INDUCTION OF TUMOR-NECROSIS-FACTOR-ALPHA IN CULTURED GLIAL-CELLS BY TRIMETHYLTIN

Within the central nervous system, cytokines are thought to play an ac tive role in pathophysiological changes seen in various neurodegenerat ive diseases and trauma. Previous studies in our laboratory demonstrat ed that systemic administration of the neurotoxicant trimethyltin (TMT ) produced a rapid and sustained elevation of CNS TNF alpha mRNA level s. In order to examine the effects of TMT on glial cultures in the abs ence of a neuronal component, primary glial cultures were exposed to T MT. Cultured glial cells undergo distinct morphological changes within 6 h of exposure to 10 mu M TMT. This is characterized by an initial r etraction of astrocytic processes revealing long, thin GFAP-dense proc esses and enlarged cell bodies, progressing to distinct retraction of plasmalemmna processes by 24 h. Prior to morphological changes, mRNA l evels for the astrocyte-specific protein, glial fibrillary acidic prot ein (GFAP), increased within 3 h, as determined by Northern blot hybri dization. Approximately a four-fold increase in TNF alpha mRNA levels was observed after 6 h as determined by competitive RT-PCR. This stimu lation resulted in a 10-fold increase in the biologically active form of TNF alpha protein. These results suggest that a direct stimulation of glial cells may produce an early and critical response of the nervo us system in chemical-induced neurotoxicity. Published by Elsevier Sci ence Ltd.