳态失衡介导的，这会导致一种依赖钙蛋白酶、不依赖半胱天冬酶的细胞死亡。在涉及两种蛋白酶激活的情况下，钙蛋白酶而非半胱天冬酶可能介导细胞死亡，这可能与其他神经元死亡模型相关。
