Local sensory ganglion ischemia induced by endothelin vasoconstriction: vulnerability of diabetic neurons and microvessels

Abstract

In some disorders of the peripheral nervous system, it is relevant to understand how sensory neurons respond to selective ganglion ischemia. Sensory dorsal root ganglia may be susceptible to ischemic damage and irretrievable neuron loss because of their metabolic requirements. In diabetes, heightened sensitivity to ischemia associated with elevated endothelin levels might render ganglia particularly vulnerable. In this work, we created a model of local sensory ganglion ischemia by generating intense local vasoconstriction from applied endothelin-1 (ET). In this model, we compared relative vulnerability of L5 ganglia microvessels and neurons to ET in streptozotocin-induced diabetic rats and nondiabetic controls. Diabetic ganglia had reductions in baseline core ganglion blood flow (GBF) measured using microelectrode hydrogen clearance polarography and ET induced particularly profound declines. Serial GBF measurements made using a laser Doppler flowmetry probe also indicated that diabetic ganglia exposed to ET had a marked prolongation in its action. Neuron perikarya and proximal axon segments were more vulnerable in diabetes. Neurons exhibited loss of neurofilament labeling, dissolution of the neurons, replacement of neurons with “nests of Nageotte,” displacement of nuclei to the periphery of perikarya, and nuclear labeling with TUNEL. Both intraganglionic axons and downstream sural sensory axons developed evidence of axonal degeneration. Local endothelin-induced vasoconstriction of microvessels supplying dorsal root ganglia provides a selective model of ischemia. Diabetic vessels and neurons, exposed to a greater depth and duration of ischemia from endothelin, are especially vulnerable.