PATHOGENESIS OF TOXIC AND METABOLIC NEUROPATHIES

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Diabetes-induced peripheral neuropathy is the most common of the complications associated with diabetes mellitus and the most prevalent neuropathy in the country. However, while hyperglycemia has been identified as the fundamental metabolic disturbance in the pathogenesis of diabetic neuropathy, the relationship between metabolic events and subsequent structural changes remains unclear. Previous work has shown that hyperglycemia-induced exaggerated polyol pathway flux underlies a number of biochemical and functional disorders of peripheral nerve in experimental diabetes and more recently, that it is associated with structural changes such as axonal dwindling and degenerative Schwann cell changes that may lead to axonopathy and segmental demyelination. Elucidating the link between exaggerated polyol pathway activity, and structural changes is the broad, long-term objective of this research proposal. These studies will be performed in three of the best- characterized rat models of hyperglycemia: streptozotocin induced diabetes, galactose intoxication and the genetically diabetic BB/Wistar rat. The localization of aldose reductase, the first enzyme of the polyol pathway, to the Schwann cell suggests that disruption of this cell's function may be the primary lesion. The structural integrity of the Schwann cell and other cellular elements of the nerve microenvironment will be examined by qualitative and quantitative electron microscopy at time points that span the onset of Schwann cell damage and subsequent axonal degeneration along with evaluation of aldose reductase content by enzyme assay and gel electrophoresis. Also, as accumulating evidence implicates the necessity of continuous Schwann cell-axon interaction, levels of the Schwann cell-derived neuronotropic factor, ciliary neuronotrophic factor, will be assayed with a microbioassay at time points prior to and including the onset of Schwann cell structural damage. The temporal sequence of physiologic and biochemical changes in the nerve microenvironment will be characterized by correlating nerve conduction velocity, as an index of functional impairment, with endoneurial fluid electrolytes, polyols and water content using electrophysiology, energy dispersive spectrometry and gas chromatography. As axonal damage may also result from polyol-pathway- induced changes via altered blood-nerve barrier permeability and reduced nerve blood flow, in vivo tracer methods for determining permeability- surface area products and nerve blood flow will be used at appropriate time points. All studies will include aldose reductase inhibitor treated groups to assess the role of the polyol pathway in nerve disorders. Thus, this research proposal, will integrate morphologic, physiologic and biochemical techniques to study the pathophysiology of diabetic neuropathy.