Aims/hypothesis. A strong positive correlation has been found between lipid peroxidation product and vascular endothelial growth factor concentrations in the vitreous of patients with proliferative diabetic retinopathy. To establish a causal relation between diabetes-associated enhanced oxidative stress and vascular endothelial growth factor production, we evaluated two antioxidants, dl-a-lipoic acid and taurine, on retinal vascular endothelial growth factor protein and mRNA expression and on parameters of oxidative stress in streptozotocin-diabetic rats. Methods. Our experiments were on control rats and streptozotocin-diabetic rats with a 6-week duration of diabetes, treated with or without dl-a-lipoic acid (100 mg´kg ±1´d±1 , i. p.) or taurine (1 % in the diet) starting from induction of diabetes. Vascular endothelial growth factor protein in retinal homogenates was assessed by sandwich ELISA with an affinity-purified polyclonal antibody and vascular endothelial growth factor mRNA by ribonuclease protection assay. Retinal lipid peroxidation products i. e. malondialdehyde plus 4-hydroxyalkenals were quantified with n-methyl-2-phenylindole. Retinal reduced and oxidized glutathione, ascorbate, dehydroascorbate, and sorbitol pathway intermediates were measured spectrofluorometrically, and taurine by reverse-phase HPLC.Results. Vascular endothelial growth factor protein concentration (means SD) was increased in diabetic rats compared with control rats (33 7 vs 19 5 pg/mg total protein, p < 0.01) This increase was attenuated by taurine (26 8, p < 0.05) and prevented by dla-lipoic acid (21 4, p < 0.01). Vascular endothelial growth factor mRNA abundance was reduced by 1.4-fold in diabetic rats compared with control rats and this decrease was attenuated but not completely prevented by both antioxidants. Malondialdehyde plus 4-hydroxyalkenal concentration was increased in diabetic rats compared with control rats, and both antioxidants arrested accumulation of lipid peroxidation products. Taurine, reduced glutathione, oxidized glutathione, ascorbate, dehydroascorbate and sorbitol pathway intermediate concentrations as well as oxidized glutathione/reduced glutathione and dehydroascorbate/ascorbate ratios were similar in control and diabetic rats treated with or without taurine. Conclusion/interpretation. Oxidative stress is directly involved in up regulation of vascular endothelial growth factor protein in the retina during early diabetes. [Diabetologia (2001

According to the data of the National Diabetes Data Group [1], the prevalence of cataracts ± one of the major ocular disorders in patients with diabetes mellitus ± is at least 50 % higher in both Type I (insulindependent) diabetes mellitus and Type II (non-insulin-dependent) diabetes than in corresponding agematched non-diabetic subjects. Sugar cataractogenesis is initiated by osmotic stress caused by intralenticular accumulation of polyols produced by the enzyme aldose reductase [2±6]. Although growing evidence indicates the key role of an osmotic mechanism in the sequelae of biochemical and morphological chan- Diabetologia (1998) Summary The study was aimed at evaluating changes in lens antioxidant status, glucose utilization, redox state of free cytosolic NAD(P)-couples and adenine nucleotides in rats with 6-week streptozotocin-induced diabetes, and to assess a possibility of preventing them by dl-a-lipoic acid. Rats were divided into control and diabetic groups treated with and without dl-a-lipoic acid (100 mg × kg body weight ±1 × day ±1 , i. p.). The concentrations of glucose, sorbitol, fructose, myo-inositol, oxidized glutathione, glycolytic intermediates, malate, a-glycerophosphate, and adenine nucleotides were assayed in individual lenses spectrofluorometrically by enzymatic methods, reduced glutathione and ascorbate ± colorimetrically, and taurine by HPLC. Free cytosolic NAD + :NADH and NADP + :NADPH ratios were calculated from the lactate dehydrogenase and malic enzyme systems. Sorbitol pathway metabolites were found to increase, and antioxidant concentrations were reduced in diabetic rats compared with controls. The profile of glycolytic intermediates (increase in glucose 6-phosphate and fructose 6-phosphate, decrease in fructose1,6-diphosphate, increase in dihydroxyacetone phosphate, 3-phosphoglycerate, phosphoenolpyruvate, pyruvate, and no change in lactate), and 5.9-fold increase in a-glycerophosphate suggest diabetes-induced inhibition of glycolysis. Free cytosolic NAD + :-NADH ratios, ATP levels, ATP/ADP´inorganic phosphate (P i ), and adenylate charge were reduced in diabetic rats while free cytosolic NADP + :NADPH ratios were elevated. Diabetes-induced changes in the concentrations of antioxidants, key glycolytic intermediates, free cytosolic NAD + :NADH ratios, and energy status were partially prevented by dl-a-lipoic acid, while sorbitol pathway metabolites and free cytosolic NADP + :NADPH ratios remained unaffected. In conclusion, diabetes-induced impairment of lens antioxidative defense, glucose intermediary metabolism via glycolysis, energy status and redox changes are partially prevented by dl-a-lipoic acid. The findings support the important role of oxidative stress in lens metabolic imbalances in diabetes. [Diabetologia (1998

Oxidative stress has a key role in the pathogenesis of diabetic complications. We have previously reported that taurine (T), which is known to counteract oxidative stress in tissues (lens, kidney, retina) of diabetic rats, attenuates nerve blood flow and conduction deficits in early experimental diabetic neuropathy (EDN). The purpose of this study was to evaluate whether dietary T supplementation counteracts oxidative stress and the nerve growth factor (NGF) deficit in the diabetic peripheral nerve. The experiments were performed in control rats and streptozotocin‐diabetic rats fed standard or 1% T‐supplemented diets for 6 weeks. All measurements were performed in the sciatic nerve. Malondialdehyde (MDA) plus 4‐hydroxyalkenals (4‐HA) were quantified with N‐methyl‐2‐phenylindole. GSH, GSSG, dehydroascorbate (DHAA), and ascorbate (AA) were assayed spectrofluorometrically, T by reverse‐phase HPLC, and NGF by ELISA. MDA plus 4‐HA concentration (mean +/− SEM) was increased in diabetic rats (0.127 +/−0.006 vs 0.053 +/−0.003 mu mol/g in controls, P<0.01), and this increase was partially prevented by T (0.0960.004, P<0.01 vs untreated diabetic group). GSH levels were similarly decreased in diabetic rats treated with or without taurine vs controls. GSSG levels were similar in control and diabetic rats but were lower in diabetic rats treated with T (P<0.05 vs controls). AA levels were decreased in diabetic rats (0.133+0.015 vs 0.219 +/−0.023 mu mol/g in controls, P<0.05), and this deficit was prevented by T. DHAA/AA ratio was increased in diabetic rats vs controls (P<0.05), and this increase was prevented by T. T levels were decreased in diabetic rats (2.7 +/−0.16 vs 3.8 +/−0.1 mu mol/g in controls, P<0.05) and were repleted by T supplementation (4.20.3). NGF levels were decreased in diabetic rats (2.35 +/−0.20 vs 3.57 +/−0.20 ng/g in controls, P<0.01), and this decrease was attenuated by T treatment (3.160.28, P<0.05 vs diabetic group). In conclusion, T counteracts oxidative stress and the NGF deficit in early EDN. Antioxidant effects of T in peripheral nerve are, at least in part, mediated through the ascorbate system of antioxidative defense. The findings are consistent with the important role for oxidative stress in impaired neurotrophic support in EDN.

The role for nerve blood flow (NBF) vs. other factors in motor nerve conduction (MNC) slowing in short‐term diabetes was assessed by evaluating alpha(1)‐adrenoceptor antagonist prazosin on NBF, MNC, as well as metabolic imbalances and oxidative stress in the neural tissue. Control and diabetic rats were treated with or without prazosin (5 mg.kg (−1).d(−1) for 3 wk). NBF was measured by hydrogen clearance. Both endoneurial vascular conductance and MNC velocity were decreased in diabetic rats vs. controls, and this decrease was prevented by prazosin. Free NAD(+):NADH ratios in mitochondrial cristae, matrix, and cytosol assessed by metabolite indicator method, as well as phosphocreatine levels and phosphocreatine/creatine ratios, were decreased in diabetic rats, and this reduction was ameliorated by prazosin. Neither diabetes‐induced accumulation of two major glycation agents, glucose and fructose, as well as sorbitol and total malondialdehyde plus 4‐hydroxyalkenals nor depletion of myo‐inositol, GSH, and taurine or decrease in (Na/K)‐ATP‐ase activity were affected by prazosin. In conclusion, decreased NBF, but not metabolic imbalances or oxidative stress in the neural tissue, is a key mechanism of MNC slowing in short‐term diabetes. Further experiments are needed to estimate whether preservation of NBF is sufficient for prevention of nerve dysfunction and morphological abnormalities in long‐standing diabetes or whether the aforementioned metabolic imbalances closely associated with impaired neurotropism are of greater importance in advanced than in early diabetic neuropathy.

Chloramphenicol in the newborn infant. A physiological explanation of its toxicity when given in excessive dose. New Engl. J. Med., 262, 787-794. system do not change with increasing age.