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Antioxidative Defense in Diabetic Peripheral Nerve: Effects of DL-a-Lipoic Acid, Aldose Reductase Inhibitor, and Sorbitol Dehydrogenase Inhibitor

Irina G. Obrosova and Douglas A. Greene

University of Michigan Medical Center, Ann Arbor, Michigan

Hans-Jochen Lang

Hoechst Marion Roussel, Frankfurt, Germany

Diabetes-induced oxidative stress in target tissues for diabetic complications, including peripheral nerve, results from at least three mechanisms (Fig. 1), including glucose autooxidation, formation of advanced glycation end products, and increased aldose reductase (AR) activity (1). The contribution of oxidative stress to peripheral diabetic neuropathy has been well established (1-6). Diabetes-induced oxidative stress leads to decreased endoneurial blood flow with resulting endoneurial hypoxia (1-4,6,7). Increased formation of reactive oxygen species (ROS) impairs neurotrophic support (8) and causes redox imbalances (9), energy deficiency (9), and perhaps defects in ion-transport mechanisms, which theoretically can be both mediated by and be independent of the corresponding changes in nerve blood flow.

Although the role of oxidative stress in diabetes-induced nerve vascular dysfunction and nerve conduction deficits is no longer a subject for debate, there is still a number of questions that need to be addressed. It is still unclear

Figure 1 Mechanisms and pathogenetic consequences of oxidative stress in diabetic peripheral nerve.

(and no consensus has been reached so far) what the relative contribution of oxidative stress-linked defects in endoneurial blood flow, metabolism, and neurotrophic support to nerve conduction deficits is. It remains to be established whether ROS-induced neurovascular dysfunction and resulting endoneurial hypoxia mediate the diabetes-induced decrease in neurotrophic support as they, at least partially, mediate metabolic defects (10), considering that the levels of substance P (a product of nerve growth factor [NGF]-influenced gene in primary afferents) in the nerve are decreased under hypoxic conditions (11). Mechanisms leading from hyperglycemia to increased ROS formation require further studies as well. In particular, the relative contribution of the three aforementioned ROS-generating mechanisms to diabetes-induced nerve free radical damage remains to be identified. Little information is available on the changes in antioxidative defense enzymes (1) and mechanisms of their downregulation in diabetic peripheral nerve and a possibility of modulation of their activity with antioxidants and other pharmacological interventions. In addition, the role for AR in diabetes-induced changes in nerve antioxidant status needs further studies because reports (2,12) indicate an inconsistency between marked depletion of nerve total glutathione (TG) versus very minor increase in oxidized glutathione (GSSG) in diabetes and restoration of TG levels with

AR inhibitor (ARI) treatment, which points to the contribution of other AR-dependent mechanism(s) in addition to or instead of AR-mediated NADPH deficiency to nerve antioxidant deficit. Also, it remains to be established whether there is any role for the second enzyme of the sorbitol pathway, sorbitol dehydrogenase, in diabetes-induced nerve oxidative injury.

Some of the aforementioned questions were addressed in the present study, which was designed to identify diabetes-related deficits of peripheral nerve antioxidative defense enzymes; to evaluate a role of oxidative stress in impairment of protective mechanisms against superoxide, hydrogen peroxide, and semiquinone radical-induced oxidative injury by assessing a possibility of preventing downregulation of superoxide dismutase, catalase, and total quinone reductase by antioxidant dl-a-lipoic acid; and to compare the effects of ARI and sorbitol dehydrogenase inhibitor (SDI) on parameters of oxidative stress and antioxidative defense in diabetes and thus to identify the role for two enzymes of the sorbitol pathway in diabetes-induced nerve oxidative injury.

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