Neurotoxicant-induced elevation of adrenomedullin expression in hippocampus and glia cultures

Adrenomedullin (AM), a vasoactive peptide first isolated from pheochromocyt oma, has been reported to be present in neurons in the central nervous syst em and in tumors of neural and glial origin. In this study, we investigated AM expression both in the hippocampus and in glial cell cultures using a c hemical-induced model of injury. An acute intraperitoneal injection of the organometal trimethyltin (TMT) results in neurodegeneration of the hippocam pal CA3-4 pyramidal cell layer. Within 4 days of injection, sparse, punctat e staining for AM and lectin was evident in the CA3-4 region; by 10 days, a minimal level of CA3-4 neuronal degeneration was evident, with an increase in glial fibrillary acidic protein (GFAP)-positive astrocytes throughout t he hippocampus. Degeneration progressed in severity until 30 days post-TMT, with distinct positive immunoreactivity for AM in the CA4 region. mRNA lev els for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 alpha, GFAP, and AM in the hippocampus were increased over control levels within 4 days following TMT. In cultured glial cells, a 6 hr exposure to TMT (10 muM) pro duced a morphological response of the cells and increased immunoreactivity for vimentin, GFAP, and AM. mRNA levels for TNF alpha, IL-1 alpha, GFAP, vi mentin, and AM were elevated within 3-6 hr of exposure. In culture, neutral izing antibodies to IL-1 alpha and TNF alpha were effective in inhibiting t he TMT-induced elevation of AM mRNA. These data suggest an interaction betw een the proinflammatory cytokines and glia response in the regulation of AM in response to injury. Published 2001 Wiley-Liss, Inc.