Effect of treatment of diabetic rats with dehydroepiandrosterone on vascular and neural function

Nutritional supplementation with dehydroepiandrosterone (DHEA) may be a candidate for treating diabetes-induced vascular and neural dysfunction. DHEA is a naturally occurring adrenal androgen that has antioxidant properties and is reportedly reduced in diabetes. Using a prevention protocol, we found that dietary supplementation of streptozotocin-induced diabetic rats with 0.1, 0.25, or 0.5% DHEA caused a concentration-dependent prevention in the development of motor nerve conduction velocity and endoneurial blood flow impairment, which are decreased in diabetes. At 0.25%, DHEA significantly prevented the diabetes-induced increase in serum thiobarbituric acid-reactive substances and sciatic nerve conjugated diene levels. This treatment also reduced the production of superoxide by epineurial arterioles of the sciatic nerve. DHEA treatment (0.25%) significantly improved vascular relaxation mediated by acetylcholine in epineurial vessels of diabetic rats. Sciatic nerve Na+-K+-ATPase activity and myoinositol content was also improved by DHEA treatment, whereas sorbitol and fructose content remained elevated. These studies suggest that DHEA, by preventing oxidative stress and perhaps improving sciatic nerve Na+-K+-ATPase activity, may improve vascular and neural dysfunction in diabetes.     

Effect of Fidarestat and α-Lipoic Acid on Diabetes-Induced Epineurial Arteriole Vascular Dysfunction

In the present study, the authors examined whether treating streptozotocin-induced diabetic rats with the combination of α-lipoic acid and fidarestat, an aldose reductase inhibitor, can promote the formation of dihydrolipoic acid in diabetic animals and thereby enhance the efficacy of α-lipoic acid as monotherapy toward preventing diabetic vascular and neural dysfunction.Treating diabetic rats with the combination of 0.25% α-lipoic acid (in the diet) and fidarestat (3 mg/kg body weight) prevented the diabetesinduced slowing of motor nerve conduction velocity and endoneurial blood flow. This therapy also significantly improved acetylcholine-mediated vasodilation in epineurial arterioles of the sciatic nerve compared to nontreated diabetic rats. Treating diabetic rats with 0.25% α-lipoic acid and fidarestat (3 mg/kg body weight) was equally or more effective in preventing vascular and neural dysfunction than was monotherapy of diabetic rats with higher doses of α-lipoic acid or fidarestat. Treating diabetic rats with the combination of 0.25% α-lipoic acid and fidarestat (3 mg/kg body weight) significantly improved several markers of oxidative stress and increased the serum levels of both α-lipoic acid and dihydrolipoic acid. These studies suggest that combination therapy consisting of α-lipoic acid and fidarestat may be more efficacious in preventing diabetes-induced vascular and neural dysfunction in peripheral tissue compared to monotherapy, which requires higher doses to be equally effective. The effect of this combination therapy may in part be due to the increased production and/or level of dihydrolipoic acid.     

Preventing superoxide formation in epineurial arterioles of the sciatic nerve from diabetic rats restores endothelium-dependent vasodilation

We have previously reported that in streptozotocin-induced diabetic rats that increased formation of superoxide and peroxynitrite is associated with impairment in vascular relaxation in epineurial arterioles of the sciatic nerve. In this study we demonstrate that pretreating epineurial arterioles from diabetic rats in vitro with alpha-lipoic acid, dihydrolipoic acid, tempol or arginine restores acetylcholine-mediated vascular relaxation to near the reactivity observed in vessels from control rats. Suggesting that increased oxidative stress and reduction in nitric oxide availability is partially responsible for the impairment in endothelium-dependent vasodilation observed in epineurial arterioles from diabetic rats. In contrast, pretreating epineurial arterioles from diabetic rats with aminoguanidine or allopurinol had no effect. Studies designed to investigate the source of superoxide formation provided results suggesting that complex I of the mitochondrial electron transport chain and NAD(P)H oxidase are responsible for the increase in superoxide formation observed with epineurial arterioles from the sciatic nerve. Pretreating epineurial arterioles from diabetic rats with the protein kinase C inhibitor bisindolymaleimide I (GF 109203X) improved acetylcholine-mediated vascular relaxation but did not prevent the increase in superoxide formation suggesting that activation of protein kinase C by oxidative stress is downstream of superoxide formation. These studies imply that increased superoxide formation via the mitochondrial electron transport chain and perhaps NAD(P)H oxidase is partially responsible for reduced vascular reactivity observed in epineurial arterioles of the sciatic nerve from diabetic rats.     

Pentoxifylline Effects on Nerve Conduction Velocity and Blood Flow in Diabetic Rats

Pentoxifylline has several actions that improve blood rheology and tissue perfusion and may therefore potentially be applicable to diabetic neuropathy. The aims of this study were to ascertain whether 2 weeks of treatment with pentoxifylline could correct nerve conduction velocity and blood flow deficits in 6-week streptozotocin-diabetic rats and to examine whether the effects were blocked by co-treatment with the cyclooxygenase inhibitor, flurbiprofen, or the nitric oxide synthase inhibitor, N^G-nitro-ʟ-arginine. Diabetic deficits in sciatic motor and saphenous sensory nerve conduction velocity were 56.5% and 69.8% corrected, respectively, with pentoxifylline treatment. Sciatic endoneurial blood flow was approximately halved by diabetes and this deficit was 50.4% corrected by pentoxifylline. Flurbiprofen co-treatment markedly attenuated these actions of pentoxifylline on nerve conduction and blood flow whereas N^G-nitro-ʟ-arginine was without effect. Thus, pentoxifylline treatment confers neurovascular benefits in experimental diabetic neuropathy, which are linked at least in part to cyclooxygenasemediated metabolism.     

Slowing of Motor Nerve Conduction Velocity in Streptozotocin-induced Diabetic Rats is Preceded by Impaired Vasodilation in Arterioles that Overlie the Sciatic Nerve

Diabetes mellitus produces marked abnormalities in motor nerve conduction, but the mechanism is not clear. In the present study we hypothesized that in the streptozotocin (STZ)-induced diabetic rat impaired vasodilator function in arterioles that provide circulation to the region of the sciatic nerve is associated with reduced endoneural blood flow (EBF) and that these defects precede slowing of motor nerve conduction velocity, and thereby may contribute to nerve dysfunction. As early as three days after the induction of diabetes endoneural blood flow was reduced in the STZ-induced diabetic rat. Furthermore, after 1 week of diabetes acetylcholine- induced vasodilation was found to be impaired. This was accompanied by an increase in the superoxide level in arterioles that provide circulation to the region of the sciatic nerve as well as changes in the level of other markers of oxidative stress including an increase in serum levels of thiobarbituric acid reactive substances and a decrease in lens glutathione level. In contrast to the vascular related changes that occur within 1 week of diabetes, motor nerve conduction velocity and sciatic nerve Na⁺/k⁺ ATPase activity were significantly reduced following 2 and 4 weeks of diabetes, respectively. These studies demonstrate that changes in vascular function in the STZ-induced diabetic rat precede the slowing of motor nerve conduction velocity (MNCV) and are accompanied by an increase in superoxide levels in arterioles that provide circulation to the region of the sciatic nerve.     

Evaluation of alpha(1)-adrenoceptor antagonist on diabetes-induced changes in peripheral nerve function, metabolism, and antioxidative defense.

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.     

Progression of vascular and neural dysfunction in sciatic nerves of Zucker diabetic fatty and Zucker rats

We have examined the progression of vascular and neural deficits in Zucker rats, Zucker diabetic fatty (ZDF) diabetic rats, and age-matched lean ZDF rats from 8 to 40 wk of age. Both the ZDF diabetic and Zucker rats were glucose intolerant at 8 wk of age. The Zucker rats did not become hyperglycemic but were hyperinsulinemic through 32 wk of age. All ZDF diabetic rats became hyperglycemic by 8 wk of age. Through their life span, serum free fatty acids and triglycerides levels were significantly higher in Zucker and ZDF diabetic rats compared with age-matched lean ZDF rats. After 24 and 28 wk of age, endoneurial blood flow was significantly decreased in ZDF diabetic and Zucker rats. Motor nerve conduction velocity was significantly decreased after 12-14 wk of age in ZDF diabetic rats and at 32 wk of age in Zucker rats. ACh-mediated vascular relaxation of epineurial arterioles of the sciatic nerve was impaired after 8-10 wk of age in ZDF diabetic rats and after approximately 16 wk of age in Zucker rats. In contrast, vascular relaxation mediated by calcitonin gene-related peptide was impaired significantly after 28 wk of age in ZDF diabetic rats but not impaired in Zucker rats up to 40 wk of age. Markers of oxidative stress were differentially elevated in ZDF diabetic rats and Zucker rats. These data indicate that vascular and neural dysfunction develops in both Zucker and ZDF diabetic rats but at different rates, which may be the result of hyperglycemia.     

Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats

Evidence for important roles of the highly reactive oxidant peroxynitrite in diabetic complications is emerging. We evaluated the role of peroxynitrite in early peripheral neuropathy and vascular dysfunction in STZ-diabetic rats. In the first dose-finding study, control and STZ-diabetic rats were maintained with or without the potent peroxynitrite decomposition catalyst Fe(III)tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) at 3, 5, or 10 mg.kg(-1).day(-1) in the drinking water for 4 wk after an initial 2 wk without treatment for assessment of early neuropathy. In the second study with similar experimental design, control and STZ-diabetic rats were maintained with or without FP15, 5 mg.kg(-1).day(-1), for vascular studies. Rats with 6-wk duration of diabetes developed motor and sensory nerve conduction velocity deficits, mechanical hyperalgesia, and tactile allodynia in the absence of small sensory nerve fiber degeneration. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve and dorsal root ganglia. All these variables were dose-dependently corrected by FP15, with minimal differences between the 5 and 10 mg.kg(-1).day(-1) doses. FP15, 5 mg.kg(-1).day(-1), also corrected endoneurial nutritive blood flow and nitrotyrosine, but not superoxide, fluorescence in aorta and epineurial arterioles. Diabetes-induced decreases in acetylcholine-mediated relaxation by epineurial arterioles and coronary and mesenteric arteries, as well as bradykinin-induced relaxation by coronary and mesenteric arteries, were alleviated by FP15 treatment. The findings reveal the important role of nitrosative stress in early neuropathy and vasculopathy and provide the rationale for further studies of peroxynitrite decomposition catalysts in long-term diabetic models.     

Effect of the NAD(P)H oxidase inhibitor,apocynin, on peripheral nerve perfusion and function in diabetic rats

Upregulation of vascular NAD(P)H oxidase has been considered an important source for elevated levels of reactive oxygen species that contribute to several cardiovascular disease states, including the vascular complications of diabetes mellitus. Previous studies have shown that treatment with antioxidants corrects impaired nerve function and blood flow in diabetic rats. The aim was to assess the degree of involvement of NAD(P)H oxidase in experimental diabetic neuropathy. To this end, after 6 weeks of untreated streptozotocin-diabetes, rats were treated for 2 weeks with the NAD(P)H oxidase, apocynin. Two high doses (15 and 100 mg/kg) were used to ensure that maximal effects were registered. Diabetes caused a 20% reduction in sciatic nerve motor conduction velocity, and a 14% deficit for sensory saphenous nerve. Apocynin treatment corrected these defects by 32% and 48%, respectively: there were no significant differences between the effects of the 2 doses. Sciatic nerve nutritive endoneurial perfusion was measured by hydrogen clearance microelectrode polarography. Blood flow and vascular conductance were 47% and 40% reduced by diabetes, respectively. Both doses of apocynin had similar effects, correcting the blood flow deficit by 31% and conductance by 47%. Thus, the data show that NAD(P)H oxidase contributes to the neurovascular deficits in diabetic rats. While only accounting for part of the elevated reactive oxygen species production in diabetes, this mechanism could provide a novel therapeutic candidate for further investigation in diabetic neuropathy and vasculopathy.     

A new prostaglandin E1 analogue (TFC-612) prevents a decrease in motor nerve conduction velocity in streptozocin-diabetic rats

A new prostaglandin E1 analogue (TFC-612) was orally given to streptozocin-diabetic rats for 4 weeks after the induction of diabetes and its effects on motor nerve conduction velocity were studied. The compound significantly prevented a decrease of the velocity but did not reverse abnormal sorbitol and myo-inositol contents of the sciatic nerve. The results suggest that TFC-612 has a potent effect on diabetic nerve dysfunction via other mechanism than the correction of sorbitol and myo-inositol metabolisms and could be a potential compound for therapy of diabetic polyneuropathy.     

Attenuation of vascular/neural dysfunction in Zucker rats treated with enalapril or rosuvastatin

Objective: Obese Zucker rats, animal model for the metabolic syndrome, develop a diabetes‐like neuropathy that is independent of hyperglycemia. The purpose of this study was to determine whether drugs used to treat cardiovascular dysfunction in metabolic syndrome also protect nerve function. Methods and Procedures: Obese Zucker rats at 20 weeks of age were treated for 12 weeks with enalapril or rosuvastatin. Lean rats were used as controls. Vasodilation in epineurial arterioles was measured by videomicroscopy. Endoneurial blood flow (EBF) was measured by hydrogen clearance and nerve conduction velocity was measured following electrical stimulation of motor or sensory nerves. Results: Enalapril treatment decreased serum angiotensin‐converting enzyme (ACE) activity and both drugs reduced serum cholesterol levels. In obese Zucker rats at 32 weeks of age superoxide levels were elevated in the aortas and epineurial arterioles, which were reduced by treatment with either drug. Nitrotyrosine levels were increased in epineurial arterioles and reduced with enalapril treatment. EBF was decreased and corrected by treatment with either drug. Motor nerve conduction velocity was decreased and significantly improved with enalapril treatment. Obese Zucker rats were hypoalgesic in response to a thermal stimulus and this was significantly improved with either treatment. Treatment with either enalapril or rosuvastatin significantly reversed the decrease in acetylcholine‐mediated vascular relaxation of epineurial arterioles in obese Zucker rats. Discussion: Even though obese Zucker rats have normal glycemia vascular and neural dysfunctions develop with age and can be improved by treatment with either enalapril or rosuvastatin.     

Transplantation of bone marrow-derived mononuclear cells improves mechanical hyperalgesia, cold allodynia and nerve function in diabetic neuropathy

Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.     

Normal blood flow but lower oxygen tension in diabetes of young rats: microenvironment and the influence of sympathectomy.

Studies of rats with experimental streptozotocin (STZ)-induced diabetes at 4 months have identified sciatic nerve trunk oligemia and hypoxia, but it is uncertain how early these abnormalities develop or which develops first. We studied young (4-week-old) rats after 6 or 16 weeks of STZ-induced diabetes (or after citrate buffer injection in controls) by recording multi-fiber conduction in three different nerve territories and by measuring sciatic endoneurial blood flow (NBF) and oxygen tension (PnO2) at end point. To evaluate the impact of sympathectomy on this diabetic model, separate animal groups were treated for 5 weeks with guanethidine monosulfate given at the onset of diabetes (group 1, end point 6 weeks) or after 6 weeks of diabetes (group 2, end point 16 weeks). Diabetes was associated with deficits in sensory and motor caudal conduction and increased resistance to ischemic conduction failure (RICF). NBF was comparable to control animals at both time points and was within the published normal range of NBF. In contrast, oxygen tensions were shifted to lower values in diabetic animals. Sympathectomy was associated with blunting of the RICF increase in group 2 but worsened caudal sensory conduction despite evidence of modest improvement in sciatic nerve oxygenation. Our findings support the concept that neuropathy occurs early in diabetes and that hypoxia develops before oligemia. Sympathectomy did not benefit this diabetic model.     

Protective effect of stobadine on NCV in streptozotocin-diabetic rats: augmentation by vitamin E

Hyperglycaemia-induced oxidative stress makes an important contribution to the aetiology of diabetic neuropathy. Elevated reactive oxygen species (ROS) cause cumulative damage to neurons and Schwan cells, however, they also have a deleterious effect on nerve blood flow causing endoneurial hypoxia, which is responsible for early nerve conduction velocity (NCV) deficits and contributes to an increase in resistance to ischaemic conduction failure (RICF). We tested whether antioxidants - stobadine, vitamin E or the combination of these drugs, could prevent the early signs of neural dysfunction in animal model of diabetes in 8-9 weeks old male Wistar rats, made diabetic by streptozotocin (55 mg/kg i.v.) 4 months prior to testing. Neuropathy was evaluated electrophysiologically by measuring motor NCV and RICF of sciatic nerve in vitro. We observed that treatment with the combination of stobadine and vitamin E significantly (p < 0.001) reduced the NCV slowing in diabetic rats, although it did not fully prevent the NCV impairment. Significant effect (p < 0.05) was observed also in stobadine monotherapy. The RICF elevated in diabetic animals was not affected by any drug applied. This study confirmed that treatment with appropriate antioxidants, especially their combination could partially prevented the decrease in NCV in diabetic rats.     

神经生长因子与冻干异体神经桥接大鼠神经缺损的研究

实验采用冻干处理的异体神经与外源性神经生长因子（ＮＧＦ）结合来桥接大鼠的坐骨神经１．０ｃｍ的缺损。用雄性Ｗｉｓｔａｒ大鼠进行的四组实验结果表明：冻干处理的异体神经可降低其抗原性,但处理后并不损害雪旺氏细胞（ＳＣ）基底膜的完整性,在移植后可能成为轴突再生的通道和支架;外源性ＮＧＦ与冻干神经结合形成的复合体,可为神经的再生提供一个较好的微环境,具有成为理想桥接材料的可能性     

Alterations of Na,K-ATPase Isoenzymes in the Rat Diabetic Neuropathy: Protective Effect of Dietary Supplementation with n-3 Fatty Acids

Abstract: Diabetic neuropathy is a degenerative complication of diabetes accompanied by an alteration of nerve conduction velocity (NCV) and Na,K-ATPase activity. The present study in rats was designed first to measure diabetes-induced abnormalities in Na,K-ATPase activity, isoenzyme expression, fatty acid content in sciatic nerve membranes, and NCV and second to assess the preventive ability of a fish oil-rich diet (rich in n-3 fatty acids) on these abnormalities. Diabetes was induced by intravenous streptozotocin injection. Diabetic animals (D) and nondiabetic control animals (C) were fed the standard rat chow either without supplementation or supplemented with either fish oil (DM, CM) or olive oil (DO, CO) at a daily dose of 0.5 g/kg by gavage during 8 weeks. Analysis of the fatty acid composition of purified sciatic nerve membranes from diabetic animals showed a decreased incorporation of C16:1(n-7) fatty acids and arachidonic acids. Fish oil supplementation changed the fatty acid content of sciatic nerve membranes, decreasing C18:2(n-6) fatty acids and preventing the decreases of arachidonic acids and C18:1(n-9) fatty acids. Protein expression of Na,K-ATPase α subunits, Na,K-ATPase activity, and ouabain affinity were assayed in purified sciatic nerve membranes from CO, DO, and DM. Na,K-ATPase activity was significantly lower in sciatic nerve membranes of diabetic rats and significantly restored in diabetic animals that received fish oil supplementation. Diabetes induced a specific decrease of α1- and α3-isoform activity and protein expression in sciatic nerve membranes. Fish oil supplementation restored partial activity and expression to varying degrees depending on the isoenzyme. These effects were associated with a significant beneficial effect on NCV. This study indicates that fish oil has beneficial effects on diabetes-induced alterations in sciatic nerve Na,K-ATPase activity and function.     

Ganglioside treatment of diabetic rats; effects on nerve adenosine triphosphatase activity and motor nerve conduction velocity

Ouabain-sensitive ATPase activity (expressed as nmol ADP produced/h/mg (wet) nerve +/- SEM) was measured in homogenates of sciatic nerve from control rats and rats with streptozotocin-induced diabetes of 8 wk duration. Nerves from diabetic rats showed activity (21.7 +/- 2.0) which was significantly (p less than 0.05) less than that of controls (34.6 +/- 4.8). These animals also showed a deficit in conduction velocity (m/sec +/- SEM) of sciatic nerve motoneurones (50.7 +/- 0.4 vs. 57.7 +/- 0.7 in controls; p less than 0.001). In parallel, matched control and diabetic groups were treated daily with mixed gangliosides extracted from bovine brain (10 mg/kg i.p.). After such treatment for 8 wk the deficit in ouabain-sensitive ATPase activity did not develop in the diabetic group (treated diabetics, 31.9 +/- 3.7; treated controls, 34.5 +/- 3.8). However, the treatment did not affect the deficit in motor nerve conduction velocity (treated diabetics, 50.9 +/- 1.1 vs. treated controls, 57.9 +/- 0.5; p less than 0.001). Accumulations of the polyol pathway metabolites--sorbitol and fructose--together with depletion of nerve myo-inositol were similar in both diabetic groups. These data indicate an etiology for the conduction velocity deficit which differs from that of the deficit in ouabain-sensitive ATPase.     

Pyridoxal-aminoguanidine adduct is more effective than aminoguanidine in preventing neuropathy and cataract in diabetic rats.

We examined the ability of a pyridoxal-aminoguanidine adduct with both antiglycation and antioxidant activities in vitro to protect against neuropathy and cataract in streptozotocin-diabetic rats and compared the result with that of aminoguanidine. In vivo antiglycation and antioxidant activities were also compared between the adduct and aminoguanidine. Diabetic rats were given either of the compounds in their drinking water (9 mM) for 7 weeks. Neither compound affected body weight, blood glucose level or urine volume. The adduct, but not aminoguanidine, significantly improved motor nerve conduction velocity. The time to develop cataract was longer in adduct-treated rats than in untreated and aminoguanidine-treated rats. The increase in opacification of lenses in culture medium containing high glucose levels (55.5 mM) was more efficiently attenuated by the adduct than by aminoguanidine. Adduct and aminoguanidine similarly lowered glycated hemoglobin levels. The level of urinary 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage, and the level of liver malondialdehyde plus 4-hydroxy-2-alkenals, a marker of tissue lipid peroxidation, both of which were elevated by diabetes, were significantly reduced by the adduct but not by aminoguanidine. These findings indicate that the pyridoxal-aminoguanidine adduct is superior to aminoguanidine in preventing diabetic neuropathy and cataracts, and we suggest that this may be at least partly due to the higher antioxidant activity of the former.     

Ganglioside Treatment of Streptozotocin-Diabetic Rats Prevents Defective Axonal Transport of 6-Phosphofructokinase Activity

This study measured axonal transport of 6-phosphofructokinase (PFK) and aldolase activities in the sciatic nerves of rats with short-term streptozotocin-induced diabetes. The diabetic rats showed deficits in anterograde (69% of controls; p less than 0.001) and retrograde (33% of controls; p less than 0.01) accumulations of PFK activity as well as its content per unit length of unconstricted sciatic nerve (86% of controls; p less than 0.05). There were no accumulation deficits in aldolase activity in the nerves of the diabetic rats, although the activity per unit length of unconstricted nerve was deficient (81% of controls; p less than 0.05). Treatment of diabetic rats with mixed bovine brain gangliosides (10 mg/kg of body weight/day, i.p.) did not affect the deficit in PFK activity in unconstricted nerve (84% of ganglioside-treated controls; p less than 0.01), but all the other defects in enzyme activities were prevented completely. The diabetic rats also showed a reduction of 7% (p less than 0.01) in sciatic nerve dry weight per unit length, which was prevented by ganglioside treatment. In contrast, the reduced motor nerve conduction velocity, accumulation of polyol pathway metabolites, and depletion of myo-inositol, characteristic of untreated short-term diabetes, were unaffected by ganglioside treatment.