Polyneuropathy In Rats Research Articles

Trimetazidine provides protection against diabetic polyneuropathy in rats via modulation of soluble HMGB1.

The aim of this study was to evaluate the neuroprotective efficacy of trimetazidine (TMZ) in a diabetic neuropathy model of the sciatic nerve. We performed intraperitoneal (IP) single-dose streptozotocin (STZ) injection for a diabetes mellitus neuropathy model in 24 rats; 8 rats were in the control group, and no chemical administration was performed. 24 diabetic rats were randomly divided into 3 groups: Group 1 rats (n = 8; diabetes and saline groups) were given 1 ml/kg saline treatment. Diabetes and trimetazidine (TMZ)-treated rats (n = 8) were given TMZ 10 mg/kg/day i.p. in Group 2. Group 3 rats were given TMZ 20 mg/kg/day by i.p. for 4 weeks. At the end of the study, EMG and inclined plane testing were used, and blood samples were taken. Amplitudes of CMAP increased significantly in the TMZ treatment group when compared with the group that had been given saline treatment. The latency of CMAP was significantly shortened in the TMZ treatment group as compared to the saline treatment group. When compared to the saline treatment group, 10 mg/kg and 20 mg/kg TMZ treatment significantly reduced HMGB1, Pentraxin-3, TGF-beta, and MDA levels. We demonstrated the neuroprotective effect of TMZ on diabetic polyneuropathy in rats via modulation of soluble HMGB1.

Influence of the complex drug Cocarnit on the sciatic nerve in the development of diabetic polyneuropathy in rats

AbstractUlcers and slow wound healing are common in diabetic polyneuropathy (DP), as well as shooting or burning pain, sensitivity to touch or lack of sensitivity, low oxygenation of nerve tissue, conductivity disorders and various vascular disorders. The mechanisms of DP development are complex and have not been completely studied. To take into account the role of B group vitamins, we investigated histological structure of nerve tissue, the level of different growth factors and the qualitative composition of active proteolytic enzymes in rats with DP and after the use of the metabolic drug Cocarnit for 9 days. This drug composition include nicotinamide, cocarboxylase, cyanocobalamin, adenosine triphosphate disodium trihydrate. We used an histological study of sciatic nerve; enzyme-linked immunosorbent assay and enzyme electrophoresis methods. In rats with DP, fragmentation of nerve tissue and their necrosis was established. Moreover, degraded forms of plasmin that has a fully functional serine proteinase domain are evident, and, therefore, it exhibits proteolytic properties. DP led to a decrease of neuron growth factor (NGF), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). After treatment, the histological structure of nerve tissue was significantly improved, and the expression of growth factors NGF and bFGF was increased. Our study demonstrated that administration of Corcarnit brought about the complete restoration of the activation potential of plasmin and the almost disappearance of all degraded forms which were evident in the group with DP.

Oxytocin provides protection against diabetic polyneuropathy in rats

Purpose: The aim of the present study is to investigate the protective effects of oxytocin (OT) on diabetic neuropathy (DNP) in rats.Materials and methods: Eighteen rats were used to induce diabetes using single dose streptozotocin (STZ, 60 mg/kg). Diabetic DNP was verified by electromyography (EMG) and motor function test on 21st day following STZ injection. Six rats served as naïve control group and received no drug (n = 6). Following EMG, diabetic rats were randomly divided into three groups and administered with either 1 ml/kg saline or 80 μg/kg OT or 160 μg/kg OT intraperitoneally for four weeks. Then, EMG, motor function test, biochemical analysis (plasma lipid peroxides and glutathione), histological, and immunohistochemical analysis of sciatic nerves (bax, caspase 3, caspase 9, and NGF) were performed.Results: Diabetic rats developed neuropathy, which was apparent from decreased compound muscle action potentials amplitudes and prolonged distal latency in saline-treated rats (p < 0.001) whereas 160 μg/kg OT significantly improved EMG findings. OT treatment significantly lessened the thickening of perineural fibrosis when compared with saline group (p < 0.001). Besides, OT significantly reduced plasma lipid peroxides (p < 0.05) and increased glutathione levels in diabetic rats (p < 0.001). The sciatic nerves of saline-treated rats showed considerable increase in bax, caspase 3 and caspase 8 expressions (p < 0.001) while OT treatment significantly suppressed these apoptosis markers. Also, OT improved NGF expression in diabetic rats compared to saline group.Conclusion: Present results demonstrate that OT appears to alleviate harmful effects of hyperglycemia on peripheral neurons by suppressing inflammation, oxidative stress and apoptotic pathways.

Mechanical hyperalgesia in rats with diabetic polyneuropathy is selectively inhibited by local peripheral nociceptin/orphanin FQ receptor and µ-opioid receptor agonism

Peripheral receptors may contribute to the effects of systemically administered centrally available analgesics. In the present study, we analysed the effect of local peripheral injection of the nociceptin/orphanin FQ peptide (NOP) receptor agonist Ro65-6570 and compared it to the µ-opioid peptide (MOP) receptor agonist morphine in streptozotocin-induced diabetic polyneuropathy in rats. Ro65-6570 and morphine were injected intraplantarly into the hind paw of diabetic rats, and mechanical withdrawal thresholds were determined in both paws (ipsi- and contralateral to the injection site). Ro65-6570 in the dose range of 7.1–71.4nmol/animal showed antihyperalgesic effects with maximal efficacy of 57.1±15.4% maximal possible effect (MPE) at the dose of 23.8nmol/animal. Intraplantar administration of morphine showed dose-dependent antihyperalgesic effects in the dose range of 25.8–257.8nmol/animal in a similar efficacy range with a maximal efficacy of 76.0±12.1% MPE at the dose of 257.8nmol/animal. Both compounds did not induce overt confounding side effects across the tested dose range. The NOP receptor antagonist J-113397 and the MOP receptor antagonist naloxone, intraplantarly co-administered with the respective agonists, selectively and completely prevented the antihyperalgesic action of the respective NOP and MOP receptor agonist. These results indicate that the activation of peripheral NOP and MOP receptors by Ro65-6570 and morphine, respectively, mediated antihyperalgesic effects in rats with diabetic polyneuropathy.

Temporal course of streptozotocin-induced diabetic polyneuropathy in rats.

The temporal course of diabetic polyneuropathy in a rat model plays a critical role in studies on diabetic polyneuropathy treatment. In this study, the temporal course of neuropathic symptoms was investigated in diabetic rats induced by streptozotocin and evaluated by nerve conduction velocity and behavioral assays, including the von Frey test for mechanical allodynia and the hot plate test for hyperalgesia. The results revealed that both mechanical allodynia and heat hyperalgesia started on the 2nd week, while nerve conduction velocity significantly decreased from the 1st week. In addition, the severity of allodynia did not change after the 3rd week. Hyperalgesia and nerve conduction velocity progressively aggravated even to the 8th week. Transmission electron microscopy showed that loss of unmyelinated axons, loosening of the myelin structure, and thickening of the perineurium layer were visible from the 4th week and worsened on the 8th week. Differences in the temporal course of neuropathic symptoms are discussed.

High Energy Diets-Induced Metabolic and Prediabetic Painful Polyneuropathy in Rats

To establish the role of the metabolic state in the pathogenesis of polyneuropathy, an age- and sex-matched, longitudinal study in rats fed high-fat and high-sucrose diets (HFSD) or high-fat, high-sucrose and high-salt diets (HFSSD) relative to controls was performed. Time courses of body weight, systolic blood pressure, fasting plasma glucose (FPG), insulin, free fatty acids (FFA), homeostasis model assessment-insulin resistance index (HOMA-IR), thermal and mechanical sensitivity and motor coordination were measured in parallel. Finally, large and small myelinated fibers (LMF, SMF) as well as unmyelinated fibers (UMF) in the sciatic nerves and ascending fibers in the spinal dorsal column were quantitatively assessed under electron microscopy. The results showed that early metabolic syndrome (hyperinsulinemia, dyslipidemia, and hypertension) and prediabetic conditions (impaired fasting glucose) could be induced by high energy diet, and these animals later developed painful polyneuropathy characterized by myelin breakdown and LMF loss in both peripheral and central nervous system. In contrast SMF and UMF in the sciatic nerves were changed little, in the same animals. Therefore the phenomenon that high energy diets induce bilateral mechanical, but not thermal, pain hypersensitivity is reflected by severe damage to LMF, but mild damage to SMF and UMF. Moreover, dietary sodium (high-salt) deteriorates the neuropathic pathological process induced by high energy diets, but paradoxically high salt consumption, may reduce, at least temporarily, chronic pain perception in these animals.

Strategies to prevent sepsis-induced intensive care unit–acquired weakness: are there any options? Commentary on “Comparison of melatonin and oxytocin in the prevention of critical illness polyneuropathy in rats with surgically induced sepsis”

* Corresponding author. Department of Surg Suite 2M, New York, NY 10003. Tel.: þ1 212 E-mail address: mleitman725@me.com (I 0022-4804/$ e see front matter a 2013 Elsev http://dx.doi.org/10.1016/j.jss.2012.12.019 Intensive care unit-acquired weakness (ICUAW) is one of the leading causes of morbidity in critically ill patients and a significant risk factor for the development of chronic critical illness. In 2008, 727,000 patients were hospitalized for sepsis, with mortality rate of 17% at an estimated cost of $14.6 billion [1]. The risk of critical illness neuromuscular abnormalities in

Comparison of melatonin and oxytocin in the prevention of critical illness polyneuropathy in rats with experimentally induced sepsis

BackgroundCritical illness polyneuropathy is an acute neuromuscular disorder of critically ill patients and is characterized by limb and respiratory muscle weakness. The purpose of the study was to evaluate the neuroprotective effects of melatonin (MEL) and oxytocin (OT) on the early stage of sepsis by recording compound muscle action potentials and measuring plasma tumor necrosis factor (TNF)-α levels, lipid peroxidation (malondialdehyde; MDA), and total antioxidant capacity. Materials and methodsOne hundred adult male Sprague-Dawley rats were included in the study. The cecal ligation and puncture (CLP) procedure was performed to induce the sepsis model. MEL (10, 20, and 40 mg/kg), OT (0.4, 0.8, and 1.6 mg/kg), and a combination of MEL (20 mg/kg) and OT (0.8 mg/kg) were administered intraperitoneally in the first hour of surgery. Electromyography (EMG) studies were achieved 24 h after CLP surgery and then blood samples were collected for biochemical measurements. ResultsEMG findings revealed that compound muscle action potential amplitude was significantly decreased and distal latency was prolonged in the CLP group compared with the sham group (P < 0.05 and P < 0.0005). Moreover, the animals that received CLP surgery showed significantly higher TNF-α and MDA levels and lower total antioxidant capacity values than the sham group. The administration of MEL and OT to rats significantly abolished the EMG alterations and suppressed oxidative stress and TNF-α release in CLP-induced rats. ConclusionsThe inflammatory processes and imbalance in oxidative/antioxidative status play important roles in the pathogenesis of critical illness polyneuropathy. We suggest that both oxytocin and melatonin may have beneficial effects against sepsis-induced polyneuropathy in critical illness.

Mesenchymal Stem Cell Recruitment and Improved Bladder Function After Bladder Outlet Obstruction: Preliminary Data

Mesenchymal stem cells have various therapeutic benefits in various organ injury models. Bladder outlet obstruction causes smooth muscle hypertrophy and fibrosis, leading to lowered compliance, increased storage pressures and renal injury. Decreased blood flow and hypoxia may contribute to obstruction related bladder decompensation. We used a mouse model to determine whether mesenchymal stem cell recruitment occurred after bladder outlet obstruction and whether this was associated with changes in bladder hypoxia, histology and function. We also identified potential chemokines involved in mesenchymal stem cell recruitment. A total of 20 female mice underwent bladder outlet obstruction. Three days later 2 million green fluorescent protein labeled mesenchymal stem cells were intravenously administered. After 4 weeks urodynamic and histological evaluation was performed. Quantitative reverse transcriptase-polymerase chain reaction was done to determine relative expression of the chemokines CCL2, CCL20, CCL25, CXCL9 and CXCL16. We simultaneously studied mice with bladder outlet obstruction only without mesenchymal stem cell injection and a control group. In 10 of 15 surviving mesenchymal stem cell injected mice mesenchymal stem cells were identified in the detrusor, and decreased hypoxia, hypertrophy and fibrosis was seen. Nine of 10 mice with mesenchymal stem cell engraftment had improved compliance compared to those without engraftment (mean±SD 9.6±5.1 vs 3.9±2.6 μl/cm H2O, p=0.012). Polymerase chain reaction revealed a 2-fold increase in CCL2 expression but there were no significant changes in other chemokine levels. Mesenchymal stem cell recruitment to the bladder after bladder outlet obstruction appears to be associated with increased blood flow and decreased tissue hypoxia, which may contribute to improvement in histopathological and functional parameters. Mesenchymal stem cell recruitment may be related to CCL2 over expression. Additional studies in larger samples are needed but these initial results suggest a potential role for mesenchymal stem cell based therapy for bladder outlet obstruction related bladder injury.

Transplantation of Bone Marrow–Derived Mesenchymal Stem Cells Improves Diabetic Polyneuropathy in Rats

OBJECTIVE—Mesenchymal stem cells (MSCs) have been reported to secrete various cytokines that exhibit angiogenic and neurosupportive effects. This study was conducted to investigate the effects of MSC transplantation on diabetic polyneuropathy (DPN) in rats.RESEARCH DESIGN AND METHODS—MSCs were isolated from bone marrow of adult rats and transplanted into hind limb skeletal muscles of rats with an 8-week duration of streptozotocin (STZ)-induced diabetes or age-matched normal rats by unilateral intramuscular injection. Four weeks after transplantation, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) productions in transplanted sites, current perception threshold, nerve conduction velocity (NCV), sciatic nerve blood flow (SNBF), capillary number–to–muscle fiber ratio in soleus muscles, and sural nerve morphometry were evaluated.RESULTS—VEGF and bFGF mRNA expression were significantly increased in MSC-injected thigh muscles of STZ-induced diabetic rats. Furthermore, colocalization of MSCs with VEGF and bFGF in the transplanted sites was confirmed. STZ-induced diabetic rats showed hypoalgesia, delayed NCV, decreased SNBF, and decreased capillary number–to–muscle fiber ratio in soleus muscles, which were all ameliorated by MSC transplantation. Sural nerve morphometry showed decreased axonal circularity in STZ-induced diabetic rats, which was normalized by MSC transplantation.CONCLUSIONS—These results suggest that MSC transplantation could have therapeutic effects on DPN through paracrine actions of growth factors secreted by MSCs.

P.8.039 Differing mental health practice among general practitioners, private psychiatrists and public psychiatrists

Peripheral receptors may contribute to the effects of systemically administered centrally available analgesics. In the present study, we analysed the effect of local peripheral injection of the nociceptin/orphanin FQ peptide (NOP) receptor agonist Ro65-6570 and compared it to the µ-opioid peptide (MOP) receptor agonist morphine in streptozotocin-induced diabetic polyneuropathy in rats. Ro65-6570 and morphine were injected intraplantarly into the hind paw of diabetic rats, and mechanical withdrawal thresholds were determined in both paws (ipsi- and contralateral to the injection site). Ro65-6570 in the dose range of 7.1–71.4 nmol/animal showed antihyperalgesic effects with maximal efficacy of 57.1±15.4% maximal possible effect (MPE) at the dose of 23.8 nmol/animal. Intraplantar administration of morphine showed dose-dependent antihyperalgesic effects in the dose range of 25.8–257.8 nmol/animal in a similar efficacy range with a maximal efficacy of 76.0±12.1% MPE at the dose of 257.8 nmol/animal. Both compounds did not induce overt confounding side effects across the tested dose range. The NOP receptor antagonist J-113397 and the MOP receptor antagonist naloxone, intraplantarly co-administered with the respective agonists, selectively and completely prevented the antihyperalgesic action of the respective NOP and MOP receptor agonist. These results indicate that the activation of peripheral NOP and MOP receptors by Ro65-6570 and morphine, respectively, mediated antihyperalgesic effects in rats with diabetic polyneuropathy.

Acetone potentiation and influence on the reversibility of 2,5-hexanedione-induced neurotoxicity studied with behavioural and morphometric methods in rats.

The neurobehavioural and morphologic changes and the reversibility in 2,5-hexanedione-induced polyneuropathy in rats were studied. The potentiation and influence of acetone on the reversibility of the induced neurotoxicity was also evaluated. Male rats were treated for 6 weeks with 0.5% w/v 2,5-hexanedione alone or in combination with 0.50% w/v acetone in the drinking water. During the treatment period, neurobehavioural tests (ambulation and rearing in open field, balance on the accelerating rotarod and fore-and hindlimb muscle strength measurements) were performed weekly. After 6 weeks half of the rats was sacrificed and histopathological lesions in the sciatic nerve and tibial nerve were evaluated by morphometry. Neurotoxicity was induced by 2,5-hexanedione, and acetone caused a potentiation of this effect in open field ambulation and rearing and in the rotarod test. In the pathological evaluation, giant axonal swelling was observed after 2,5-hexanedione and 2,5-hexanedione plus acetone. In nerve fibre cross sections, a significant change of the distribution of fibre area size was observed in animals treated with 2,5-hexanedione. Aggravation of the lesions was seen in rats treated with both 2,5-hexanedione and acetone. The other half of the animals was used to study the reversibility of the neurotoxic effects within a dose-free period of 10 weeks. Reversibility of the effect on ambulation was complete within the recovery period, but the effects on rearing and balance in the rotarod test were only reversible within the 10 weeks in the 2,5-hexanedione-treated rats and not in the combined 2,5-hexanedione and acetone-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Histologic evidence for a toxic polyneuropathy due to exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a considerable environmental hazard in industrial societies. Its toxic effects on animals and humans are numerous, but little is known about its neurotoxicity. We studied the neurotoxic effects of TCDD in 80 male, adult Wistar rats. The substance was dissolved in corn oil and a single dose injected intraperitoneally (8.8 micrograms, 6.6 micrograms, 4.4 micrograms or 2.2 micrograms/kg). Neurophysiological examinations proved a dose-related, statistically significant slowing of sensory and motor conduction velocities. Ten months after the application of TCDD peripheral nerves showed a progressive, and proximally accentuated neuropathy. The extent of changes, however, differed remarkably between individual animals. Our data indicate that TCDD caused a toxic polyneuropathy in rats.

Electrophysiologic evidence for a toxic polyneuropathy in rats after exposure to 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)

At present, experimental data on the neurotoxicity of 2,3,7,8-tetrachlorodibenzo- p-dioxin are still lacking. Therefore, electrophysiologic studies were performed in 80 adult, male Han/Wistar rats intraperitoneally injected with a single, low dose of TCDD (8.8, 6.6, 4.4 or 2.2 μg/kg) dissolved in corn oil. 20 control animals received corn oil only. The typical ‘wasting syndrome’ of high-dose TCDD-intoxication was therefore not observed. Motor and sensory nerve conduction velocities in the right sciatic nerve showed dose-dependent and statistically significant slowing in TCDD-exposed rats as compared to controls. Spontaneous activity in the flexor digitorum muscle of the right hind paw and in tail muscles could be seen in the electromyogram of TCDD-group 1 (100%), group 2 (93%), groups 3 and 4 (87% each). This was significantly less frequent in the controls (21%). These findings give electrophysiologic evidence for a toxic polyneuropathy in rats after a single, low dose of TCDD.

Clinical expression of organophosphate-induced delayed polyneuropathy in rats

Single doses of certain organophosphates (OP), such as dibutyl-2,2-dichlorovinyl phosphate (DBDCVP) cause organophosphate-induced delayed polyneuropathy (OPIDP) in hens. Clinical effects correlate with inhibition of neuropathy target esterase (NTE) which is considered the target for this toxicity. Pre-treatment with non-neuropathic NTE inhibitors, such as phenylmethanesulfonyl fluoride (PMSF), protects from OPIDP. However, when given after OPs, these compounds promote OPIDP. Chicks are relatively resistant to OPIDP despite high NTE inhibition. It has also always been reported that rats represent a species which is resistant to OPIDP and that they might develop morphological but not clinical signs of OPIDP. We report here that clinical OPIDP can be produced in 3.5- and 6-month-old rats by DBDCVP (5 mg/kg s.c.) and that it correlates with high (> 90%) NTE inhibition. When PMSF (120 mg/kg s.c. × 2) was given after DBDCVP, OPIDP was promoted. Pretreatment with PMSF protected from OPIDP. We conclude that resistance to OPIDP in the rat is age-related, as it is in the hen.

Experimental neurotoxicity and urinary metabolites of the C5-C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture.

Rats were intermittently exposed (9 to 10 h/d, 5 to 6 d/week) to controlled concentrations of single analytical grad solvents in ambient air. After periods ranging from 7 to 30 weeks the animals were perfused with glutaraldehyde and samples of nerves were processed for light microscopy of sections and of teased fibers. Animals treated with n-hexane at 5000 ppm (14 weeks) or 2500 ppm (30 weeks) developed the typical giant axonal degeneration already described in rats treated continuously with 400 to 600 ppm of the same solvent for 7 weeks or more. No such alterations were found in rats subjected to the following intermittent respiratory treatments: n-hexane 500 ppm (30 weeks) or 1500 ppm (14 weeks), cyclohexane 1500 or 2500 (30 weeks), n-pentane 3000 ppm (30 weeks), n-heptane 1500 ppm (30 weeks), 2-methylpentane 1500 ppm (14 weeks), and 3-methylpentane 1500 ppm (14 weeks). The following metabolites were found in the urine of rats according to treatment (in parenthesis): 2-methyl-2-pentanol (2-methylpentane); 3-methyl-2-pentanol and 3-methyl-3-pentanol (3-methylpentane), 2-hexanol, 3-hexanol, gamma-valerolactone, 2,5-dimethylfuran, and 2,5-hexanedione (n-hexane). 2-Hexanol was found to be the main urinary metabolite of n-hexane, while 2,5-hexanedione was present only in a lesser proportion. This feature of rat metabolism suggests that in this species 2,5-hexanedione reaches an effective level at its site of action during intermittent respiratory treatment with n-hexane with difficulty and explains the high concentrations necessary to cause polyneuropathy in rats subjected to this treatment.

Hypermyoinositolemic polyneuropathy in rats: A possible mechanism for uremic polyneuropathy

Elevated plasma myoinositol levels were induced in normal rats by feeding diets containing 35% myoinositol or by the repeated intraperitoneal injection of myoinositol. This reproducibly resulted in the development of decreased sciatic motor nerve conduction velocity without any initial change in the amplitude of the evoked muscle action potential or in whole nerve sensitivity to threshold stimulation. These observations suggest the development of dysfunction of the Schwann cell-myelin complex rather than of the axons or anterior horn cells. The recent recognition that hypermyoinositolemia is a common concomitant of human uremia, and the similarities in the electrophysiological derangements in peripheral nerve function in experimental hypermyoinositolemia and in subclinical uremic neuropathy suggest that elevated plasma myoinositol levels may contribute to the pathogenesis of uremic polyneuropathy.