There are many toxicants that cause peripheral neuropathy, yet the mechanisms by which these toxicants produce demyelination or axonal degeneration in the peripheral nervous system (PNS) are poorly understood. Toxicant-induced injury in the PNS results not only in a variety of regressive and reactive changes in the target cells, but also causes breakdown of the blood-nerve barrier (BNB), an influx of macrophages into nerve for the catabolism of myelin an axons, and a variety of reactive changes in other cell types associated with the target cells. This section within the Program Project focuses on the role of this BNB breakdown in the pathogenesis of toxicant-induced neuropathy. We have found that BNB breakdown may persist for long periods in certain toxic neuropathies and may be associated with increased vulnerability of the nerve fibers to further toxicant-induced injury. We will work with two models, ricin neuropathy and unilateral dorsal-root ganglionectomy, in which we can selectively produce BNB breakdown limited to one sciatic nerve. With these models of localized BNB breakdown, we will test the hypothesis that an altered BNB increases the vulnerability of nerve fibers to toxic injury. Using toxicants that selectively target specific structures within the PNS, we will determine if chronic BNB breakdown leads to increased vulnerability of nerve fibers to toxicant-induced Schwann-cell injury, myelin injury, or axonal injury. We will also test the hypothesis that restitution of the BNB over the course of toxic neuropathy requires axonal regeneration or remyelination. The ability of the axonal regeneration following nerve- crush-induced axonal degeneration and the remyelination following tellurium-induced demyelination to restore the BNB in rats with persistent barrier breakdown due to intraneural ricin injection or unilateral dorsal- root ganglionectomy will be assessed. The third hypothesis to be tested is that the reactions of the BNB and Schwann cells to nerve-fiber injury are determined in part by the influx of macrophages in nerve that occurs after onset of neuropathy. The effects of macrophages on the temporal course of BNB breakdown, Schwann-cell metabolism, axonal regeneration and remyelination will be assessed after selectively ablating macrophages with dichloromethylene diphosphonate (clodronate)-containing mannose liposomes in rats with tellurium-induced demyelinating neuropathy, ricin-induced axonal degeneration, and a nerve-crush model that permits axonal regeneration and remyelination.
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