The Use of Glial Fibrillary Acidic Protein in First-Tier Assessments of Neurotoxicity

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Abstract
Diverse neurotoxic insults result in proliferation and hypertrophy of astrocytes, a subtype of central nervous system glia. The hallmark of this response, often termed “reactive gliosis,” is the enhanced expression of the major intermediate filament protein of astrocytes, glial fibrillary acidic protein (GFAP). These morphological observations suggest that GFAP may be a useful biochemical indicator of neurotoxicity. To investigate this possibility we have administered prototype neurotoxicants to experimental animals and then assessed the effects of these agents on the tissue content of GFAP, as determined by radioimmunoassay. We found that assays of GFAP reveal dose-, time-, and region-dependent patterns of neurotoxicity at toxicant dosages below those that cause light microscopic evidence of cell loss or damage. No false positives have been seen following exposure to a variety of pharmacological agents. By using regional assessments of GFAP in a first-tier evaluation, it should be possible to localize areas of damage. A second-tier evaluation, using assays of proteins or transmitters associated with cells in the affected region, may reveal the cellular targets of neurotoxicity. This two-tiered approach should serve as a foundation for guiding studies aimed at determining mechanisms of neurotoxicity.