Experimental diabetic peripheral neuropathy (DPN) is marked by impaired nerve conduction velocity (NCV), reduced nerve blood flow (NBF), and a variety of metabolic abnormalities in peripheral nerve that have been variously ascribed to hyperglycemia, abnormal fatty acid metabolism, ischemic hypoxia, and/or oxidative stress. Some investigators propose that NCV slowing in experimental DPN can be explained entirely on the basis of nerve energy depletion secondary to reduced NBF. This article reports highly selective effects of administration of the antioxidant DL-␣-lipoic acid (LA) to streptozotocin-injected diabetic rats. LA improved digital sensory but not sciatic-tibial motor NCV, corrected endoneurial nutritive but not composite NBF, increased the mitochondrial oxidative state without correcting nerve energy depletion, and enhanced the accumulation of polyol pathway intermediates without worsening myo-inositol or taurine depletion. These studies implicate oxidative stress as an important pathophysiological factor in experimental DPN. They reveal complex interrelationships among nerve perfusion, energy metabolism, osmolyte content, conduction velocity, and oxidative stress that may reflect the heterogeneous and compartmentalized composition of peripheral nerve.

Aldose reductase inhibitors (ARIs) prevent peripheral nerve dysfunction and morphological abnormalities in diabetic animal models. However, some experimental intervention studies and clinical trials of ARIs on diabetic neuropathy appeared disappointing because of either 1) their inadequate design and, in particular, insufficient correction of the sorbitol pathway activity or 2) the inability to reverse established functional and metabolic deficits of diabetic neuropathy by AR inhibition in general. We evaluated whether diabetes-induced changes in nerve function, metabolism, and antioxidative defense are corrected by the dose of ARI (sorbinil, 65 mg/kg/d in the diet), resulting in complete inhibition of increased sorbitol pathway activity. The groups included control rats and streptozotocin-diabetic rats treated with/without ARI for 2 weeks after 4 weeks of untreated diabetes. ARI treatment corrected diabetes-induced nerve functional changes; that is, decrease in endoneurial nutritive blood flow, motor and sensory nerve conduction velocities, and metabolic abnormalities (i.e., mitochondrial and cytosolic NAD+/NADH redox imbalances and energy deficiency). ARI restored nerve concentrations of two major non-enzymatic antioxidants, reduced glutathione (GSH) and ascorbate, and completely arrested diabetes-induced lipid peroxidation. In conclusion, treatment with adequate doses of ARIs (that is, doses that completely inhibit increased sorbitol pathway activity) is an effective approach for reversal of, at least, early diabetic neuropathy.

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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

Heterogeneous myocardial sympathetic denervation complicating diabetes has been invoked as a factor contributing to sudden unexplained cardiac death. In subjects with diabetic autonomic neuropathy (DAN), distal left ventricular (LV) denervation contrasts with preservation of islands of proximal innervation, which exhibit impaired vascular responsiveness. The aims of this study were to determine whether this heterogeneous pattern of myocardial sympathetic denervation occurs in a rat model of diabetes and to explore a potential association with regional fluctuations in myocardial nerve growth factor (NGF) protein. Myocardial sympathetic denervation was characterized scintigraphically using the sympathetic neurotransmitter analog C-11 hydroxyephedrine ([11C]HED) and compared with regional changes in myocardial NGF protein abundance and norepinephrine content after 6 and 9 months in nondiabetic (ND) and streptozotocin-induced diabetic (STZ-D) rats. In ND rats, no difference in [11C]HED retention or norepinephrine content was detected in the proximal versus distal myocardium. After 6 months, compared with ND rats, myocardial [11C]HED retention had declined in the proximal segments of STZ-D rats by only 9% (NS) compared with a 33% decrease in the distal myocardium (P < 0.05). Myocardial norepinephrine content was similar in both ND and STZ-D rats. At 6 months, LV myocardial NGF protein content in STZ-D rats decreased by 52% in the proximal myocardial segments (P < 0.01 vs. ND rats) and by 82% distally (P < 0.01 vs. ND rats, P < 0.05 vs. proximal segments). By 9 months, [11C]HED retention had declined in both the proximal and distal myocardial segments of the STZ-D rats by 42% (P < 0.01 vs. ND rats), and LV norepinephrine content and NGF protein were decreased in parallel. Therefore, 6 months of STZ-induced diabetes results in heterogeneous cardiac sympathetic denervation in the rat, with maximal denervation occurring distally, and is associated with a proximal-to-distal gradient of LV NGF protein depletion. It is tempting to speculate that regional fluctuations of NGF protein in the diabetic myocardium contribute to heterogeneous cardiac sympathetic denervation complicating diabetes.

alpha-Lipoic acid (thioctic acid) was tested for its neuroprotective activity in a Mongolian gerbil model of forebrain ischemia/reperfusion. Adult gerbils were treated for 7 days with two intraperitoneal injections per day of alpha-lipoic acid (20 mg/kg), vehicle or saline and on the 7th day the animals were subjected to 5 min of forebrain ischemia. Ischemic injury was assessed by monitoring the increases in locomotor activity and from the extent of damage to the CA1 hippocampal pyramidal cell layer after 5 days of recovery. By both criteria, alpha-lipoic acid was neuroprotective against ischemia/reperfusion evoked cerebral injury.

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