NEURONAL PERIKARYAL RESPONSES TO NEUROTOXIC CHEMICALS

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The ability to differentiate secondary consequences of toxic chemical exposure from direct toxic effects is an important problem in toxicology. Moreover, in neurons, which can extend long axonal processes, secondary morphological changes may arise in a portion of the cell (e.g. the neuronal perikaryon) far removed from the site of injury. This has led to the search for new probes to decipher these morphological clues. Monoclonal antibodies directed against phosphorylated neurofilament epitopes provide new tools to study pathological alterations and have been applied to several human neurofibrillary disorders, including amyotrophic lateral sclerosis (ALS). In this disorder, phosphorylated epitopes, which are not normally present in neuronal perikarya, are abnormally expressed in cell bodies from affected regions. The significance of these findings remains unknown. It has been suggested that this alteration may be related to a possible defect in neurofilament transport. Alternatively, it may represent a nonspecific response to axonal injury. Animal models employing toxic chemicals offer a means to distinguish between these possibilities. Previous studies following chronic acrylamide administration, which produces axonal degeneration, appear to support the latter possibility. The major hypothesis of the present proposal is that abnormal expression of at least some phosphorylated neurofilament epitopes in neuronal perikarya represents a stereotypic response to axonal injury. This will be tested by correlating the time course of any abnormal expression of phosphorylated epitopes with the development of, 1) proximal swellings in IDPN neuropathy, 2) Distal swellings and axonal degeneration in chronic 2,5-hexanedione (HD) neuropathy, 3) proximal swellings and distal degeneration in 3,4-dimethyl HD (DMHD) neuropathy, and 4) Proximal swellings and degeneration following combined IDPN administration and nerve transection. Furthermore, studies using colchicine will explore the possible role of retrogradely transported "trophic" signals in the initiation of this response. Finally, the relationship between this phenomenon and axonal regeneration will be examined following subepineural acrylamide injection to impair regeneration. These studies may establish a more universal marker for the presence of secondary changes in neuronal perikarya and will clarify the significance of these alterations in several human disorders; e.g. ALS.