Stoltenburg-Didinger G, Boegner F
Institute of Neuropathology, Klinikum Steglitz, Free University of Berlin, Germany.
Neurotoxicology. 1992 Spring;13(1):179-84.
Intravenously applied cyclosporine is the most effective and best analyzed immunosuppressive agent to date. Most frequently, this drug shows nephrotoxic or hepatotoxic side effects, which have already been investigated in detail. In addition to these adverse effects, there is also clear clinical evidence for toxic damage to the central nervous system. On the basis of magnetic resonance tomography and computed tomography studies, the white matter seems to be primarily affected. A systematic approach to neurotoxicity has been established in the following model. Mixed in-vitro cell cultures of dorsal root ganglia (DRG) and of the central nervous system were prepared from 6 to 14 day old chick embryos (E6-E14). For cultivation of nerve and glia cells we used beta NGF, a soluble trophic factor, and NTF B 82 as a matrix factor. Differentiated cultures were incubated with cyclosporine for intravenous application. Within a period of several days up to two weeks the cultures were analyzed using phase contrast microscopy, light microscopy, scanning and transmission electron microscopy. Glia cells and fibroblasts showed the most pronounced toxic effects. Their cytoplasm was infiltrated with smaller and larger vesicles which contained neutral lipids. Control cultures remained unaffected. Because of the close correlation between the in-vitro damage of glia cells and the clinically observed alteration of the white matter, we think our in-vitro model is helpful for the investigation of the neurotoxic effects of cyclosporine and immunotherapeutic drugs.
静脉注射用环孢素是迄今为止最有效且分析最充分的免疫抑制剂。该药物最常出现肾毒性或肝毒性副作用，对此已进行了详细研究。除了这些不良反应外，还有明确的临床证据表明其对中枢神经系统有毒性损害。基于磁共振断层扫描和计算机断层扫描研究，白质似乎是主要受影响部位。在以下模型中建立了一种针对神经毒性的系统研究方法。从6至14日龄的鸡胚（E6 - E14）制备背根神经节（DRG）和中枢神经系统的混合体外细胞培养物。为培养神经细胞和神经胶质细胞，我们使用了可溶性营养因子β神经生长因子（beta NGF）和作为基质因子的NTF B 82。将分化的培养物用静脉注射用环孢素进行孵育。在几天至两周的时间内，使用相差显微镜、光学显微镜、扫描电子显微镜和透射电子显微镜对培养物进行分析。神经胶质细胞和成纤维细胞表现出最明显的毒性作用。它们的细胞质中充满了含有中性脂质的大小不一的囊泡。对照培养物未受影响。由于神经胶质细胞的体外损伤与临床上观察到的白质改变密切相关，我们认为我们的体外模型有助于研究环孢素和免疫治疗药物的神经毒性作用。
