Vogt Cornelia, Hailer Nils P, Ghadban Chalid, Korf Horst-Werner, Dehghani Faramarz
Dr. Senckenbergische Anatomie, Institut für Anatomie II, Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
J Neurosci Res. 2008 Nov 15;86(15):3314-21. doi: 10.1002/jnr.21792.
Interleukin (IL)-1 is an important mediator of neuronal demise and glial activation after acute central nervous system lesions and is antagonized by IL-1 receptor antagonist (IL-1RA). Here we determined the time window in which IL-1RA elicits neuroprotective effects in rat organotypic hippocampal slice cultures (OHSC). OHSC were lesioned with N-methyl-D-aspartate (NMDA) and treated with IL-1RA (100 ng/ml) at different time points postinjury or were left untreated. Damaged neurons, microglial cells, and astrocytes were labelled with NeuN, propidium iodide, isolectin B(4), or glial fibrillary acidic protein (GFAP), respectively, and were analyzed by confocal laser scanning microscopy. In lesioned OHSC, the most dramatic increase in microglial cell number occurred between 8 and 16 hr postinjury, and the maximal neuronal demise was found between 16 and 24 hr postinjury. The cellular source of IL-1beta was investigated by immunohistochemistry, and IL-1beta immunoreactivity was found in few microglial cells at 4 hr postinjury and in numerous microglial cells and astrocytes at 16 hr postinjury. In both glial populations, IL-1beta immunoreactivity peaked at 24 hr postinjury. IL-1RA treatment potently suppressed neuronal damage by 55% when initiated within the first 16 hr postinjury (P < 0.05), and IL-1RA treatment initiated at 24 hr postinjury resulted in weaker but still significant neuroprotection. IL-1RA treatment also reduced the number of microglial cells significantly when initiated within 36 hr postinjury (P < 0.05). In conclusion, IL-1RA exhibits significant neuroprotective effects in this in vitro model of excitotoxic injury even after delayed application.
白细胞介素（IL）-1是急性中枢神经系统损伤后神经元死亡和胶质细胞活化的重要介质，可被IL-1受体拮抗剂（IL-1RA）拮抗。在此，我们确定了IL-1RA在大鼠器官型海马脑片培养物（OHSC）中发挥神经保护作用的时间窗。OHSC用N-甲基-D-天冬氨酸（NMDA）损伤，并在损伤后的不同时间点用IL-1RA（100 ng/ml）处理，或不进行处理。分别用NeuN、碘化丙啶、异凝集素B(4)或胶质纤维酸性蛋白（GFAP）标记受损神经元、小胶质细胞和星形胶质细胞，并通过共聚焦激光扫描显微镜进行分析。在损伤的OHSC中，小胶质细胞数量在损伤后8至16小时增加最为显著，最大神经元死亡发生在损伤后16至24小时。通过免疫组织化学研究IL-1β的细胞来源，在损伤后4小时，少数小胶质细胞中发现IL-1β免疫反应性，在损伤后16小时，大量小胶质细胞和星形胶质细胞中发现IL-1β免疫反应性。在这两种胶质细胞群体中，IL-1β免疫反应性在损伤后24小时达到峰值。在损伤后16小时内开始给予IL-1RA治疗可有效抑制55%的神经元损伤（P < 0.05），在损伤后24小时开始给予IL-1RA治疗导致的神经保护作用较弱，但仍具有显著意义。在损伤后36小时内开始给予IL-1RA治疗也可显著减少小胶质细胞数量（P < 0.05）。总之，即使在延迟应用后，IL-1RA在这种兴奋性毒性损伤的体外模型中仍表现出显著的神经保护作用。
