Effect of d-amphetamine on tryptophan and other aromatic amino acids in brain.

The investigation examined the mechanism of the increase in brain tryptophan concentration of rats treated with d-amphetamine. Certain well recognised influences upon brain tryptophan have been excluded as responsible. Thus, the effect is not associated with changes in the plasma concentrations of NEFA or free tryptophan. It is probably not due to a tryptophan-specific mechanism, because amphetamine increases the ratio of brain/plasma concentrations not only of tryptophan but also of tyrosine and phenylalanine. The concentration ratios for liver/plasma also rose, as did the liver tryptophan concentration, but these changes were less striking than for brain. Both alpha- and beta-adrenergic blocking drugs opposed the changes in brain, but in different ways. Thus, after treatment of rats with phentolamine, amphetamine decreased the plasma concentrations of the three aromatic amino acids; however, as the brain concentrations were little altered, the brain/plasma concentration ratios rose. Propranolol (and the dopamine blocker pimozide) opposed the increases of the ratios, so that the brain concentrations again altered little. The increased brain/plasma ratios resulting from the administration of amphetamine were associated with hyperthermia. Propranolol, pimozide and the diabetogenic drug streptozotocin opposed the changes in both plasma and brain; phentolamine affected neither. Despite the increase in brain tryptophan caused by amphetamine this drug had relatively little concurrent effect on 5HT synthesis. Experiments with adrenergic blockers suggest that the small rise of plasma insulin after the injection of amphetamine into rats did not cause the brain changes; these are probably a consequence of hyperthermia. The findings with streptozotocin suggest that the hyperthermic effect of amphetamine is manifested only in states of normal insulin secretion.     

Fluoxetine attenuates thermal hyperalgesia through 5-HT1/2 receptors in streptozotocin-induced diabetic mice

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. A lack of understanding of its aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect and possible mechanism of action of a serotonin reuptake inhibitor, fluoxetine, in streptozotocin-induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail-immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia compared with control mice. Fluoxetine (10 and 20, but not 5 mg/kg, i.p.) injected into diabetic mice produced an antinociceptive effect in both the tail-immersion and hot-plate assays. The percentage maximum possible effect (% MPE) produced by fluoxetine (20 mg/kg, i.p.) was significantly lower in diabetic mice than in control mice. The antinociceptive effect of fluoxetine (20 mg/kg) in diabetic mice was dose-dependently potentiated by pindolol (5 and 10 mg/kg, i.p., a selective 5-HT(1A/1B) receptor antagonist), attenuated by ritanserin (1 and 2 mg/kg, i.p., a selective 5-HT(2A/2C) receptor antagonist) and remained unaffected by ondansetron (1 and 2 mg/kg, i.p., a selective 5-HT(3) receptor antagonist) in both test systems. These results suggest that fluoxetine-induced antinociception primarily involves serotonin pathway modulation through 5-HT(1) and 5-HT(2) receptors, but not through 5-HT(3) receptors, in the chronic pain associated with streptozotocin-induced diabetic neuropathy. Further, the potentiation of the antinociceptive effect of fluoxetine by pindolol indicates the usefulness of a combination of an antidepressant and a 5-HT(1A/1B) receptor antagonist in the treatment of diabetic neuropathic pain in humans.     

Effect of Coccinia indica leaf extract on plasma antioxidants in streptozotocin- induced experimental diabetes in rats

The present study was carried out to investigate the antioxidant effect of an ethanolic extract of Coccinia indica leaves, an indigenous plant used in Ayurvedic Medicine in India, in Streptozotocin-diabetic rats. Oral administration of Coccinia indica leaf extract (CLEt) (200 mg/kg body weight) for 45 days resulted in a significant reduction in plasma thiobarbituric acid reactive substances, hydroperoxides, vitamin E and ceruloplasmin. The extract also caused a significant increase in plasma vitamin C and reduced glutathione, which clearly shows the antioxidant property of CLEt. The effect of CLEt at 200 mg/kg body weight was more effective than glibenclamide.     

糖尿病性记忆障碍的临床及动物模型研究现状

糖尿病因慢性高血糖而导致认知障碍的严重性已为医学界广为关注,糖尿病引起的学习记忆障碍是糖尿病最重要的并发症之一。随着抗糖尿病药物的深入研究,动物模型有很好发展和应用。本文综述了链脲霉素腹腔注射或脑室内注射所致大鼠糖尿病记忆障碍模型和临床糖尿病患者引起认知障碍的研究进展。     

Effect of dietary supplementation with the pyridoindole antioxidant stobadine on antioxidant state and ultrastructure of diabetic rat myocardium

Consistent with the postulated role of oxidative stress in the etiology of late diabetic complications, pharmacological interventions based on biological antioxidants have been suggested. The aim of the present study was to investigate the effect of dietary supplementation with the pyridoindole antioxidant stobadine on the myocardial antioxidant status and ultrastructure of streptozotocin-diabetic rats. Diabetic male Wistar rats were fed for 32 weeks a standard diet or a diet supplemented with stobadine (0.05% w/w). Control rats received a standard diet or stobadine-supplemented diet (0.16% w/w). Plasma levels of glucose, cholesterol and triglycerides were increased significantly by diabetes. Activities of superoxide dismutase and catalase were markedly elevated in the diabetic myocardium. Myocardial levels of conjugated dienes increased after eight months of diabetes, in spite of significantly increased myocardial α-tocopherol and coenzyme Q₉ content. The long-term treatment of diabetic animals with stobadine (i) reduced plasma cholesterol and triglyceride levels yet left the severe hyperglycemia unaffected, (ii) reduced oxidative damage of myocardial tissue as measured by conjugated dienes, (iii) reversed myocardial levels of α-tocopherol and coenzyme Q₉ to near control values, (iv) reduced elevated activity of superoxide dismutase in the diabetic myocardium, and (v) attenuated angiopathic and atherogenic processes in the myocardium as assessed by electron microscopy examination. These results are in accordance with the postulated prooxidant role of chronic hyperglycemia and provide further evidence that development of pathological changes in diabetic myocardium is amenable to pharmacological intervention by biological antioxidants. Received: 7 June 2000 / Accepted in revised form: 27 November 2000     

Effects of neonatal capsaicin treatment and streptozotocin-induced diabetes on urinary bladder function in rats

A significant increase in the size and weight of the urinary bladder was observed 2 weeks after streptozotocin treatment and 2 months after neonatal capsaicin treatment. Both treatments induced a significant increase in the level of [³H]quinuclidinyl benzilate binding to muscarinic cholinergic receptors in the urinary bladder membranes. However, contractile responses of urinary bladder muscle strips to carbachol (0.3–20 μM) were not significantly affected by either treatment. On the other hand, neonatal capsaicin treatment, but not streptozotocin treatment, significantly enhanced contractile responses of bladder strips to electric field stimulation.     

Resveratrol,a natural phytoalexin,normalizes hyperglycemia in streptozotocin-nicotinamide induced experimental diabetic rats

Resveratrol is a polyphenolic phytoalexin produced in appreciable amounts as a secondary metabolite in grapevines in response to fungal infections. Based on the present knowledge, it appears to be a promising bioactive natural molecule with potential applications in phytotherapy or pharmacology. The present study was aimed to evaluate the antidiabetic properties of resveratrol in streptozotocin-nicotinamide induced experimental diabetes in rats. The diabetic rats orally treated with resveratrol (5 mg kg⁻¹ b.w d⁻¹) for 30 days resulted in significant (p < 0.05) decrease in the levels of blood glucose, glycosylated hemoglobin, blood urea, serum uric acid, serum creatinine and diminished activities of pathophysiological enzymes such as aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). The antihyperglycemic nature of resveratrol is also evidenced from the improvement in the levels of plasma insulin and hemoglobin. Further, the results are comparable with glyclazide, an oral standard drug. Thus, the present findings suggest that resveratrol may be considered as an effective therapeutic agent for the treatment of diabetes mellitus.     

The mechanisms of alloxan- and streptozotocin-induced diabetes

Alloxan and streptozotocin are toxic glucose analogues that preferentially accumulate in pancreatic beta cells via the GLUT2 glucose transporter. In the presence of intracellular thiols, especially glutathione, alloxan generates reactive oxygen species (ROS) in a cyclic redox reaction with its reduction product, dialuric acid. Autoxidation of dialuric acid generates superoxide radicals, hydrogen peroxide and, in a final iron-catalysed reaction step, hydroxyl radicals. These hydroxyl radicals are ultimately responsible for the death of the beta cells, which have a particularly low antioxidative defence capacity, and the ensuing state of insulin-dependent ‘alloxan diabetes’. As a thiol reagent, alloxan also selectively inhibits glucose-induced insulin secretion through its ability to inhibit the beta cell glucose sensor glucokinase. Following its uptake into the beta cells, streptozotocin is split into its glucose and methylnitrosourea moiety. Owing to its alkylating properties, the latter modifies biological macromolecules, fragments DNA and destroys the beta cells, causing a state of insulin-dependent diabetes. The targeting of mitochondrial DNA, thereby impairing the signalling function of beta cell mitochondrial metabolism, also explains how streptozotocin is able to inhibit glucose-induced insulin secretion.     

Increased dose-response relationship of liver plasma membrane adenylate cyclase to glucagon stimulation in diabetic rats. A possible role of the guanyl nucleotide-binding regulatory protein

Summary In view of controversial findings regarding the mechanism for the increased intracellular hepatic cyclic 3:5 adenosine monophosphate levels in diabetic rats, we studied the dose-response relationship of the adenylate cyclase to glucagon stimulation in severely diabetic and in diabetic, insulin-treated rats. An enhanced response to glucagon and an additional augmenting effect of guanosine triphosphate on hormonal stimulation of the adenylate cyclase activity were found in diabetes which were reversible with insulin treatment. The results suggest a role of the regulatory guanyl nucleotide-binding protein in diabetes leading to an increased dose response relationship of the hepatic adenylate cyclase system to glucagon.     

Glomerular selective permeability to macromolecular neutral dextrans in experimental diabetes

Summary Rats with streptozotocin-induced chronic diabetes mellitus develop a glomerulopathy functionally manifested by proteinuria. The ability of the glomerular capillary wall to retard filtration of macromolecules was examined in 5 chronically diabetic Munich-Wistar rats exhibiting excessive proteinuria (39±7mg/24h, mean±SEM) and 5 age-matched normal Munich-Wistar rats without increased proteinuria (4.7±0.2 mg/24 h). Urinary albumin excretion was not increased in the diabetic rats (2.0±0.6 mg/24h vs 1.6±0.3 mg/24h) suggesting that the normal net electronegative charge of the glomerular capillary wall was not altered. Fractional clearances of macromolecular neutral dextrans were similar in diabetic and normal rats throughout a wide range of molecular size (18–42 Å). Glomerular filtration rate was the same in the two groups of rats (2.77±0.16ml/min in diabetics and 2.72±0.11ml/ min in normals) suggesting that renal haemodynamic factors did not influence fractional clearances of neutral dextrans in diabetic rats. We conclude that the proteinuria exhibited by these chronically diabetic rats is not attributable to alterations of size-selective properties of the glomerular capillary wall, such as increases in the size or the number of pores.