18 / 2b2f 5055 Mp 18 Thursday Oct 02 02:37 PM EL–FRB 5055 Free Radical Biology & Medicine, Vol. 24, No. 1, pp. 18–26, 1998 Copyright  1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0891-5849/98 $19.00 / .00 PII S0891-5849( 97 ) 00122-6 Original Contribution NERVE FUNCTION AND OXIDATIVE STRESS IN DIABETIC AND VITAMIN E-DEFICIENT RATS P. SYTZE VAN DAM,* ² B. SWEDER VAN ASBECK, ² BERT BRAVENBOER,* JOHANNES F. L. M. VAN OIRSCHOT, ² WILLEM HENDRIK GISPEN,* and JOANNES J. M. MARX ² *Department of Medical Pharmacology, Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht, The Netherlands; and ² Department of Internal Medicine and Eijkman-Winkler Institute, University Hospital, Utrecht, The Netherlands ( Received 21 October 1996; Revised 26 February 1997; Accepted 25 March 1997) Abstract—Nerve dysfunction in diabetes is associated with increased oxidative stress. Vitamin E depletion also leads to enhanced presence of reactive oxygen species ( ROS ) . We compared systemic and endoneurial ROS activity and nerve conduction in vitamin E-depleted control and streptozotocin-diabetic rats ( CE0 and DE0 ), and in nor- mally fed control and diabetic animals (CE/ and DE/ ). Nerve conduction was reduced in both diabetic groups. Vitamin E depletion caused a small further nerve conduction deficit in the diabetic, but not in the control animals. The combination of vitamin E deficiency and streptozotocin-diabetes ( group DE0 ) appeared to be lethal. In the remaining groups, an important rise in sciatic nerve malondialdehyde ( MDA ) was observed in the vitamin E-depleted control rats. In contrast, plasma MDA levels were elevated in group DE/ only, whereas hydrogen peroxide levels were increased in group CE0. Endoneurial total and oxidized glutathione and catalase were predominantly elevated in group DE/. These data show that nerve lipid peroxidation induced by vitamin E depletion does not lead to reduced nerve conduction or changes in antioxidant concentrations as observed in STZ-diabetes. The marked sys- temic changes in MDA and antioxidants suggest that nerve dysfunction in experimental hyperglycemia is rather a consequence of systemic than direct nerve damage.  1997 Elsevier Science Inc. Keywords—Neuropathy, Vitamin E deficiency, Oxidative stress, Free radicals INTRODUCTION Enhanced oxidative stress and changes in antioxidant capacity, observed in both clinical and experimental diabetes mellitus, have been implicated in the aetiology of chronic diabetic complications. 1–4 The beneficial use of antioxidant drugs, including glutathione, 5 probucol, 6 a-lipoic acid, 7 N-acetylcysteine 8 and vitamin E, 9 for the prevention and treatment of experimental diabetic neuropathy has been demonstrated. However, in- creased production of reactive oxygen species (ROS) is not the only causal factor in the complex process of the pathogenesis of diabetic neuropathy. 10 The possible toxic effects of increased oxidative Address correspondence to: P. Sytze van Dam, Rudolf Magnus Institute for Neurosciences, Utrecht University, Postbus 80040, 3508 TA Utrecht, The Netherlands. Grant support: Diabetes Fonds Nederland. stress in isolation, without hyperglycemia, on the pe- ripheral nerve remain to be determined. Experimental vitamin E deficiency is a potential model to study the relative contribution of enhanced ROS production on the development of experimental diabetic neuropathy. In vitamin E-deficient rats, peripheral nerve dysfunc- tion has been observed and is associated with increased ROS-mediated damage. 11 Experimental vitamin E de- ficiency can lead to a variety of general symptoms, such as weight loss or liver necrosis, but also to specific neurological deficits, such as muscle weakness, in- creased muscle damage after exercise, ataxia and mus- cle denervation. 12,13 In vitamin E-depleted rats, the neu- rological symptoms are mainly associated with a combined central-peripheral distal axonopathy, with emphasis on the dorsal columns. 13 As experimental di- abetes is not associated with attenuated, but rather with somewhat increased tissue vitamin E levels, 4,11,14 it is