Sodium nitrate preconditioning prevents progression of the neuropathic pain in streptozotocin-induced diabetes Wistar rats (original) (raw)
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Endocrine Regulations
Objective. Diabetes induces sensory symptoms of neuropathy as positive (hyperalgesia), negative (hypoalgesia), or both. Methods. In the present study, fifty male Wistar rats were allocated to five groups: control, control+nitrate, diabetes, diabetes+insulin, and diabetes+nitrate. Thirty days after diabetes confirmation, insulin (2–4 U/day) was injected subcutaneously in diabetes+insulin group and nitrate (100 mg/l) was added into drinking water of the control+nitrate and diabetes+nitrate groups for a period of 2 months. In order to assess the mechanical and thermal algesia, tail immersion, hot plate, and von Frey tests were performed. The serum insulin levels were determined with insulin ELISA Kit. Serum level of NOx was determined by the Griess method. Results. Both thermal and mechanical nociceptive thresholds showed a significant decrease (p<0.05) which was followed by a significant increase (p<0.01) in the thermal nociceptive threshold in the diabetes group. Chronic nitrat...
Naringin Attenuates the Diabetic Neuropathy in STZ-Induced Type 2 Diabetic Wistar Rats
Life
The application of traditional medicines for the treatment of diseases, including diabetic neuropathy (DN), has received great attention. The aim of this study was to investigate the ameliorative potential of naringin, a flavanone, to treat streptozotocin-induced DN in rat models. After the successful induction of diabetes, DN complications were measured by various behavioral tests after 4 weeks of post-induction of diabetes with or without treatment with naringin. Serum biochemical assays such as fasting blood glucose, HbA1c%, insulin, lipid profile, and oxidative stress parameters were determined. Proinflammatory cytokines such as TNF-α and IL-6, and neuron-specific markers such as BDNF and NGF, were also assessed. In addition, pancreatic and brain tissues were subjected to histopathology to analyze structural alterations. The diabetic rats exhibited increased paw withdrawal frequencies for the acetone drop test and decreased frequencies for the plantar test, hot plate test, and t...
Treatment of peripheral diabetic neuropathy in Zucker diabetic fatty (ZDF) rats with cariporide
Journal of Diabetes Mellitus, 2014
To determine the effect of Na+/H+-exchanger-1 on diabetic neuropathy in Type 2 diabetes Zucker diabetic fatty (ZDF) rats and lean controls were treated with cariporide (10 or 20 mg/kg/d), a Na+/H+-exchanger-1 inhibitor, for 4 weeks at 15 weeks of age. Neuropathy endpoints included motor (MNCV) and sensory (SNCV) nerve conduction velocities, thermal nociception, tactile allodynia and intraepidermal nerve fiber density. Advanced glycation endproduct and markers of oxidative stress including nitrated protein levels in sciatic nerve and dorsal root ganglion were also evaluated. Expression of Na+/H+-exchanger-1 in dorsal root ganglion neurons was increased in ZDF rats. At 15 weeks of age ZDF rats displayed hyperglycemia, MNCV and SNCV deficits, thermal hypoalgesia and tactile allodynia. At 20 but not 10 mg/kg/d, cariporide significantly improved MNCV and SNCV deficits, thermal hypoalgesia and tactile allodynia. Cariporide treatment was also associated with reduction of diabetes-induced accumulation of advanced glycation end-product (AGE), oxidative stress and nitrated proteins in sciatic nerve and dorsal root ganglion neurons. In conclusion, these findings support an important role for Na+/H+exchanger-1 in peripheral diabetic neuropathy, and provide rationale for development of Na+/ H+-exchanger-1 inhibitors for treatment of diabetic neural complications.
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.
American Journal of Pharmacology and Toxicology, 2014
It was shown that hyperglycemia in diabetic patients is the main factor of diabetic peripheral neuropathies. Various pathways related to oxidative stress, vascular defect and defective endothelium dependent relaxation have been implicated in the development of diabetic peripheral neuropathy. A substantial number of studies have shown that antioxidant treatment are promising therapeutics that can prevent or correct reduced motor nerve conduction in diabetic rats by acting on these mechanisms. This study was designed to investigate the possible role of insulin treatment along with or without vitamin E or L-arginine on diabetic neuropathy. This goal was accessed by examining nerve conduction, parameters of oxidative stress and lipid peroxidation as well as the expression level of endothelial nitric oxide synthase in the sciatic nerve of control and streptozotocine-induced diabetic rats. Data showed that diabetic rats showed increased levels of serum glucose (382.5%) and sciatic nerve lipid peroxidation Marker (MDA, 261.6%) with a concomitant decrease in the expression of sciatic nerve eNOS mRNA as compared to control rats. The nerve conduction studies of the sciatic nerves of these rats showed decrease conduction as evident by delayed NCV (63.6%) and low Amplitude of Muscle Contraction (AMC, 36.4%). Solitary insulin treatment (but not vitamin-E or L-arginine) corrected serum glucose to control values and corrected nerve conduction parameters in the sciatic nerve. However, treating diabetic rats with different doses of vitamin E (300 mg kg −1 and 600 mg kg −1 ) significantly reduced oxidative stress by decreasing MDA and increasing GPx activity, corrected NCV by reducing the latency and improving AMC and increased eNOS mRNA expression in sciatic nerve with a more profound effect to seen with the high dose (600 mg kg −1 ). However, the maximum potent ameliorating effect of the vitamin E on these parameters was seen when administered in combination with insulin. On the other hand, L-arginine treatment alone or in combination with insulin had no effect on the oxidative stress markers nor eNOS expression but significantly and maximally improved NCV through reducing the conduction latency and increasing AMC. This study supported the notion that diabetic peripheral neuropathy is a multifactorial complication, caused by hyperglycemia, oxidative stress and vascular impairment. It is concluded that conjugate treatment with vitamin-E, especially in higher doses, with insulin could be of great value. Moreover correction of impaired nerve blood flow by drugs that induce nitric oxide has proved to be efficient in the protection against and correction of experimental diabetic peripheral neuropathy.
Evaluation of Effect of Nishamalaki on STZ and HFHF Diet Induced Diabetic Neuropathy in Wistar Rats
Diabetes Mellitus (DM) is a metabolic disorder; alarmingly increase in the incidence observed globally. DM considered as a major threat to human health in developing and developed countries due to its complications. In spite of control of DM, complications may develop over due course of disease. Neuropathy is the most common chronic complication of DM affecting more than 50% of the patients [1]. The duration of disease and level of hyperglycaemia are important determinants of microvascular complications of diabetes [2]. Pain due to diabetic neuropathy affects most often lower extremities above the knees and upper extremities [3]. Abnormal excitement of immaturely regenerated nerve fibers causes spontaneous pain, numbness and paresthesia [4]. Pain occurs even after the exposure to mild pain stimuli i.e., hyperalgesia and allodynia. Diabetic neuropathy shows significant impact on Quality Of Life (QOL) and costs of management [5]. Apart from tight glycaemic control, no other evidence-based treatments are known to prevent neuropathy [6]. The exact pathology of diabetic neuropathy is not known, but it involves oxidative stress, advanced glycation end products, polyol pathway flux activation contribute to microvascular disease and nerve dysfunction [7]. Current treatment based on the use of desipramine, amitriptyline, capsaicin, tramadol, gabapentin, bupropion, and venlafaxine etc., [8]. But these drugs provides only symptomatic relief and has no effect on Blood Sugar Level (BSL) and progression of disease. Nishamalaki (Na) is an Ayurvedic formulation prepared from Amla (Emblica officinalis) and Turmeric (Curcuma longa) with the traditional method as per the ancient literature [9]. Traditional use mentioned its utility to control DM in initial phase and continued with addition of other agents for maintenance [10,11]. Individual agents in NA show hypoglycaemic, anti-oxidant and neuro-protective effect [12,13]. No studies are available for effect of combined formulation using modern medicinal parameters for neuropathy. Present study was planned to assess the efficacy of NA in diabetic neuropathy. MatERIals and MEthods Wistar rats of either sex having average weight of 150-200g were used for the study. Housing was done in accordance with Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) guidelines in standard cages. The animals were given food and water ad libitum and were exposed to12 hours light and dark cycle. Study started after obtaining the approval (IAEC:BVDUMC/88/2014-15
Diabetologia, 2008
Aims/hypothesis Evidence for the importance of peroxynitrite, a product of superoxide anion radical reaction with nitric oxide, in peripheral diabetic neuropathy is emerging. The role of specific nitric oxide synthase isoforms in diabetesassociated nitrosative stress and nerve fibre dysfunction and degeneration remains unknown. This study evaluated the contribution of inducible nitric oxide synthase (iNOS) to peroxynitrite injury to peripheral nerve and dorsal root ganglia and development of peripheral diabetic neuropathy. Methods Control mice and mice with iNos (also known as Nos2) gene deficiency (iNos −/−) were made diabetic with streptozotocin, and maintained for 6 weeks. Peroxynitrite injury was assessed by nitrotyrosine and poly(ADP-ribose) accumulation (immunohistochemistry). Thermal algesia was evaluated by paw withdrawal, tail-flick and hot plate tests, mechanical algesia by the Randall-Selitto test, and tactile allodynia by a von Frey filament test. Results Diabetic wild-type mice displayed peroxynitrite injury in peripheral nerve and dorsal root ganglion neurons. They also developed motor and sensory nerve conduction velocity deficits, thermal and mechanical hypoalgesia, tactile allodynia and ∼36% loss of intraepidermal nerve fibres. Diabetic iNos −/− mice did not display nitrotyrosine and poly(ADP-ribose) accumulation in peripheral nerve, but were not protected from nitrosative stress in dorsal root ganglia. Despite this latter circumstance, diabetic iNos −/− mice preserved normal nerve conduction velocities. Small-fibre sensory neuropathy was also less severe in diabetic iNos −/− than in wild-type mice. Conclusions/interpretation iNOS plays a key role in peroxynitrite injury to peripheral nerve, and functional and structural changes of diabetic neuropathy. Nitrosative stress in axons and Schwann cells, rather than dorsal root ganglion neurons, underlies peripheral nerve dysfunction and degeneration. Keywords iNOS. Nerve conduction. Nitrosative stress. Peripheral diabetic neuropathy. Tactile allodynia. Thermal algesia Abbreviations DAB 3,3′-diaminobenzidine DRG dorsal root ganglion INFD intraepidermal nerve fibre density iNOS inducible nitric oxide synthase MNCV motor nerve conduction velocity NT nitrotyrosine PAR poly(ADP-ribose) PARP poly(ADP-ribose) polymerase PDN peripheral diabetic neuropathy PGP 9.5 protein gene product 9.5 SNCV sensory nerve conduction velocity STZ streptozotocin TBS TRIS-buffered saline
AJP: Endocrinology and Metabolism, 2013
The Na + -H + -exchanger-1 (NHE-1) controls intracellular pH and glycolytic enzyme activities, and its expression and activity are increased by diabetes and high glucose. NHE-1-dependent upregulation of the upper part of glycolysis, under conditions of inhibition (lens) or insufficient activation (retina) of glyceraldehyde 3-phosphate dehydrogenase, underlies diversion of the excessive glycolytic flux towards several pathways contributing to oxidative stress, a causative factor in diabetic cataractogenesis and retinopathy. This study evaluated the role for NHE-1 in diabetic cataract formation and retinal oxidative stress and apoptosis. Control and streptozotocindiabetic rats were maintained with or without treatment with the NHE-1 inhibitor cariporide (Sanofi-Aventis, 10 mgkg -1 d -1 ) for 3.5 months. In in vitro studies, bovine retinal pericytes and endothelial cells were cultured in 5 or 30 mM glucose, with or without 10 µM cariporide, for 7 days. A several-fold increase of the by-product of glycolysis, α-glycerophosphate, indicative of activation of the upper part of glycolysis, was present in both rat lens and retina at an early (1-month) stage of streptozotocindiabetes. Cariporide did not affect diabetic hyperglycemia and counteracted lens oxidative-nitrative stress and p38 MAPK activation, without affecting glucose or sorbitol pathway intermediate accumulation. Cataract formation (indirect ophthalmoscopy and slit-lamp examination) was delayed, but not prevented. The number of TUNEL-positive cells per flatmounted retina was increased 4.4-fold in diabetic rats (101±17 vs. 23±8 in controls , P<0.01), and this increase was attenuated by cariporide (45±12, P<0.01). Nitrotyrosine and poly(ADPribose) fluorescence and percentage of TUNEL-positive cells were increased in pericytes and endothelial cells cultured in 30 mM glucose, and these changes were at least partially prevented by cariporide. In conclusion, NHE-1 contributes to diabetic cataract formation, and retinal oxidative-nitrative stress and apoptosis. The findings identify a new therapeutic target for diabetic ocular complications.
Phytotherapy Research, 2007
Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognized as one of the most difficult types of pain to treat. The underlying mechanisms of painful symptoms may be closely associated with hyperglycaemia but a lack of the understanding of its proper 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 of insulin and its combinations with resveratrol and curcumin in attenuating diabetic neuropathic pain. The study also aimed to examine the effect of these combinations on tumour necrosis factor-alpha (TNF-α α α α α) and nitric oxide (NO) levels in streptozotocin (STZ) 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 along with increased plasma glucose and decreased body weights compared with control mice. Chronic treatment with insulin (10 IU/kg/day, s.c.) and its combinations with antioxidants (resveratrol 20 mg/kg or curcumin 60 mg/kg, p.o.) for 4 weeks starting from the 4th week of STZ injection significantly attenuated thermal hyperalgesia and the hot-plate latencies. There was a significant inhibition of TNF-α α α α α and NO levels when these drugs were given in combination compared with their effects per se. These results indicate an antinociceptive activity of resveratrol and curcumin and point towards the beneficial effect of these combinations with insulin in attenuating diabetic neuropathic pain, possibly through the participation of NO and TNF-α α α α α.
Nitrosative Stress, Uric Acid, and Peripheral Nerve Function in Early Type 1 Diabetes
Diabetes, 2002
The present study was performed to determine whether nitric oxide overproduction is associated with deterioration in peripheral nerve function in type 1 diabetes. We measured peripheral nerve function and biochemical indicators of nitrosative stress annually for 3 years in 37 patients with type 1 diabetes. Plasma nitrite and nitrate (collectively NOx) were 34.0 ± 4.9 μmol/l in the control subjects and 52.4 ± 5.1, 50.0 ± 5.1, and 49.0 ± 5.2 in the diabetic patients at the first, second, and third evaluations, respectively (P < 0.01). Nitrotyrosine (NTY) was 13.3 ± 2.0 μmol/l in the control subjects and 26.8 ± 4.4, 26.1 ± 4.3, and 32.7 ± 4.3 in the diabetic patients (P < 0.01). Uric acid was suppressed by 20% in the diabetic patients (P < 0.001). Composite motor nerve conduction velocity for the median, ulnar, and peroneal nerves was decreased in patients with high versus low NTY (mean Z score −0.522 ± 0.25 versus 0.273 ± 0.22; P < 0.025). Patients with high NOx had decrea...