SS-11-4 Effect of a prostacyclin derivative on cutaneous nerves in diabetic neuropathy

Abstract

Chronic constriction injury (CCI) to peripheral nerve causes a painful neuropathy in association with a process of axonal degeneration and endoneural remodeling that involves macrophage recruitment and local increase in extracellular proteases and tumor necrosis factor alpha (TNF-α). Cell surface activation of TNF-α from its transmembrane precursor, as well as sequestration of TNF-α receptors II and I, is performed by the zinc-dependent endopeptidase family of matrix metalloproteinases (MMPs). Among TNF-α-converting MMPs, basal lamina degrading gelatinases are thought to play a role in sciatic nerve injury. In the present study, we determined the forms of TNF-α involved in the development of CCI neuropathy in rats, using Western blot analysis, and the temporal correlation of TNF-α and TNFRI protein profiles with gelatinases activity at the site of peripheral nerve injury. We observed two peaks in TNF-α protein during the first week of CCI that correspond to previously reported peaks in painful behavior. We propose that the first peak at 6 h post-CCI is due to the local expression of the cytotoxic transmembrane 26 kDa TNF-α protein released by resident Schwann cells, mast cells and macrophages. This peak in TNF-α protein expression corresponds to an increase in gelatinase B (MMP-9) activity, which is greatly upregulated as early as 3 h following CCI to rat sciatic nerve. The second peak occurs at 5 days post-CCI, and may represent TNF-α protein released by hematogenously recruited macrophages. This peak is marked by the increase in active soluble 17 kDa TNF-α and by gelatinase A (MMP-2) upregulation. These observations suggest that there is a pathogenic role for the TNF-α-converting function of MMP-2 in painful CCI neuropathy. We conclude that severe nerve injury induces MMPs, TNF-α and TNFRI, which interactively control the privileged endoneurial environment and the pathogenesis of the painful neuropathies associated with the macrophage-dependent processes of Wallerian degeneration.