Evaluation of ameliorative effect of sodium nitrate in experimental model of streptozotocin-induced diabetic neuropathy in male rats (original) (raw)
Related papers
Journal of Diabetes & Metabolic Disorders, 2020
Purpose The purpose of the study was to evaluate the possible protective effects of low dose sodium nitrate preconditioning on the peripheral neuropathy in streptozotocin (STZ)-induced diabetic model. Methods Male Wistar rats were randomly divided into five groups: control (no intervention), control treated sodium nitrate (100 mg/L in drinking water), diabetic (no intervention), diabetic treated NPH insulin (2-4 U), and diabetic treated sodium nitrate (100 mg/L in drinking water). Diabetes was induced by intraperitoneal injection of STZ (60 mg/kg). All interventions were done for 60 days immediately following diabetes confirmation. Thermal and mechanical algesia thresholds were measured by means of hot-plate test, von Frey test, and tail-withdrawal test before the diabetic induction and after diabetes confirmation. At the end of the experiment, serum NOx level and serum insulin level were assessed. Blood glucose concentration and body weight have recorded at the base and duration of the experiment. Results Both hypoalgesia, hyperalgesia along with allodynia developed in diabetic rats. Significant alterations including, decrease in tail withdrawal latency (30th day), decreased mechanical threshold (60th day), and an increase in hot plate latency (61st day) were displayed in diabetic rats compared to control rats. Nitrate and insulin preconditioning produced protective effects against diabetesinduced peripheral neuropathy. Data analysis also showed a significant increase in glucose level as well as a considerable reduction in serum insulin and body weight of diabetic rats, which restored by both insulin and nitrate preconditioning. Conclusion Sodium nitrate preconditioning produces a protective effect in diabetic neuropathy, which may be mediated by its antihyperglycemic effects and increased serum insulin level.
Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat
Pain, 1999
Streptozotocin (STZ)-induced diabetes in the rat has been increasingly used as a model of painful diabetic neuropathy to assess the efficacies of potential analgesic agents. We have established this model, and here we question whether the changes in nocifensive reflex activity, used as a measure of hyperalgesia, are genuinely indicative of peripheral neuropathy or may rather be attributed to the extreme poor health of the animals. For comparison we have examined animals with peripheral neuropathy induced by partial ligation of the sciatic nerve. Diabetic animals were chronically ill, with reduced growth rate, polyuria, diarrhoea, and had enlarged and distended bladders. Indicative of their poor health, diabetic animals showed markedly reduced motor activity. In contrast, following partial sciatic nerve ligation rats showed none of these adverse effects and their motor activity was not different to naive animals. Diabetic animals displayed marked mechanical hyperalgesia, and some thermal hypoalgesia. Morphine and l-baclofen partially reversed established STZ-induced mechanical hyperalgesia, whilst the NK-1 receptor-antagonist RP-67580, the NMDA-antagonists MK801 and ketamine, and the nitric oxide synthase inhibitor l-NAME were without significant effect. Morphine and l-baclofen produced greater reversal of mechanical hyperalgesia following partial nerve ligation, although RP67580 and MK801 showed little or no activity. These data confirm previous findings that STZ-induced diabetes in rats produces long-lasting mechanical, but not thermal hyperalgesia. In our experience this mechanical hyperalgesia is largely resistant to a range of pharmacological tools. However, we feel that the profound ill-health of the animals, together with the poor activity of a range of potential analgesic drugs, must raise questions on the predictive value of these animals as a model for the human condition of chronic diabetic pain seen in patients receiving long-term insulin treatment, as well as ethical concerns on the use of the animals themselves.
Nitric oxide involvement in the trigeminal hyperalgesia in diabetic rats
Journal of the …, 2000
Trigeminal hyperalgesia frequently appears in diabetic neuralgia altering the transmission of orofacial sensory information. This study was designed to explore the effects of trigeminal hyperalgesia in streptozotocin-induced diabetes monitoring the expression of nitric oxide synthase in the trigeminal ganglion cells. The threshold to heat noxious stimuli decreased in diabetic animals. The number of NADPH-diaphorase (NADPH-d)-positive neurons significantly decreased in the diabetic rats compared with controls. Insulin treatment prevented the decreased nociceptive threshold and reduction of the number of NADPH-d-positive neurons. These findings point out that there is a relationship between the trigeminal nociceptive perception and NADPH-d neuronal expression suggesting that NO may play a role in the pathogenesis of trigeminal sensory neuropathy.
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
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...
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...
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.
Role of nitric oxide in diabetes-induced attenuation of antinociceptive effect of morphine in mice
European Journal of Pharmacology, 2000
The study was designed to investigate the role of nitric oxide NO in the diabetes-induced decrease of the antinociceptive effect of Ž morphine. The nociceptive threshold in diabetic and non-diabetic mice was measured in the tail-flick test. Streptozotocin 200 mgrkg. i.p. was administered to induce experimental diabetes in the mice. Four weeks after the administration of streptozotocin, the tail-flick test was performed and urinary nitrite concentration was estimated using Greiss reagent. Experimental diabetes markedly decreased the Ž. antinociceptive effect of morphine 10 mg in 5 mlrmice i.c.v. and significantly increased the urinary nitrite concentration. Administra-Ž. tion of aminoguanidine 12 mgrmice markedly improved the antinociceptive effect of morphine and attenuated the increase in urinary nitrite concentration in diabetic mice. It may be tentatively concluded that an increase in NO formation may be responsible for the observed decrease in antinociceptive effect of morphine in diabetic mice.
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.
Neuroscience …, 2000
We explored and compared the diabetic neuralgia induced in streptozotocin-treated rats, monitoring the expression of nitric oxide synthase in several areas of the central nervous system involved in nociceptive transmission, in the spinal ganglia and in the nodose ganglia. The threshold for heat noxious stimuli decreased in diabetic animals. The number of NADPH-d positive neurons decreased significantly in the spinal ganglia and in the nodose ganglia but not in the spinal cord, periaqueductal gray matter and cortex of diabetic animals. Insulin treatment prevented the decrease of the nociceptive threshold and the loss of NADPH-d positive neurons in the spinal and nodose ganglia. We confirmed the relationship between nociception, diabetes and NADPH-d neuronal expression in the spinal ganglia. We showed also that the nitric oxide is probably involved in the vagal diabetic neuropathy. These results suggest a different sensitivity to diabetes of central and peripheral nitroxidergic neurons.