Acute Nerve Ischemia

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It is important when considering some types of neuropathy in diabetes to ask whether ischemia plays a role. Peripheral nerve trunks are resistant to acute ischemia in part because of their rich anastamotic vascular supply and their limited metabolic demands. Several models of experimental ischemic neuropathy have been developed ranging from multiple arterial ligation, embolization by microspheres or other agents, and the topical application of the potent vasoconstrictor endothelin (3,41-50). Chronic constriction injury, a model of neuropathic pain (51) likely develops from ischemia generated by the placement of four loose ligatures applied around a nerve trunk with gradual swelling and "strangulation" (52). To irreversibly damage axons acutely, ischemia must be severe and continuous for approximately 3 hours in nondiabetic peripheral nerves (50).

Several important observations have emerged from these studies that are of relevance to the understanding of localized, or focal diabetic neuropathies. It is clear that focal compressive types of nerve injury, such as ulnar neuropathy at the elbow or carpal tunnel syndrome, are unlikely to be ischemic in origin; it is unlikely that a single compressive lesion would disrupt the rich nerve vascular supply. Direct investigations of blood flow at sites of nerve crush or transection have not identified ischemia (53,54). Instead, blood flow is well maintained even immediately after injury at crush sites, and tends to rise with time. However, as discussed later, it is possible that diabetic microangiopathy might impair reactive changes in local blood flow that support regeneration after injury.

Some forms of focal diabetic nerve injury at "nonentrapment" sites might have an ischemic origin. For example, diabetic lumbosacral plexopathy is thought to be a consequence of focal plexus ischemia either from microangiopathy or superimposed vascular inflammation (55,56). As demonstrated in work by Nukada (57,58), experimental diabetic nerves rendered even mildly ischemic develop more severe axonal damage than nondia-betic nerve. Similar findings were encountered in nerve trunks exposed to the potent vasoconstrictor endothelin (5,59). Rat diabetic sciatic nerves exposed to topical endothelin experienced more prolonged and severe vasoconstriction leading to focal axon nerve conduction block followed by local axonal degeneration. Axonal damage in diabetic nerves exposed to epineurial topical endothelin also had a striking multifocal distribution, resembling changes in human diabetic sural nerve biopsies. Rises in serum endothelin levels have been reported in some human studies, but not others, and it is not certain whether transient or acute localized rises might damage human peripheral nerves (60-62).

Models of sensory ganglion ischemia might be relevant in considering acute focal exacerbations of sensory neuropathy in diabetes. This possibility has had less attention, but as in nerve trunks, ganglia also appear more sensitive in diabetes to ischemic damage from exposure to local endothelin vasoconstriction. Ischemia generated ischemic necrosis of some sensory neurons, intraganglionic axon damage, and downstream degeneration of the distal sural nerve axon branches of the targeted perikarya (63) (Fig. 1). Neurons disappeared and were replaced by nests of Nageotte, had peripheral displacement of their nuclei, loss of neurofilaments, nuclear disruption, and had nuclear Terminal transferase dUTP nick end labeling (TUNEL). Interestingly, ischemia of diabetic ganglia thus resulted in three separate pathological reactions among neuron perikarya: ischemic necrosis of neurons, probable apoptosis of sensory neurons, and a retrograde cell body response to axonal damage.

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Supplements For Diabetics

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