Glia toxicity in dissociation cell cultures induced by cyclosporine.

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.