Weeks Of Streptozotocin Research Articles

Okanin alleviates symptoms of nociceptive-like responses in diabetic peripheral neuropathy in type 1 diabetic Wistar rats by regulating the AGEs/NF-κB/Nrf-2 pathway

Elevated reactive species and AGEs contribute to deregulation of transcription factors e.g., NF-κB and Nrf2 in diabetic peripheral neuropathy (DPN). Okanin, a bioactive chalcone, is active against redox imbalance, immune response, and pro-inflammatory events. The current investigation assessed effects of okanin in streptozotocin-induced DPN in rats. Wistar rats were divided into 6 groups (n = 6): Control, DPN, Okanin 2.5, Okanin 5, Okanin 10, and Gpn (Gabapentin). After 6 weeks of streptozotocin (55 mg/kg) injection, okanin (2.5, 5, 10 mg/kg), and gabapentin (50 mg/kg), were administered for 4 weeks. The streptozotocin-induced reduction in body weight, and increased feed/water intake, insulin, glucose, and HbA1c levels were mitigated by okanin or gabapentin. In DPN rats, Okanin or gabapentin ameliorated insulin resistance and β-cell function, inflammatory indices, and oxidative stress in the sciatic nerve of rodents thereby culminating in a decrease in hyperalgesia and allodynia. Okanin and streptozotocin-treated rats had significantly declined levels of AGEs, the receptor for AGEs, and NF-κB, and an upsurge in Nrf2 expression. In streptozotocin-induced DPN model, okanin ameliorates nociceptive-like responses by regulating the AGEs/NF-κB/Nrf2 pathway, suggesting that okanin has therapeutic value against DPN which needs further studies involving human subjects.

Abstract P2077: FoxO3 Transcription Factor Regulates Myocyte Contractility And Calcium Homeostasis In Diabetic Cardiomyopathy

Diabetes is a risk factor for heart failure with preserved ejection fractions (HFpEF). Calcium (Ca 2+ ) mishandling and diastolic abnormalities are the characteristics of diabetic cardiomyopathy (DCM), but the molecular mechanisms of these are elusive. FoxO transcription factors (FoxOs) are suppressed by insulin and this study evaluated the role of FoxO3 in myocardial contractility and Ca 2+ handling in the heart of a mouse model of type 1 diabetes. We show that cardiomyocyte-restricted deletion of FoxO3 (H-FoxO3 KO) prevented reduction in the peak rate of left ventricular (LV) pressure (dP/dt max) and prevented the increase in the minimum rate of fall in LV pressure (dP/dt min) that was evident after 4-7 weeks of Streptozotocin (STZ) diabetes. Time for pressure decay of LV while relaxation (Tau) was partially increased in STZ hearts and tended to decrease in STZ H-FoxO3 KO. Echocardiography showed LVEF was unchanged in control and H-FoxO3 KO animals treated with/without STZ. Ca 2+ imaging in perfused hearts found that Ca 2+ transient amplitude was decreased and decay kinetics prolonged (indicates decreased SERCA activity) in STZ hearts, but these changes were prevented in STZ H-FoxO3 KO. Phosphorylation of SERCA at Thr484 by SPEG (Striated muscle preferentially expressed protein kinase) controls Ca 2+ re-uptake and cardiac contractility. We show that STZ diabetes decreases SPEG protein and pSERCA2a Thr484 , but levels of each were normalized or increased in STZ H-FoxO3 KO. Mechanistically, overexpression of FoxO3 in neonatal cardiomyocytes increases high-molecular weight SPEG adducts when proteasome degradation was inhibited with MG-132, suggesting that ubiquitin-mediated degradation of SPEG is a mechanism by which FoxO3 controls Ca 2+ handling via SERCA phosphorylation. SERCA function requires ATP, thus, we evaluated mitochondrial energetics in these animals. Respiratory capacity in saponin-permeabilized cardiac fibers was unchanged in hearts from controls and H-FoxO3 KO treated with/without STZ. ATP generation was decreased in STZ hearts but was not normalized in STZ-H FoxO3 KO. These data indicate FoxO3 regulates myocyte contractility via SPEG degradation to control intracellular Ca 2+ via pSERCA2a Thr484 in the heart in a type 1 diabetes model.

The effect of estrogen therapy on cerebral metabolism in diabetic female rats

The impact of estrogen on brain function, especially in individuals with diabetes, remains uncertain. This study aims to compare cerebral glucose metabolism levels in intact rats, ovariectomized (OVX) rats, and 17β-estradiol (E2)-treated OVX diabetic female rats. Sixteen rats were administered a single intraperitoneal injection of 70 mg/kg streptozotocin (STZ) to induce diabetes (intact, n = 6; OVX, n = 6; OVX+E2-treated, n = 4). Additionally, 18 rats received an equivalent solvent dose via intraperitoneal injection (intact, n = 6; OVX, n = 6; OVX+E2-treated, n = 6). After 4 weeks of STZ or solvent administration, positron emission tomography scans with 18F-fluorodeoxyglucose (18F-FDG) injection were employed to assess cerebral glucose metabolism. The diabetic rats exhibited substantial reductions in 18F-FDG uptake across all brain regions (all P < 0.01), in contrast to the control rats. Moreover, intact and OVX + E2-treated diabetic female rats displayed more pronounced decreases in cerebral glucose metabolism in the amygdala and hippocampus compared to OVX diabetic female rats (P < 0.05). These findings suggest that diabetes creates an environment wherein estrogen exacerbates neuropathology and intensifies neuronal activity.

Modulatory effects of vitamin B3 and its derivative on the levels of apoptotic and vascular regulators and cytoskeletal proteins in diabetic rat brain as signs of neuroprotection

BackgroundBeneficial effects of nicotinamide (NAm) and its derivates have been earlier shown in animal models of diabetes mellitus (DM), but the mechanisms of their neuroprotective activities are still largely unknown. The aim of the present study was to investigate if NAm and conjugate of nicotinic acid with gamma-aminobutyric acid (N-GABA) are able to modulate expression levels of apoptosis regulators, angiogenesis-related molecules, and specific cytoskeletal proteins in diabetic rat brain. MethodsAfter six weeks of streptozotocin induced type 1 DM, rats were daily administered either by NAm (100 mg/kg) or N-GABA (55 mg/kg) intraperitoneally for two weeks. Protein levels were assessed by western blot and immunohistochemistry. ResultsBoth NAm and N-GABA down-regulated NF-κB and Bax levels in diabetic rat brain, suggesting their anti-apoptotic activities. Tested compounds normalized VEGF and nNOS contents improving pro-angiogenic signaling reduced by hyperglycemia. Western blot showed marked up-regulation of astroglial marker GFAP and lowering neurofilament protein levels in DM group, confirmed immunohistochemically, indicating the development of reactive astrogliosis as a major response to diabetes-induced neurodegeneration. NAm had no effects on GFAP and Nf-L levels in the diabetic brain, while N-GABA increased their expression. Inversely, NAm and N-GABA dramatically reduced enhanced levels of GFAP and Nf-L found in the blood serum of diabetic rats, providing for the first time strong evidence for preserving blood-brain barrier integrity by studied compounds. ConclusionThus, NAm and N-GABA may exert neuroprotective effects by decreasing pro-apoptotic regulators levels and improving expression of angiogenic and cytoskeletal proteins impaired by hyperglycemia in rat brain.

REDD1 deletion prevents the development of renal dysfunction in diabetic mice

Diabetic kidney disease (DKD) results in chronic loss of kidney function and is the leading cause of end‐stage renal disease. Hyperglycemia is an important mediator of diabetic complications, including DKD. Hyperglycemic conditions promote renal redox imbalance, resulting in glomerular/tubular damage and compromised renal function. Presently, much remains unknown regarding the molecular events that contribute to development of oxidative stress in the context of DKD. In the present study, we evaluated the hypothesis that hyperglycemic conditions promote expression of the stress response protein REDD1 in the kidney in a manner that contributes to the development of renal pathology and compromised function. After 16 weeks of streptozotocin (STZ)‐induced diabetes, urinary albumin to creatinine ratio and kidney to body weight ratios were elevated in wild‐type mice. These markers of renal dysfunction were associated with increased renal REDD1 expression. In contrast to wild‐type mice, REDD1 knockout (KO) mice failed to exhibit a diabetes‐induced deficit in kidney function. Histopathologic examination of the kidney found glomerular damage in diabetic wild‐type mice, but not in diabetic REDD1 KO mice. In cultured human podocytes, exposure to hyperglycemic conditions elevated REDD1 expression concomitant with increased oxidative stress and cell death. Oxidative stress and cellular apoptosis were not observed in podocyte cultures upon REDD1 deletion. Similarly, REDD1 deletion prevented diabetes‐induced oxidative stress in the kidney in coordination with upregulation of the Nrf2 antioxidant response. These findings provide new insights into how diabetes and hyperglycemia contribute to development of renal pathology and support the possibility that therapeutics targeting REDD1 could be beneficial in the context of DKD.

Anti-CXCL10 monoclonal antibody therapy protects against the diabetic retinopathy in the mouse model induced by streptozotocin

ObjectiveTo explore the effect of CXC chemokine CXCL10 in the mice with diabetic retinopathy (DR). MethodsDR models were constructed on mice via injection of streptozotocin (STZ). At 3 weeks of STZ, mice were treated with anti-CXCL10 monoclonal antibodies (mAb)/control mAb, and a series of experiments were then conducted at 6 weeks of STZ, including HE staining, western blotting, retinal trypsin digestion, real-time qPCR and enzyme-linked immuno sorbent assay (ELISA). The corresponding kits were used to detect the activity of oxidative stress markers. ResultsCompared with nondiabetic eyes, DR mice both at 3 and 6 weeks presented the decreases in the total retinal thickness, the retinal outer nuclear layer (ONL) thickness, and the cells of ganglion cell layer (GCL), with the upregulated CXCL10, pro-inflammatory cytokines and malondialdehyde (MDA), as well as the downregulated levels of superoxide dismutase (SOD), glutathione peroxidase (GPx) and CAT, especially in those at 6 weeks, which were attenuated by the anti-CXCL10 mAb treatment. Moreover, in comparison with the DR mice, mice in the DR + anti-CXCL10 mAb group gained the significant decrease in the number of acellular capillaries of retina, with up-regulations of Claudin-5 and ZO-1 and down-regulations of VEGF and FGF-2. The DR mice injected with anti-CXCL10 mAb demonstrated alleviated retinal pathology as compared to mice at 3 weeks of STZ. ConclusionAnti-CXCL10 mAb could mitigate the retinal pathology of DR mice, with the decreased inflammation and oxidative stress, thus mediating a delay in the development or disease improvement in patients of DR.

Erratum to: Adenosine Monophosphate-Activated Protein Kinase Abates Hyperglycaemia-Induced Neuronal Injury in Experimental Models of Diabetic Neuropathy: Effects on Mitochondrial Biogenesis, Autophagy and Neuroinflammation.

Impaired adenosine monophosphate kinase (AMPK) signalling under hyperglycaemic conditions is known to cause mitochondrial dysfunction in diabetic sensory neurons. Facilitation of AMPK signalling is previously reported to ameliorate inflammation and induce autophagic response in various complications related to diabetes. The present study assesses the role of AMPK activation on mitochondrial biogenesis, autophagy and neuroinflammation in experimental diabetic neuropathy (DN) using an AMPK activator (A769662). A769662 (15 and 30 mg/kg, i.p) was administered to Sprague–Dawley rats (250–270 g) for 2 weeks after 6 weeks of streptozotocin (STZ) injection (55 mg/kg, i.p.). Behavioural parameters (mechanical/thermal hyperalgesia) and functional characteristics (motor/sensory nerve conduction velocities (MNCV and SNCV) and sciatic nerve blood flow (NBF)) were assessed. For in vitro studies, Neuro2a (N2A) cells were incubated with 25 mM glucose to simulate high glucose condition and then studied for mitochondrial dysfunction and protein expression changes. STZ administration resulted in significant hyperglycaemia (>250 mg/dl) in rats. A769662 treatment significantly improved mechanical/thermal hyperalgesia threshold and enhanced MNCV, SNCV and NBF in diabetic animals. A769662 exposure normalised the mitochondrial superoxide production, membrane depolarisation and markedly increased neurite outgrowth of N2A cells. Further, AMPK activation also abolished the NF-κB-mediated neuroinflammation. A769662 treatment increased Thr-172 phosphorylation of AMPK results in stimulated PGC-1α-directed mitochondrial biogenesis and autophagy induction. Our study supports that compromised AMPK signalling in hyperglycaemic conditions causes defective mitochondrial biogenesis ultimately leading to neuronal dysfunction and associated deficits in DN and activation of AMPK can be developed as an attractive therapeutic strategy for the management of DN.

6z, a novel 5HT3 receptor antagonist reverses depression-like behavior in streptozotocin-induced diabetic mice by normalizing serotonin deficiency and HPA-axis hyperactivity.

Event Abstract Back to Event 6z, a novel 5HT3 receptor antagonist reverses depression-like behavior in streptozotocin-induced diabetic mice by normalizing serotonin deficiency and HPA-axis hyperactivity. Deepali Gupta1* and Radhakrishnan Mahesh1 1 Birla Institute of Technology and Science, Department of Pharmacy, India Individuals with diabetes are three times more likely to have depression than without it. The impairment of brain serotonin activity and hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity has been linked with the pathogenesis of depression in diabetes, while antagonism of 5HT3 receptors (5HT3Rs) has been shown to facilitate serotonin neurotransmission and normalize HPA-axis hyperactivity in animal models of depression. In addition, 5HT3Rs have been implicated in regulation of glucose homeostasis and energy metabolism. We earlier reported that 6z (N-(Benzo [d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide), a novel 5HT3R antagonist posses potential antidepressant activity in preclinical models of depression. In extension to that, the present study was aimed at investigating the antidepressant-like effects of 6z, in depression associated with diabetes. Mice with 8 weeks of streptozotocin (STZ)-induced diabetes were given vehicle/ 6z (1 and 2 mg/kg, i.p.)/ fluoxetine (10 mg/kg, i.p.) for 21 days and then subjected to neurobehavioral models including forced swim test (FST), tail suspension test (TST), hole board test (HBT) and light-dark test (LDT). 24 hrs after the last behavioral assay mice were decapitated, and blood and brains were collected for biochemical analysis. Results showed that STZ-induced diabetic mice exhibited a significant despair behavior (increased duration of immobility) in FST and TST, and reduced exploratory behavior indicated by reduced head dipping activity and exposure to bright chamber in HBT and LDT respectively. This was accompanied by reduced serotonin levels in discrete brain regions and elevated plasma corticosterone levels (a marker of HPA-axis hyperactivity). 6z (1 and 2 mg/kg), similar to fluoxetine reversed diabetes-induced behavioral and biochemical perturbations. It suggests that 6z was able to reverse diabetes-induced depression-like behavior mice and its antidepressant effect was associated with normalization of serotonin deficits and HPA-axis hyperactivity. Keywords: Depression, in vivo, diabetes, hypothalamic-pituitary-adrenal (HPA)-axis hyperactivity, neurobehavioural test Conference: 14th Meeting of the Asian-Pacific Society for Neurochemistry, Kuala Lumpur, Malaysia, 27 Aug - 30 Aug, 2016. Presentation Type: O02: Postgraduate Travel Awardees Oral Session 2 Topic: 14th Meeting of the Asian-Pacific Society for Neurochemistry Citation: Gupta D and Mahesh R (2016). 6z, a novel 5HT3 receptor antagonist reverses depression-like behavior in streptozotocin-induced diabetic mice by normalizing serotonin deficiency and HPA-axis hyperactivity.. Conference Abstract: 14th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00086 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 04 Aug 2016; Published Online: 11 Aug 2016. * Correspondence: Ms. Deepali Gupta, Birla Institute of Technology and Science, Department of Pharmacy, Pilani, Rajasthan, India, deepaligupta2010@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Deepali Gupta Radhakrishnan Mahesh Google Deepali Gupta Radhakrishnan Mahesh Google Scholar Deepali Gupta Radhakrishnan Mahesh PubMed Deepali Gupta Radhakrishnan Mahesh Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Neurorestorative effects of eugenol, a spice bioactive: Evidence in cell model and its efficacy as an intervention molecule to abrogate brain oxidative dysfunctions in the streptozotocin diabetic rat

Eugenol (EU), an active principle of cloves, is also widely distributed in various other plants (eg. basil, cinnamon, etc). While its antioxidant and anti-inflammatory properties are well established, biochemical insights related to its neuromodulatory potential in diabetic conditions are not clear. In the present study, initially we investigated its potential to modulate specific biochemical responses in SHSY5Y cells under experimentally -induced hyperglycemic condition. Co-exposure of cells with EU (5–10 μM) not only enhanced the cell viability, but significantly offset glucose -associated oxidative stress (as evidenced by diminished levels of reactive oxygen species and hydroperoxides). Further EU enhanced the reduced glutathione (GSH) levels and also ameliorated the levels of 3 – nitrotyrosine and expression of HSP70. We subsequently examined its efficacy to attenuate biochemical aberrations in brain regions of a streptozotocin (STZ) diabetic rat employing an intervention approach. Brain regions of EU treated (10 mg/kg bw/d, post 6 weeks of STZ) diabetic rats showed diminished levels of oxidative markers and protein carbonyls in both cytosolic and mitochondrial fractions. EU treatment caused enhanced activities of enzymic antioxidants and diminished both GSH and total thiols. Further, activities of complex I – III, succinate dehydrogenase and citrate synthase in brain regions were also significantly restored. Interestingly, EU treatment differentially attenuated the elevated activity of acetylcholinesterase and levels of calcium in brain regions. Collectively, based on the data obtained in in vitro and in vivo models, we hypothesize that EU may be employed as an adjuvant therapeutic molecule to alleviate complications under diabetic conditions.

Neuroprotective effect of ginger in the brain of streptozotocin-induced diabetic rats

Diabetes mellitus results in neuronal damage caused by increased intracellular glucose leading to oxidative stress. Recent evidence revealed the potential of ginger for reducing diabetes-induced oxidative stress markers. The aim of this study is to investigate, for the first time, whether the antioxidant properties of ginger has beneficial effects on the structural brain damage associated with diabetes. We investigated the observable neurodegenerative changes in the frontal cortex, dentate gyrus, and cerebellum after 4, 6, and 8 weeks of streptozotocin (STZ)-induced diabetes in rats and the effect(s) of ginger (500 mg/kg/day). Sections of frontal cortex, dentate gyrus, and cerebellum were stained with hematoxylin and eosin and examined using light microscopy. In addition, quantitative immunohistochemical assessments of the expression of inducible NO synthase (iNOS), tumor necrosis factor (TNF)-α, caspase-3, glial fibrillary acidic protein (GFAP), acetylcholinesterase (AChE), and Ki67 were performed. Our results revealed a protective role of ginger on the diabetic brain via reducing oxidative stress, apoptosis, and inflammation. In addition, this study revealed that the beneficial effect of ginger was also mediated by modulating the astroglial response to the injury, reducing AChE expression, and improving neurogenesis. These results represent a new insight into the beneficial effects of ginger on the structural alterations of diabetic brain and suggest that ginger might be a potential therapeutic strategy for the treatment of diabetic-induced damage in brain.

CHARACTERIZATION OF A RAT MODEL OF INSULIN DEFICIENCY INDUCED VASCULAR COMPLICATION

Vascular dysfunction is one of the important diabetic complications. Here we fully characterized a rat model of streptozotocin (STZ) induced vascular complication. Diabetes was induced by single intraperitoneally injection of STZ (50 mg.kg-1, ip).Blood pressure (BP) and isolated aorta responses phenylephrine (PE), KCl, acetylcholine (ACh), sodium nitroprusside (SNP) were recorded after 6, 8 and 10 weeks of STZ injection.In addition, serum levels of glucose, tumor necrosis factor α (TNFα), lipids, advancedglycation end products (AGEs), and arginase activity were determined. Furthermore, aortic reactive oxygen species(ROS) generation, hemeoxygenase-1 expression and collagen deposition were examined. Streptozotocin injection resulted in a significant hyperglycemia after 3 days of injection which was stable for 10 weeks. Diabetes was associated with a significant increasein BP after 6 weeks which was stable at 8 weeks. Aorta isolated from diabetic animals showed exaggerated contractility to PE and KCland impaired relaxation to ACh compared to control after 6 weeks which were clearer at 8 weeks of STZ injection. In addition, diabetic animals showed significant increases in serum levels of lipids, AGEs, TNFα and arginase enzyme activity after 8 weeks of STZ compared to control. Furthermore, aortae isolated from diabetic animals were characterized by increased ROS generation and collagen deposition. In conclusion, injecting rats with STZ at dose 50 mg.kg-1 produces a model of diabetic vascular complication after 8 weeks that are characterized by hypertension, disturbed vascular reactivity, elevated serum lipids, inflammatory cytokines and enzymes and enhanced aortic ROS generation and collagen deposition. Key words: Diabetes; aorta; hypertension; vascular reactivity, rat Abbreviations: ANOVA, analysis of variance; NO, nitric oxide; PE, phenylephrine; ROS, reactive oxygen species; SNP, sodium nitroprusside;Ach, acetyl choline; BP, blood pressure.

Abstract 306: Mitochondrial Aldehyde Dehydrogenase, A Therapeutic Target In Post-myocardial Infarction Heart Failure In Diabetes

Development of heart failure (HF) and pathological remodeling occurs after myocardial infarction (MI). However, in diabetic patients the prognosis is far worse. Hyperglycemia leads to accumulation of reactive aldehydes like 4-hydroxy-2 nonenal (4-HNE) in the heart. 4-HNE impairs cellular function and causes organ damage by forming adducts with critical proteins. In this study, we hypothesized that 1) 4-HNE-induced impairment of mitochondrial aldehyde dehydrogenase (ALDH) i.e. ALDH2 contributed to myocardial ischemia-induced HF in diabetes mellitus (DM) and 2) pharmacological activation of ALDH2 by Alda-1 prevent post-MI cardiac damage in DM. To test these hypotheses, first 8-week old C57BLC/6J male mice were injected with streptozotocin (STZ) (150 mg/Kg). After 8 weeks of STZ, mice were infused with isoproterenol (Iso) (45 mg/Kg) for 2 weeks by mini pumps to induce chronic myocardial ischemia and HF. Cardiac dysfunction was assessed in conscious mice by echocardiography periodically until sacrifice (16 weeks after STZ). We had normal control (Con), DM control (DM), DM + Iso and non-diabetic Iso control (Iso) with n 6 in each group. Fractional shortening (FS) was reduced in DM + Iso group (47 ± 1.2%) compared to Con (53 ± 0.9 %) and DM (55 ± 1.6 %) P&lt;0.01, but not with Iso (49 ± 1.4%). Decrease in myocardial ALDH2 activity and increase in 4-HNE adduct formation in ALDH2 and mitochondrial damage were observed in DM + Iso at various degrees compared to Con, DM and Iso. Increased cardiac fibrosis was also recorded in DM + Iso (4 ± 0.4%) relative to Con (1 ± 0.2%; P&lt;0.001), DM (2 ± 0.1%; P&lt;0.05) and Iso (2.4 ± 0.3%; P&lt;0.01). In the treatment protocol, DM + Iso group were treated with Alda-1 (10mg/kg/day) from weeks 12 to 16. Alda-1 ameliorated cardiac damage in DM as evident from enhanced FS (55 ± 3.5%; P&lt;0.01) and reduced fibrosis. Besides improving ALDH activity Alda-1 also attenuated 4-HNE adduct formation on ALDH2 and mitochondrial damage. Myocardial levels of ALDH2 activity was lower in diabetic patients with cardiomyopathy (50% reduction; P&lt;0.007). Finally, we conclude that activation of ALDH2 ameliorates HF in diabetic mice and which has a potential to be developed as a therapeutic strategy for HF in diabetic patients.

Rutin prevents cognitive impairments by ameliorating oxidative stress and neuroinflammation in rat model of sporadic dementia of Alzheimer type

The objective of the present study was to assess the neuroprotective role of rutin (vitamin P) and delineate the mechanism of action. Recent evidence indicates that rutin exhibits antioxidant potential and protects the brain against various oxidative stressors. More precisely, the aim of the present study was to examine the modulating impacts of rutin against cognitive deficits and oxidative damage in intracerebroventricular-streptozotocin (ICV-STZ)–infused rats. Rats were injected bilaterally with ICV-STZ (3 mg/kg), whereas sham rats received the same volume of vehicle. After 2 weeks of streptozotocin (STZ) infusion, rats were tested for cognitive performance using Morris water maze tasks and thereafter euthanized for further biochemical, histopathological, and immunohistochemical studies. Rutin pretreatment (25 mg/kg, orally, once daily for 3 weeks) significantly attenuated thiobarbituric acid reactive substances (TBARS), activity of poly ADP-ribosyl polymerase, and nitrite level and decreased level of reduced glutathione (GSH) and activities of its dependent enzymes (glutathione peroxidase [GPx] and glutathione reductase [GR]) and catalase in the hippocampus of ICV-STZ rats. ICV-STZ rats showed significant cognitive deficits, which was improved significantly by rutin supplementation. The results indicate that rutin attenuates STZ-induced inflammation by reducing the expression of cyclooxygenase-2 (COX-2), glial fibrillary acidic protein (GFAP), interleukin-8 (IL-8), inducible nitric oxide synthase (iNOS), nuclear factor-kB, and preventing the morphological changes in hippocampus. The study thereby suggests the effectiveness of rutin in preventing cognitive deficits and might be beneficial for the treatment of sporadic dementia of Alzheimer type (SDAT).

Involvement of vascular endothelial nitric oxide synthase in development of experimental diabetic nephropathy in rats

Endothelial nitric-oxide synthase (eNOS) acts as a common pathogenic pathway in diabetic nephropathy (DN). However, its functional consequences are still not fully understood. Caveolin, a membrane protein, inhibits the eNOS by making caveolin-eNOS complex, and its expression is upregulated during diabetes mellitus (DM). This study was designed to determine the role of caveolin in eNOS-mediated NO synthesis and release in DN. DM in rat was induced by feeding of high-fat diet (HFD) for 2 weeks, followed by single dose of streptozotocin (STZ) (35 mg/kg, ip) further followed by HFD for further 8 weeks. Serum nitrite/nitrate ratio was measured to determine the plasma level of NO. Diabetic rat, after 6 weeks of STZ, developed elevated level of BUN, protein in urine, urinary output, serum creatinine, serum cholesterol, kidney weight, kidney weight/body weight, and renal cortical collagen content, while serum nitrite/nitrate concentration was significantly decreased as compared to normal control group. Treatment with sodium nitrite (NO donor), L: -arginine (NO precursor), daidzein (caveolin inhibitor), and combination of L: -arginine and daidzein for 2 weeks markedly attenuated these changes and increased serum nitrite/nitrate ratio. However, treatment with L-NAME, a eNOS inhibitor, significantly attenuated the L: -arginine-, daidzein-, or combination of L: -arginine and daidzein-induced ameliorative effects in DN. The finding of this study suggests that caveolin plays a vital role in the eNOS-mediated decrease in renal level of NO, which may be responsible for the development of DN in rats.

Mechanism of attenuation of diabetes mellitus and hypercholesterolemia induced vascular endothelial dysfunction by protein tyrosine phosphatase inhibition

The study has been designed to investigate downstream mechanisms in the PTPase inhibition mediated attenuation of diabetes mellitus and hypercholesterolemia-induced vascular endothelial dysfunction. Diabetes mellitus was induced in rats using streptozotocin (55 mg/kg, i.v. once), while hypercholesterolemia was produced by feeding high cholesterol diet. After 4 weeks of streptozotocin and Cholesterol rich diet administration, vascular endothelium dysfunction was assessed, in terms of attenuation of acetylcholine-induced, endothelium-dependent relaxation (Isolated Aortic Ring Preparation), a decrease in serum nitrate/nitrite level, as well as mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). After 14 days of daily administration, sodium orthovanadate (8 mg/kg, p.o., 16 mg/kg, p.o and 24 mg/kg, p.o) and atorvastatin (30 mg/kg, p.o) (positive control) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS and maintained integrity of vascular endothelium. However, this ameliorative effect of SOV was significantly blocked by UCN-01, (PDK inhibitor) and L-NAME (Inhibitor of eNOS). Therefore, it may be concluded that sodium orthovanadate, a specific inhibitor of PTPase, may stimulate PDK and eNOS and consequently improve vascular endothelium dysfunction. Thus, inhibition of PTPase might be a useful approach in the therapeutics of vascular endothelium dysfunction.

The effects of the receptor for advanced glycation end products (RAGE) on bone metabolism under physiological and diabetic conditions

It has been reported that AGEs and the receptor for AGEs (RAGEs) have been linked to the pathogenesis of diabetic microangiopathy. However, the relationship between RAGE and alteration in bone metabolism is unclear. Therefore, in order to determine the role of RAGE in bone metabolism, we investigated the effects of RAGE deletion on bone metabolism under physiological and diabetic conditions using RAGE knockout mice (RAGE-KO). Eight-week-old male RAGE-KO and wild-type littermates (WT) were intraperitoneally injected with either streptozotocin or vehicle. Mice were classified into four groups: (1) nondiabetic WT; (2) nondiabetic RAGE-KO; (3) diabetic WT; and (4) diabetic RAGE-KO. After 12 weeks of streptozotocin or vehicle treatment, the physical properties of femora and the static and dynamic parameters of bone histomorphometry of tibiae were assessed. The deletion of RAGE affected neither body weights nor hemoglobin A1c levels. RAGE deletion resulted in increased bone mineral density due to decreased osteoclast function under physiological conditions that is no accumulation of AGEs. In contrast, lacking RAGE did not affect the alteration in bone metabolism under diabetic conditions, suggesting that AGEs-RAGE interaction may not be involved in the pathogenesis of diabetic osteopenia, although RAGE plays a crucial role in bone metabolism.

EFFECT OF CALCIUM CHANNEL BLOCKADE ON ADRENERGICALLY INDUCED RENAL VASOCONSTRICTION IN RAT MODELS OF RENAL IMPAIRMENT

1. Calcium channel blockade attenuates adrenergically induced renal vasoconstriction and the present study examined whether the magnitude of the supression was enhanced or blunted in rat models of renal failure or diabetes-induced glomerular hyperfiltration. 2. Male Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were used that had either renal failure induced by cisplatin administration or early diabetic nephropathy (EDN) consequent to an injection of streptozotocin (STZ). After 7 days of cisplatin or 4 weeks of STZ, rats were anaesthetized and renal haemodynamic studies were performed. 3. Cisplatin-treated WKY rats and SHR exhibited reduced creatinine clearance (CCr) and increased fractional excretion of sodium (FE(Na)) and kidney index (all P < 0.05), along with tubular damage in the kidney, compared with non-treated rats. In the EDN model, there was marked albuminuria and increased FE(Na), kidney index and CCr (all P < 0.05) compared with non-diabetic nephropathy (NDN) rats. Amlodipine significantly (P < 0.05) and dose-dependently attenuated the magnitude of the neurally and adrenergically induced renal vasoconstriction in all experimental groups compared with their respective control groups (13-6 vs 9-5% in renal failure vs non-renal failure WKY rats; 26-15 vs 17-8% in renal failure vs non-renal failure SHR; 19-9 vs 14-5% in EDN vs NDN). 4. The data obtained demonstrate that not only does amlodipine blunt adrenergically induced renal vasoconstriction in normal rats, but that it also does so, and to a greater extent, in rats with either renal failure or hyperfiltration.

Central Nervous System Complications of Diabetes in Streptozotocin-Induced Diabetic Rats: A Histopathological and Immunohistochemical Examination

Diabetes mellitus is a common, potentially serious metabolic disorder. Over the long term, diabetes leads to serious consequences in a number of tissues, especially those that are insulin insensitive (retina, neurons, kidneys). It also causes a variety of functional and structural disorders in the central and peripheral nervous systems. We investigated whether neurodegenerative changes were observable in the hippocampus, cortex, and cerebellum after 4 weeks of streptozotocin (STZ)-induced diabetes in rats and the effect(s) of melatonin. Male Wistar rats (n = 32) were divided into four groups (n = 8 each): untreated controls, melatonin-treated controls, untreated diabetics, and melatonin-treated diabetics. Experimental diabetes was induced by a single dose of STZ (60 mg/kg, intraperitoneal (ip)). For 3 days before the administration of STZ, melatonin (200 μg/kg/day, ip) was injected and continued for 4 weeks. Sections of hippocampus, cortex, and cerebellum were stained with hematoxylin and eosin and examined using light microscopy. In addition, brain tissues were examined immunohistochemically for the expression of glial and neuronal markers, including glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), and heat shock protein-70 (HSP-70). No neurodegenerative changes were observed in the hippocampus, cortex, or cerebellum of the untreated diabetic group after 4 weeks compared with the other groups. We did not observe any change in GFAP, NSE, or HSP-70 immunostaining in the brain tissues of STZ-induced diabetic rats. In summary, after 4 weeks of STZ-induced diabetes in rats, no degenerative or immunohistochemical changes were detected in the hippocampus, cortex, or cerebellum.

Neuropeptide Y and CGRP concentrations in the rat tail artery: Effects of age and two types of diabetes

The changes in concentrations of two neuropeptides, neuropeptide Y (NPY) and calcitonin gene-related peptide (CGRP) in different segments of the rat tail artery have been investigated (a) after 12 and 16 weeks of streptozotocin (STZ)-induced hyperglycemia that has been induced at the age of 10 weeks, and (b) in 52-week-old Goto-Kakizaki (GK) rats that were intolerant of glucose, and age-matched Wistar controls. In the control animals at 22, 26 and 52 weeks of age, the concentration of CGRP was significantly greater in distal, relative to proximal, segments of normal arteries, and this contrasted with the pattern of distribution of NPY, which was consistently greater in the proximal than the distal segments. STZ-induced diabetes caused significant reductions in the concentrations of NPY and CGRP in the middle and distal segments of the vessel after 12 and 16 weeks of hyperglycemia. In the glucose-intolerant Goto-Kakizaki (GK) rats, the noradrenalin and adrenalin levels increased significantly in the distal segment of the artery relative to controls; in contrast there was a significant fall in dopamine concentration. The only significant change in the level of NPY in 52-week-old GK rats was an increase in the proximal segment, suggesting that in Type II pre-diabetes, noradrenalin and its co-transmitter NPY are affected independently. The concentration of CGRP increased significantly in all segments of the artery of the 12-month-old GK rats relative to controls. The similarities and differences between these measurements in Type I and Type II diabetic models are discussed.

α1B-Adrenoceptors mediate adrenergically-induced renal vasoconstrictions in rats with renal impairment

This study examined whether alpha1B-adrenoceptors are involved in mediating adrenergically-induced renal vasoconstrictor responses in rats with pathophysiological and normal physiological states. Male Wistar Kyoto and spontaneously hypertensive rats were induced with acute renal failure or experimental early diabetic nephropathy by cisplatin or streptozotocin, respectively. Cisplatin-induced renal failure was confirmed by impaired renal function and pronounced tubular damage. Experimental early diabetic nephropathy was confirmed by hyperglycemia, changes in physiological parameters, and renal function. The hemodynamic study was conducted on anesthetized rats after 7 d of cisplatin (renal failure) and 4 weeks of streptozotocin (experimental early diabetic nephropathy). In the rats with renal failure and experimental early diabetic nephropathy, there were marked reductions in their baseline renal blood flow (P<0.01). The baseline mean arterial blood pressure was either unaltered or lower (all P>0.05) in the renal failure and experimental early diabetic nephropathy rats, respectively, as compared to their non-renal failure and non-diabetic nephropathy controls. In the rats with renal impairment, chloroethylclonidine caused either accentuation or attenuation (all P<0.01) of the renal vasoconstrictor responses elicited by the adrenergic stimuli. However, in the non-renal failure and in the non-diabetic nephropathy rats, chloroethylclonidine did not cause any alteration in such responses (P>0.05). This study demonstrated the presence of functional alpha1B-adrenoceptors that mediated the adrenergically-induced renal vasoconstrictions in rats with renal impairment, but not in rats with normal renal function.