Protective effect of Umbelliferone on membranous fatty acid composition in streptozotocin-induced diabetic rats

Umbelliferone (UMB), a natural antioxidant, is benzopyrone in nature, and it is present in the fruits of golden apple and bitter orange. Earlier we evaluated and reported the effect of Umbelliferone on antidiabetic, antioxidant and antihyperlipidemic properties, and this study was designed to evaluate the effect of Umbelliferone on membrane fatty acid composition and histopathology of liver and kidney of control and streptozotocin (STZ) diabetic rats. Male albino Wistar rats (180-200 g) were made diabetic by an intraperitonial administration of STZ (40 mg/kg). The control and diabetic rats were treated with Umbelliferone and glibenclamide dissolved in 10% dimethyl sulfoxide for 45 days. Diabetic rats had decreased insulin and increased glucose, and increased levels of thiobarbituric acid reactive substances, lipid hydroperoxides and conjugated dienes. The levels of palmitic, stearic and oleic acids increased and the levels of linolenic and arachidonic acids decreased in diabetic rats as compared with control rats. Thus, the saturated fatty acids and monounsaturated fatty acids increased and the polyunsaturated fatty acids decreased in diabetic rats. Diabetic rats had decreased liver weight and increased activities of alanine transaminase and aspartate transaminase; increased kidney weight and urine albumin, and decreased levels of urea, uric acid and creatinine in the urine. Histopathological studies of liver and kidney in diabetic rats showed fatty changes surrounding portal triad; enlargement of lining cells of tubules, fatty infiltration, large area of hemorrhage and lymphocyte infiltration. Treatment with Umbelliferone and glibenclamide reversed these changes to near normalcy. Our results showed that Umbelliferone has a protective effect on membrane fatty acid composition of liver and kidney as supported by antioxidant and antihyperlipidemic effects of Umbelliferone reported earlier as evidenced by improved histopathological changes, hepatic and nephritic markers, indicating recovery from the risk of diabetic complications.     

Vasodilation of retinal arteriole mediated by corticotropin-releasing factor receptor is impaired in streptozotocin-induced diabetic rats

We investigated the vasodilator responses of retinal arterioles induced by stimulating corticotropin-releasing factor receptors in non-diabetic and diabetic rats. Male Wistar rats were treated with streptozotocin (65 mg/kg, i.v.) and experiments were performed 6-8 weeks later. Rats were treated with tetrodotoxin (50 mug/kg, i.v.) to eliminate any nerve activity and prevent movement of the eye and infused with a mixture of norepinephrine and epinephrine to maintain adequate systemic circulation under artificial ventilation. Fundus images were captured with an original high-resolution digital fundus camera system. The vasodilator responses of retinal arterioles were assessed by measuring changes in diameters of retinal arterioles in response to urocortin and urocortin 2. Both urocortin (0.03-1.0 micromol/kg, i.v.) and urocortin 2 (0.1-3.0 micromol/kg, i.v.) increased diameters of retinal arterioles and decreased systemic blood pressure in a dose-dependent manner. The responses to urocortins were reduced in diabetic rats. These results suggest that urocortin and urocortin 2 play as vasodilators in retinal and peripheral resistance arterioles. The impairment of vasodilation mediated by the corticotropin-releasing factor receptors may contribute to the alteration of retinal and systemic circulation in the diabetic state.     

Omega-3 fatty acid supplementation in schizophrenic patients

There is evidence that certain n3 and n6 essential fatty acids (EFAs) are depleted in cell membranes from red blood cells (RBC) and brains of patients suffering from schizophrenia. If these findings are of primary significance, then the possibility is raised of modifying schizophrenic symptomatology by dietary supplementation with fatty acids. We have carried out detailed analysis of dietary fatty acid intake of 20 schizophrenic patients. It was found that a greater intake of n3 fatty acids and particularly eicosapentenoic (EPA) in the normal diet, was associated with less severe schizophrenic symptoms and particularly less positive symptoms, as well as less tardive dyskinesia (TD). Furthermore, supplementation of the diet for 6 weeks with 10 g/day of concentrated fish oil (MaxEPA) resulted in significant amelioration of both schizophrenic symptoms and TD. Multiple regression analysis showed that improvement in schizophrenic symptoms was importantly related to the increased level of n3 fatty acids in RBC membranes.     

alpha 1-adrenergic receptor involvement in the LH surge in ovariectomized estrogen-primed rats

The circadian pattern of LH release observed in ovariectomized estrogen-implanted rats was inhibited by blockade of alpha-adrenergic receptors by phenoxybenzamine; in contrast, blockade of beta-receptors by propranolol was ineffective. Prasozin, an alpha 1-antagonist, was as effective as phenoxybenzamine, whereas yohimbine, an alpha 2-antagonist, was effective only at high doses. Neither phenoxybenzamine nor prazosin were able to modify the LHRH-induced release of LH from superfused pituitaries. These results suggest an involvement of hypothalamic alpha 1-receptors in the control of circadian LH release.     

Chronic administration of the cholesterol reducing drug gemfibrozil fails to alter 5-HT1A and 5-HT2A mediated receptor behaviours in rats

Some studies have suggested that reductions in plasma cholesterol might be associated with suicidal behaviour. Serotonergic systems are thought to be involved in suicidal ideation and behaviour and links with altered 5-HT1A and 5-HT2A receptors have been proposed. We have therefore examined the effects of cholesterol reduction using gemfibrozil, upon 5-HT2A and 5-HT1A receptor-related behaviours in rats. Rats were treated chronically (57 days) with gemfibrozil (50 mg/kg p.o.) or gum acacia vehicle and challenged sequentially with the 5-HT1A agonist 8-hydroxy-d-n-aminopropyl tetralin, to elicit 5-HT1A syndrome behaviours, and the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)2-amino-propane to establish their head-shake frequency. Significant cholesterol reduction, within the clinical range, failed to induce any changes in either 5-HT1A or 5-HT2A mediated behaviours. These data suggest that cholesterol reduction fails to induce changes in 5-HT1A and 5-HT2A receptor tone suggesting that the reduction of plasma cholesterol, within the human clinical range, does not result in neuroplasticity of the 5-HT1A and 5-HT2A receptors in rats.     

Recent progress in α1-adrenergic receptor research

Alpha1-Adrenergic receptors (AR) play an important role in the regulation of physiological responses mediated by norepinephrine and epinephrine, particularly in the cardiovascular system. The three cloned alpha1-AR subtypes (alpha1A, alpha1B, and alpha1D) are G protein-coupled receptors that signal through the Gq/11 signaling pathway, each showing distinct pharmacological properties and tissue distributions. However, due to the lack of highly subtype-selective drugs, the functional roles of individual subtypes are still not clear. Development of new subtype-specific drugs will greatly facilitate the identification of the functions of each subtype. Conopeptide rho-TIA has been found to be a new alpha1B-AR selective antagonist with different modes of inhibition at alpha1-AR subtypes. In addition, recent studies using genetically engineered mice have shed some light on alpha1-AR functions in vivo, especially in the cardiovascular system and brain. Several proteins have been shown to interact directly with particular alpha1-AR, and may be important in regulating receptor function. Receptor heterodimerization has been shown to be important for cell surface expression, signaling and internalization. These new observations are likely to help elucidate the functional roles of individual alpha1-AR subtypes.     

Antihyperglycemic action of isoferulic acid in streptozotocin-induced diabetic rats

Wistar rats with streptozotocin-induced diabetes (STZ-diabetic rats), which is similar to human insulin-dependent diabetic mellitus (IDDM), were employed to investigate the antihyperglycemic action of isoferulic acid. A single intravenous injection of isoferulic acid decreased the plasma glucose in a dose-dependent manner in the STZ-diabetic rats. Repeated intravenous administration of STZ-diabetic rats with isoferulic acid (5.0 mg kg(-1)) also resulted in the lowering of plasma glucose after one day. Stimulatory effects of isoferulic acid on the glucose uptake and glycogen synthesis in soleus muscles isolated from STZ-diabetic rats were also obtained indicating an increase of glucose utilization following isoferulic acid treatment which was not dependent on insulin. The mRNA level of glucose transporter subtype 4 form (GLUT4) in soleus muscle was raised by isoferulic acid after repeated treatment for 1 day in STZ-diabetic rats. Similar repeated treatment with isoferulic acid reversed the elevated mRNA level of phosphoenolpyruvate carboxykinase (PEPCK) in liver of STZ-diabetic rats to the normal level. However, expression of GLUT4 and PEPCK genes in nondiabetic rats were not influenced by similar treatment with isoferulic acid. These results suggest that isoferulic acid can inhibit hepatic gluconeogenesis and/or increase the glucose utilization in peripheral tissue to lower plasma glucose in diabetic rats lacking insulin.     

Effects of chronic ramipril treatment in streptozotocin-induced diabetic rats

The present investigation was undertaken to study the effects of chronic oral ramipril (1 mg/kg) treatment in streptozotocin (STZ) induced diabetic rats. Single tail vein injection of STZ (45 mg/kg, i.v.) produced a diabetic state exhibiting all the cardinal symptoms such as loss of body weight, polydipsia, polyuria, glucosuria, polyphagia, hypoinsulinaemia and hyperglycaemia. The diabetic state was also found to be associated with bradycardia, hypothyroidism, cardiac depression and cardiomyopathy. Ramipril treatment prevented STZ-induced hypertension, bradycardia, hypothyroidism, hyperchosesterolaemia and partially the cardiomayopathy. Ramipril treatment could not, however prevent STZ-induced loss of body weight, polyuria, polydipsia, polyphagia, hyperglycaemia, hypoinsulinaemia, hypertriglyceridaemia and cardiac depression. Our data suggests that ramipril has a few beneficial effects in the STZ-treated diabetic rats.     

Enhancement of peptone-induced gastric acid secretion in streptozotocin-induced diabetic rats

We compared the acid secretory response to peptone in normal and streptozotocin-induced diabetic rats. Animals were injected with streptozotocin and used after 5 weeks of diabetes with blood glucose levels of >350 mg/dl. Under urethane anesthesia, 2 ml peptone solution (2-8%) was instilled in the stomach through an acute fistula every 30 min. Peptone increased acid secretion in a concentration-dependent manner in normal rats, the maximal response being obtained at 8%. Likewise, the increased acid response was observed in diabetic rats, yet the maximal response observed at 4% was significantly greater than that in normal rats. In both cases, this response was inhibited potently by famotidine as well as YM-022 (a CCKB antagonist) and partially inhibited by atropine. Peptone increased luminal histamine and plasma gastrin levels in both normal and diabetic rats, and the former response was significantly greater in diabetic animals. The altered acid secretion and histamine output in diabetic rats were reverted by insulin treatment. Pentagastrin- but not histamine-induced acid secretion was also increased in diabetic rats. We conclude that peptone-induced acid secretion is increased in diabetic conditions. This phenomenon is insulin-dependent and associated with an enhanced release of histamine but not with an increased sensitivity of the parietal cells.     

Intracerebroventricular administration of cannabinoid CB1 receptor antagonists AM251 and AM4113 fails to alter food-reinforced behavior in rats

Rationale  

Drugs that interfere with cannabinoid CB1 transmission suppress food-motivated behaviors and may be useful as appetite suppressants, but there is uncertainty about the locus of action for the feeding-suppression effects of these drugs.     

Effects of brazilin on lipid and phosphatidyl fatty acid composition of erythrocyte membrane in streptozotocin-induced diabetic rats

In diabetes, the abnormal increase of the membrane cholesterol/phospholipid ratio (C/PL) is considered to be the main reason for the decreased membrane fluidity, which then results in impaired erythrocyte deformability and subsequent microcirculatory disturbances. In this study, we examined the effects of brazilin on lipid and phosphatidyl fatty acid composition of erythrocyte membranes in streptozotocin induced diabetic rats. Treatment of brazilin (10 mg/kg or 100 mg/kg for 2 weeks, i.p) altered phospholipid and cholesterol contents in diabetic erythrocyte membranes. The C/PL ratio of brazilin treated groups decreased compared with that of diabetic control group while no change was observed in normal erythrocytes. In streptozotocin induced diabetic rats, alterations in phosphatidyl fatty acid composition of erythrocyte membranes were observed and brazilin could reverse these alterations. Arachidonic acid level retumed to a normal level while linoleic acid level remained unchanged by the treatment of brazilin. The results suggest that brazilin might increase erythrocyte membrane fluidity which plays a key role in regulating erythrocyte deformability, thereby it could exert positive effects on microcirculatory disturbances.     

Tolerance to dichloroacetonitrile-induced neurotoxicity in streptozotocin-induced diabetic rats

Diabetes mellitus has potential to alter the toxicity of hazardous chemicals. Dichloroacetonitrile (DCAN) is one of high-risk nitrogenous disinfection by-products. This study evaluated the neurotoxicity of DCAN (11, 44 and 88 mg/kg) in normoglycaemic and streptozotocin (STZ)-induced diabetic rats via orally for 28 days. STZ diabetes prolonged the median survival time and total lethal time after DCAN (88 mg/kg) exposure when compared with that observed in normoglycaemic rats. DCAN altered motor activity and induced anxiety behaviour in normoglycaemic rats; but it did not exaggerate behavioural changes in STZ diabetic rats. DCAN –induced brain oxidative damage by compensatory increase glutathione content and decrease malonaldehyde levels; but it did not induce oxidative damage in diabetic rats. STZ diabetes slowed down the pathological pace of DCAN-induced brain mitochondrial dysfunction by decreasing reactive oxygen species and increasing cytochrome C oxidase activity. In conclusion, the present study indicated that STZ diabetic rats are resistant to DCAN-induced neurotoxicity at the dosage and with the dosage schedule in 28-day subacute toxicity test.     

Desensitization of epinephrine-initiated platelet aggregation does not alter binding to the alpha 2-adrenergic receptor or receptor coupling to adenylate cyclase

Several investigators have shown that incubating unstirred platelets with epinephrine blunts subsequent aggregation when the platelets are stirred. Using aspirin-treated platelets, we further characterized this desensitization of alpha 2-adrenergic receptor-initiated aggregation. Desensitization occurred with a t1/2 of 3-6 min and was maximal at 20-30 min, at which time the initial rate of aggregation and its maximal extent were about half that of control platelets. When we preincubated platelets with epinephrine, and then added phentolamine to block the alpha 2-receptors, ADP-initiated aggregation occurred normally. Thus, the desensitization of epinephrine-initiated aggregation was not associated with a generalized impairment of aggregation. At concentrations too low to initiate aggregation, epinephrine is known to potentiate aggregation initiated by other agents. Clonidine also acts at alpha 2-receptors to potentiate aggregation initiated by other agents, but it does not initiate aggregation by itself. Preincubating clonidine with platelets for 30 min abolished its potentiating effect on ADP-initiated aggregation. Thus, the ability of alpha 2-receptors to both potentiate and initiate aggregation desensitizes after a brief preincubation with agonist. We performed several types of experiments to investigate the mechanism of this desensitization. Platelet alpha 2-receptors are coupled to an inhibition of adenylate cyclase. We found, however, that alpha 2-mediated inhibition of prostaglandin E1-stimulated cAMP accumulation occurred normally in desensitized platelets. Similarly, epinephrine inhibited basal adenylate cyclase activity normally in membranes prepared from desensitized platelets. In membranes prepared from desensitized platelets, epinephrine competed normally for [3H]rauwolscine binding, and this competition was modulated normally by guanine nucleotides. Thus, the properties of the alpha 2-receptors, as measured in radioligand binding experiments, were unchanged by densensitization. In conclusion, desensitization of alpha 2-adrenergic receptor-mediated aggregation occurs without change in the alpha 2-adrenergic receptors or in their coupling to an inhibition of adenylate cyclase.     

Increased alpha 1-adrenergic receptor density in brown adipose tissue of cold-acclimated rats and hamsters

Binding sites for [3H]prazosin were characterized in crude membrane fractions from rat brown adipose tissue. Based on agonist (norepinephrine approximately equal to phenylephrine much greater than isoprenaline) and antagonist (prazosin much greater than yohimbine greater than propranolol) potencies to compete with [3H]prazosin, the binding sites were identified as alpha 1-receptors, not previously described in rat brown adipose tissue. As the [3H]prazosin binding sites could be observed in isolated brown fat cell preparations, they were probably postsynaptic. The effect of cold acclimation was studied in crude membrane fractions from control and cold-acclimated (4 degrees C) rats and hamsters. Cold acclimation did not change the affinity of the receptor for agonists and antagonists, but there was a significant increase in the number of alpha 1-receptors (per mg protein), both in rat (100% increase) and hamster (40% increase) brown fat. Based on these results and on earlier results on beta-receptors from this and other laboratories, it is suggested that activation of brown adipose tissue is associated with an increase in the relative density of alpha 1-receptors (i.e. in the alpha 1/beta ratio) and an increased significance of alpha 1-adrenergic pathways for the function of the tissue.     

Fisetin protects against streptozotocin-induced diabetic cardiomyopathy in rats by suppressing fatty acid oxidation and inhibiting protein kinase R

This study examined if the Fisetin against streptozotocin-induced diabetic cardiomyopathy (DC) in rats involves regulating cardiac metabolism and suppressing protein kinase R (PKR). Male rats were divided (12/groups) as control (non-diabetic), control + Fisetin, T1DM, and T1DM + Fisetin. Fisetin was administered orally at a final dose of 2.5 mg/kg for 12 weeks. In T1DM1-induced rats, Fisetin prevented heart and final body weights loss, lowered circulatory levels troponin I and creatinine kinase-MB (CK-MB), increased fasting insulin levels, and improved ventricular systolic and diastolic functions. It also preserved the structure of the cardiomyocytes and reduced oxidative stress, fibrosis, protein levels of transforming growth factor-β1 (TGF-β1), collagenase 1A, caspase-3, and the activation of JNK, p53, and p38 MAPK. In the control and diabetic rats, Fisetin attenuated fasting hyperglycaemia, the increases in glucose levels after the oral and insulin tolerance tests, and HOMA-IR. It also increased cardiac glucose oxidation by increasing the activity of private dehydrogenase (PDH), phosphofructokinase (PFK), protein levels of PPAR-α and suppressed cardiac inflammation by inhibiting NF-κB. These effects were associated with a reduction in the activity of PKR and subsequent increase in the activity of eeukaryotic initiation factor 2 (eIF2) with a parallel increase in protein levels of p67, a cellular inhibitor of PKR. In cultured cardiomyocytes, Fisetin, prevented high glucose (HG)-induced activation of PKR and reduction in p67, in a dose-dependent manner. However, the effect of Fisetin on PKR was diminished in LG and HG-treated cardiomyocytes with p67-siRNA. In conclusion, Fisetin protects against DC in rats by improving cardiac glucose metabolism and suppressing PKR.     

Omega-3 fatty acids in the treatment of psychiatric disorders

The importance of omega-3 fatty acids for physical health is now well recognised and there is increasing evidence that omega-3 fatty acids may also be important to mental health. The two main omega-3 fatty acids in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have important biological functions in the CNS. DHA is a major structural component of neuronal membranes, and changing the fatty acid composition of neuronal membranes leads to functional changes in the activity of receptors and other proteins embedded in the membrane phospholipid. EPA has important physiological functions that can affect neuronal activity. Epidemiological studies indicate an association between depression and low dietary intake of omega-3 fatty acids, and biochemical studies have shown reduced levels of omega-3 fatty acids in red blood cell membranes in both depressive and schizophrenic patients.Five of six double-blind, placebo-controlled trials in schizophrenia, and four of six such trials in depression, have reported therapeutic benefit from omega-3 fatty acids in either the primary or secondary statistical analysis, particularly when EPA is added on to existing psychotropic medication. Individual clinical trials have suggested benefits of EPA treatment in borderline personality disorder and of combined omega-3 and omega-6 fatty acid treatment for attention-deficit hyperactivity disorder. The evidence to date supports the adjunctive use of omega-3 fatty acids in the management of treatment unresponsive depression and schizophrenia. As these conditions are associated with increased risk of coronary heart disease and diabetes mellitus, omega-3 fatty acids should also benefit the physical state of these patients. However, as the clinical research evidence is preliminary, large, and definitive randomised controlled trials similar to those required for the licensing of any new pharmacological treatment are needed.