TRIMETHYLTIN INCREASES INTERLEUKIN(IL)1-ALPHA, IL-6 AND TUMOR-NECROSIS-FACTOR-ALPHA MESSENGER-RNA LEVELS IN RAT HIPPOCAMPUS

Within the central nervous system (CNS), cytokines are thought to have active roles in pathophysiological changes seen in various neurologic al diseases and trauma. The present study was undertaken to examine th e early response of pro-inflammatory cytokines following exposure to a specific neurotoxicant (trimethyltin; TMT). mRNA levels for interleuk in (IL)-1 alpha, IL-1 beta, IL-6 and tumor necrosis factor (TNF) alpha were measured in the hippocampus of adult male Long-Evans hooded rats following an acute injection of trimethyltin hydroxide (8 mg TMT/kg b ody weight). At various times following exposure (6 h to 8 days), hipp ocampal tissues were excised and relative changes in cytokine mRNA lev els were assessed by reverse transcription and polymerase chain reacti on. lL-1 alpha, IL-6 and TNF alpha mRNA levels in the hippocampus incr eased within 6 h and remained elevated for 8 days. Quantitative analys is of mRNA transcripts revealed a two-fold increase in both IL-6 and T NF alpha within 6 h and a continued elevation of TNF alpha to 9-fold b y 12 h. Within 96 h, glial fibrillary acidic protein (GFAP) mRNA level s were elevated in the hippocampus. Histological examination showed sp arse individual neuronal necrosis at this time in both the pyramidal a nd granule cell regions with no increase in astrocyte GFAP immunoreact ivity. However, an early, 24 h, response of microglial cells was indic ated by increased lectin binding. This morphological profile progresse d over time to a profound neuronal loss in the CA3-4 granule cell laye r and marked astrocyte hypertrophy. The onset of pro-inflammatory cyto kine mRNA expression appears to be temporally associated with histolog ical evidence of elevated microglia in the hippocampus. It is proposed that microglia and pro-inflammatory cytokines play a modulatory role in the early stages of TMT-induced neurotoxicity.