Increased susceptibility to ischemia and macrophage activation in STZ-diabetic rat nerve

Abstract

Ischemic vulnerability in diabetic nerve plays a paramount role in the development of diabetic neuropathy, yet little is known of the underlying mechanism. Diabetes enhances the inflammatory response to ischemia and reperfusion. We investigated pathological characteristics of nerve fibers and endoneurial macrophages along the length of sciatic-tibial nerves before and after ischemia (60 to 90 min) and reperfusion (6h to 7 days) in 8 weeks of STZ-induced diabetic rats. Without ischemia, diabetic nerves revealed significantly increased the density of Iba-1-positive endoneurial macrophages when compared with controls. Most of macrophages appeared slim and triangular in shape, but in diabetic nerves, some were rounded with bromodeoxyuridine (BrdU) incorporation, suggesting proliferating macrophages. Seventy-five minutes of ischemia is the minimal ischemic time to cause pathological changes in diabetic nerves. Following 90 min of ischemia and 6h of reperfusion in diabetic rats, the number of Iba-1-positive endoneurial macrophages was increased significantly at the thigh level of sciatic nerve when compared with those before ischemia. Endoneurial macrophages in diabetic nerves increased in number further significantly after 24 and 48 h of reperfusion and underwent morphological alterations; swollen and rounded including phagocytosis. After 90 min of ischemia and 7 days of reperfusion, severe pathological alterations, e.g., demyelination and endoneurial edema at proximal nerves and axonal degeneration distally, were observed in diabetic nerves, while control nerves showed normal morphology. We conclude that macrophage proliferation occurs in STZ-diabetic nerves. The acute inflammatory response after ischemia and reperfusion was intensified in diabetic nerves. Activation of resident macrophages and infiltration by recruited macrophages could be casually linked to ischemic susceptibility in diabetic nerve.