CALCIUM AND ACRYLAMIDE NEUROTOXICITY

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Acrylamide (ACR) has broad application in various chemical industries. Exposure of laboratory animals and man to ACR causes nerve damage classified as a centralperipheral distal axonopathy. The morphological characteristics of this axonopathy are paranodal swelling and degeneration of distal nerve fibers. The long-term objectives of this research project are to: 1) determine the mechanism of ACR-induced distal axon swelling and degeneration and, 2) determine the role of Schwann cells in this degenerative process. Extensive investigations of peripheral nerve elemental distribution and enzyme activity have been conducted during the current funding period. Based on this work it is hypothesized that ACR causes reverse operation of the Na/Ca-exchanger which mediates Ca entry in sensitive axons. Exchanger reversal is brought about by elevation of intraaxonal Na which, in turn, is a consequence of reduced Na/K-ATPase delivery to distal axon sites. Axoplasmic accumulation of Ca initiates an injury cascade that culminates in distal axon swelling and degeneration. The following Specific Aims have been designed to test this heuristic model. 1) The effects of ACR on in situ Na/K-ATPase function will be evaluated by determining the disposition of rubidium in myelinated axons and Schwann cells and by assessing the ability of gangliosides to affect ACR-induced elemental disruption. 2) Na/K-ATPase transport and spatial distribution will be determined in peripheral nerve of control and ACR- treated rats. 3) The possible role of increased protein kinase C activity in ACR neurotoxicity will be examined. 4) Studies will be conducted to determine whether reverse operation of the Na/Ca-exchanger can promote Ca entry. 5) The effects of ACR on voltage-gated Na+ and K+ channels will be determined. 6) Experiments have been designed to determine whether Schwann cells are injured by ACR or are responding to primary axon injury. 7) The neurotoxicological specificity of internodal elemental changes will be ascertained. ACR neurotoxicity is a prototypic injury model for chemicals that produce distal axon degeneration (DAD). Since DAD is the most common response of axons to chemicals, determining the mechanism of ACR axonopathy might have relevance to other DAD neurotoxicants. Moreover, proposed research might suggest pharmacotherapeutic modalities useful in the treatment of DAD.