Despite 20 years of research, the mechanism by which acrylamide (ACR) produces central peripheral distal axonopathy remains poorly understood. Based on accumulating evidence, it is possible that perturbation of elemental homeostasis represents an important component of the mechanism of ACR neurotoxicity. The long-term goals of this research project are: (1) to determine whether subcellular elemental deregulation plays an important role in the manifestation of ACR nerve damage, and (2) to determine the biochemical lesion responsible for disruption of elemental homeostasis. Electron probe x-ray microanalysis (EPMA) used during the previous grant period showed that ACR disrupted elemental regulation and water content in several compartments of rat distal tibial nerve. Therefore, our first specific aim for the next grant period will be to expand our EPMA study of ACR neurotoxicity in rats. Concentrations of elements (NA, K, Cl, P, Ca, S, Mg) and water content will be determined in axoplasm, mitochondria and myelin of small, medium, and large diameter fibers and in, nodes of Ranvier, Schwann cell cytoplasm and extra-cellular space. To establish the spatio-temporal nature of altered elemental regulation in ACR neuropathy, the above morphological compartments will be analyzed in proximal and distal sciatic nerve and in tibial nerve. Such determinants will be made at several times during the development of neurotoxicity. The effects of ACR intoxication on the levels of elements and water in dorsal root ganglion and spinal cord will also be defined. Recently, we found that both protein phosphorylation and phosphoinositide turnover were increased in sciatic nerve of ACR-treated rats. To identify the mechanism by which ACR produces these effects three specific aims will be pursued. We will determine the site of altered phosphoinositide metabolism and protein phosphorylation in fractions of sciatic nerve. We will determine whether the activities of phospholipase C and protein kinase C (PKc) in sciatic nerve are affected by ACR administration. We will provide evidence for a biochemical link between increased phosphoinositide turnover and protein phosphorylation by comparing the levels of 1,2-diacylglycerol in sciatic nerves from control and ACR-treated rats. Several lines of evidence indicate that alterations in phosphoinositide turnover caused by ACR might be related to observed elemental disruption through altered modulation of membrane Na/K-ATPase activity. Accordingly, the activity of this enzyme will measured in sciatic nerve of ACR intoxicated rats and compared to that of control. The final specific aim is to conduct parallel studies with 2,5-hexanedione to determine whether biochemical and elemental changes associated with ACR are shared by other agents which cause a distal axonopathy. The proposed experiments should provide new information concerning the mechanism of experimental distal axonopathies and may have relevance to the pathogenesis and treatment of comparable acquired and inherited neuropathies in humans.
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