Adil El Midaoui

Lipoic acid prevents hypertension, hyperglycemia, and the increase in heart mitochondrial superoxide production

BACKGROUND The present study was designed to investigate whether the effects of dietary supplementation with alpha-lipoic acid could prevent the increase in mitochondrial superoxide production in the heart as well as the enhanced formation of advanced glycation end-products (AGE) that are associated with the development of hypertension and insulin resistance in chronically glucose-fed rats. METHODS Sprague Dawley rats were either given or not given a 10% D-glucose solution to drink during 4 weeks, combined either with a normal chow diet or with alpha-lipoic acid supplemented diet. The oxidative stress was evaluated by measuring the heart mitochondrial superoxide production using the lucigenin chemiluminescence method. The formation of AGE was also assessed in plasma and aorta. RESULTS Chronic administration of glucose resulted in a 29% increase in blood pressure, 30% increase in glycemia, 286% increase in insulinemia, and 408% increase in insulin resistance index. Chronic glucose feeding also resulted in a 22% greater mitochondrial superoxide anion production in heart and in an increase of 63% in AGE content in aorta. Increases in blood pressure, aorta AGE content and heart mitochondrial superoxide production were prevented in the rats fed glucose supplemented with lipoic acid. The simultaneous treatment with lipoic acid also attenuated the rise in insulin levels as well as in insulin resistance in the glucose fed rats. CONCLUSIONS These findings demonstrate that alpha-lipoic acid supplementation prevents development of hypertension and hyperglycemia, presumably through its antioxidative properties, as reflected by prevention of an increase in heart mitochondrial superoxide anion production and in AGE formation in the aorta of chronically glucose treated rats.

Prevention of hypertension, hyperglycemia and vascular oxidative stress by aspirin treatment in chronically glucose-fed rats.

Objectives To examine whether an in vivo chronic treatment with aspirin could prevent insulin resistance, oxidative stress and blood pressure elevation associated with high glucose feeding in rats. Methods Sprague–Dawley rats (SD) were given a normal chow diet for 3 weeks combined or not with a 10% glucose drinking solution with or without aspirin added to their drinking water, and were compared to control SD rats which received normal chow and tap water to drink for 3 weeks. Oxidative stress was evaluated by measuring superoxide anion (O2−) production in the aorta using the lucigenin-enhanced chemiluminescence method. Antioxidant reserve was assessed by measuring the activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) in the blood. Fasting blood sugar and insulin levels were measured at the end of the study. Results The systolic blood pressure (SBP), the aortic basal superoxide production, plasma levels of insulin and glucose, as well as the insulin resistance index, were all significantly higher in rats fed glucose for 3 weeks, compared to control rats. The simultaneous treatment with aspirin prevented the increase in SBP, in plasma glucose levels and in aortic O2− production, and attenuated the rise in insulin levels as well as insulin resistance in the glucose-fed rats. Positive correlations between aortic O2− production and SBP, as well as between insulin resistance and SBP or between O2− production and insulin resistance, were found in control, glucose-fed and aspirin-treated, glucose-fed rats. The activities of GPx and SOD in the erythrocytes did not differ in the three groups. An increase in plasma SOD activity was observed in glucose-fed rats. Conclusions Chronic in vivo treatment with aspirin prevented the development of hypertension and reduced insulin resistance significantly in chronically glucose-fed rats. Aspirin seems to produce these effects through its antioxidative properties, since it was found to prevent the increase in aortic O2− production observed in chronically glucose-fed rats.

Effects of glucose and insulin on the development of oxidative stress and hypertension in animal models of type 1 and type 2 diabetes

Objectives To investigate whether glucose or insulin is the cause of increases in oxidative stress and blood pressure in insulin-resistant animals, and to evaluate the effects of α-lipoic acid (LA) on the production of the superoxide anion (O2−) in the aorta and blood pressure elevations in various models of diabetes. Methods Two models of arterial hypertension combined with insulin resistance state and one model of insulin-dependent diabetes were studied in chronically glucose-fed rats (10% in drinking water), in animals chronically treated simultaneously with insulin (9 mU/kg per min with osmotic pumps) and glucose, and in rats initially treated with streptozotocin (50 mg/kg) and glucose during 4 weeks. These three groups of rats were treated either with a normal chow diet or with LA-supplemented diet. The oxidative stress was evaluated by the O2− production using the lucigenin-enhanced chemiluminescence method either in aortic or cultured smooth muscle cells from 12-week-old normotensive rats. Fasting blood glucose and insulin levels were measured after 4 weeks. Results At the end of the study, plasma levels of insulin and glucose as well as the insulin resistance index were found to be significantly higher in glucose-fed rats or in rats treated with insulin plus glucose compared with control rats (P < 0.01). Plasma glucose levels were elevated (P < 0.01) but plasma insulin levels were not modified in streptozotocin- and glucose-treated rats. Systolic blood pressure and aorta O2− production were found to be significantly higher in either glucose-fed rats (+20%) or in insulin plus glucose-treated rats (+24%) as compared with control rats (P < 0.01). Streptozotocin-induced diabetes with glucose treatment was not accompanied by increases in systolic blood pressure or in aortic O2− production. Rises in systolic blood pressure and in aortic O2− production were significantly attenuated either in glucose-fed (+10.3%) or in insulin plus glucose-fed (+8.7%) rats treated with LA. The simultaneous treatment with LA also attenuated the rise in insulin levels as well as in insulin resistance either in glucose-fed rats or in insulin plus glucose-treated rats. Moreover, LA was found to prevent the marked increases in O2− production in cultured smooth muscle cells chronically treated with high insulin combined or not with high glucose levels. Conclusions These findings demonstrate that elevated plasma glucose levels alone do not induce vascular oxidative stress and hypertension unless it is combined with high level of insulin. The finding that the treatment with LA, a potent antioxidant, was efficacious in preventing oxidative stress and hypertension in diabetic models of insulin resistance suggests an important participation of oxidative stress in the development of hypertension in type 2 diabetes.

Increases of spinal kinin receptor binding sites in two rat models of insulin resistance

An autoradiographic study was conducted to determine whether kinin receptors are altered in the rat spinal cord in two experimental models of chronic hyperglycemia and insulin resistance. Sprague-Dawley rats were given 10% d-glucose in their drinking water alone or with insulin (9 mU/kg/min with osmotic pumps) for 4 weeks. Both groups and control rats were treated either with a normal chow diet or with an alpha-lipoic acid-supplemented diet as antioxidant therapy. After 4 weeks of treatment, glycemia, insulinemia, blood pressure, insulin resistance index, the production of superoxide anion in the aorta and the density of B2 receptor binding sites in the dorsal horn were significantly increased in the two models. These effects were prevented or attenuated by alpha-lipoic acid. In contrast, B2 receptor binding sites of most spinal cord laminae were increased in the glucose group only and were not affected by alpha-lipoic acid. Results show that chronic hyperglycemia associated with insulin resistance increases B1 and B2 receptor binding sites in the rat spinal cord through distinct mechanisms, including the oxidative stress for the B1 receptor.

Effects of alpha-lipoic acid on kinin B1 and B2 receptor binding sites in the spinal cord of chronically angiotensin-treated rats

A quantitative autoradiographic study was performed to determine whether kinin receptors are altered in the rat spinal cord in an experimental model of arterial hypertension under antioxidant therapy with alpha-lipoic acid. Sprague-Dawley rats were fed for 4 weeks with a normal chow diet or with an alpha-lipoic acid supplemented diet (1000 mg/kg feed), and treated for the last 2 weeks with angiotensin II (AT II) (200 ng/kg/min with an osmotic pump implanted s.c.). Control rats received either diet but not AT II. A 2-week administration of AT II increased significantly systolic blood pressure, the production of superoxide anion in the aorta and B1 receptor binding sites in the thoracic spinal dorsal horn. This treatment did not affect spinal B2 receptor binding sites, glycemia and insulinemia. The diet supplemented with alpha-lipoic acid reduced significantly the increase in systolic blood pressure, the production of aortic superoxide anion and prevented the increases of B1 receptor binding sites. Results show an association between the oxidative stress and the increases of B1 receptors and arterial blood pressure induced by AT II. Data also exclude the possibility that arterial hypertension is a primary mechanism leading to an increase of B2 receptor binding sites in the rat spinal cord.

Beneficial effects of kinin B1 receptor antagonism on plasma fatty acid alterations and obesity in Zucker diabetic fatty rats

Kinins are the endogenous ligands of the constitutive B2 receptor (B2R) and the inducible B1 receptor (B1R). Whereas B2R prevents insulin resistance, B1R is involved in insulin resistance and metabolic syndrome. However, the contribution of B1R in type 2 diabetes associated with obesity remains uncertain. The aim of the present study was to examine the impact of 1-week treatment with a selective B1R antagonist (SSR240612, 10 mg/kg per day, by gavage) on hyperglycemia, hyperinsulinemia, leptinemia, body mass gain, and abnormal plasma fatty acids in obese Zucker diabetic fatty (ZDF) rats. Treatment with SSR240612 abolished the body mass gain and reduced polyphagia, polydipsia, and plasma fatty acid alterations in ZDF rats without affecting hyperglycemia, hyperinsulinemia, and hyperleptinemia. The present study suggests that the upregulated B1R plays a role in body mass gain and circulating fatty acid alterations in ZDF rats. However, mechanisms other than B1R induction would be implicated in glucose metabolism disorder in ZDF rats, based on the finding that SSR240612 did not reverse hyperglycemia and hyperinsulinemia.

Effects of Alpha-Lipoic Acid on Oxidative Stress and Kinin Receptor Expression in Obese Zucker Diabetic Fatty Rats

Objective To investigate the impact of alpha-lipoic acid on superoxide anion production and NADPH oxidase activity as well as on the expression of kinin B1 and B2 receptors in key organs of obese Zucker Diabetic Fatty rats. Methods Superoxide anion production was measured by lucigenin chemiluminescence. Kinin B1 and B2 receptors expression was measured at protein and mRNA levels by western blot and qRT-PCR in key organs of Zucker Diabetic Fatty and Zucker lean control rats treated for a period of 6 weeks with a standard diet or a diet containing the antioxidant α-lipoic acid (1 g/kg). Results Superoxide anion production and NADPH oxidase activity were significantly enhanced in aorta and adipose tissue of Zucker Diabetic Fatty rats. Kinin B1 and B2 receptors expression levels were also significantly increased in the liver and the gastrocnemius muscle of Zucker Diabetic Fatty rats. Expression of both receptors was not altered in the pancreas of Zucker Diabetic Fatty rats and was undetectable in white retroperitoneal adipose tissue. Alpha-lipoic acid prevented the rise in NADPH oxidase activity in aorta and epididymal adipose tissue of Zucker Diabetic Fatty rats and the upregulation of kinin B1 receptor in liver and gastrocnemius muscle and that of kinin B2 receptor in the liver. Alpha-lipoic acid treatment was found to prevent the final body weight increase without affecting significantly hyperglycemia, hyperinsulinemia and insulin resistance index in Zucker Diabetic Fatty rats. Conclusion Findings support the hypothesis that oxidative stress is implicated in the induction of kinin B1 receptor in Zucker Diabetic Fatty rats. The ability of α-lipoic acid to blunt the body weight gain appears to be mediated in part by preventing NADPH oxidase activity rise in adipose tissue and reversing the hepatic upregulation of kinin B1 receptor in Zucker Diabetic Fatty rats.

Argan Oil as an Effective Nutri-Therapeutic Agent in Metabolic Syndrome: A Preclinical Study

The present study aims at examining the effects of argan oil on the three main cardiovascular risk factors associated with metabolic syndrome (hypertension, insulin resistance and obesity) and on one of its main complications, neuropathic pain. Male Sprague-Dawley rats had free access to a drinking solution containing 10% d-glucose or tap water for 12 weeks. The effect of argan oil was compared to that of corn oil given daily by gavage during 12 weeks in glucose-fed rats. Glucose-fed rats showed increases in systolic blood pressure, epididymal fat, plasma levels of triglycerides, leptin, glucose and insulin, insulin resistance, tactile and cold allodynia in association with a rise in superoxide anion production and NADPH oxidase activity in the thoracic aorta, epididymal fat and gastrocnemius muscle. Glucose-fed rats also showed rises in B1 receptor protein expression in aorta and gastrocnemius muscle. Argan oil prevented or significantly reduced all those anomalies with an induction in plasma adiponectin levels. In contrast, the same treatment with corn oil had a positive impact only on triglycerides, leptin, adiponectin and insulin resistance. These data are the first to suggest that argan oil is an effective nutri-therapeutic agent to prevent the cardiovascular risk factors and complications associated with metabolic syndrome.