Sciatic Nerve Of Diabetic Rats Research Articles

Structural Study of the Sciatic Nerve in Diabetic RafsTreated with Alium Sativurn

The diabetes mellitus has been induced in Sprague Dawely rats, by injection of alloxan 75 mg/ kg body weight, once daily for three successive days. Group of diabetic rats were treated with oral hyopgycemic (Glibenclamide) drug only and another group was treated with oral hyopgycemic (Glibenclamide) drug and Alium Sativum- garlic powder (250 mg / kg body weight, daily. Histological and histometric changes of sciatic nerve were investigated, by applying routine histological stains with specific application of osmium tetroxide for staining the nerve, detecting the structural changes and to measuring the improvement in the regeneration of the sciatic nerves. It has been found that the Alium Sativum treated group restored to certain degree the normal architectures of the sciatic nerve in diabetic rats and the improvement in thermal sensation as compared with non treated group or group treated with oral hypgycemic drug only.

The effect of tropisetron on peripheral diabetic neuropathy: possible protective actions against inflammation and apoptosis.

Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1 diabetes was created by a single injection of streptozotocin (50 mg/kg, ip). Tropisetron (3 mg/kg, ip) was administered daily for 2 weeks. Our analysis showed that nerve fibers and their myelin sheaths were thinned with decreased myelinated fiber number in diabetic animals. The intensity of Bcl-2 staining decreased and the intensity of Bax staining increased in the sciatic nerves of diabetic rats by using immunohistochemical staining. Furthermore, diabetes significantly increased tumor necrosis factor-alpha, interleukin 1-β (TNFα and IL-1β) and Bax/Bcl-2 ratio in sciatic nerves of rats. However, intraperitoneal injection of tropisetron significantly reversed these alterations induced by diabetes. These findings suggest that tropisetron attenuates diabetes-induced peripheral nerve injury through its anti-inflammatory and anti-apoptotic effects, and may provide a novel therapeutic strategy to ameliorate the process of peripheral neuropathy in diabetes.

Metformin Promotes Axonal Regeneration and Functional Recovery in Diabetic Rat Model of Sciatic Nerve Transection Injury

In our previous study, metformin was able to promote nerve regeneration after sciatic nerve crushing in rats under diabetic conditions. However, a crush injury also has a strong ability to spontaneously recover. Therefore, in our present study, a model of transection injury of the sciatic nerve in diabetic rats was utilized to detect whether metformin could still promote nerve regeneration. Diabetes was induced via an injection of 50 mg/kg of streptozotocin in rats. After transection injury of the sciatic nerve, the rats were randomly divided into a high-dose metformin group (500 mg/kg/d), mid-dose metformin group (200 mg/kg/d), low-dose metformin group (30 mg/kg/d) and control group (normal saline). The metformin or normal saline was intraperitoneally injected for 4 weeks. Then, behavioral, electrophysiological and morphometric analyses were performed. The results showed that metformin could significantly promote functional restoration and axonal regeneration of the sciatic nerve after transection injury under diabetic conditions. Furthermore, high doses and middle doses of metformin presented more of this ability than a low dose of metformin. In conclusion, metformin is able to accelerate sciatic nerve repair after transection injury under diabetic conditions, showing the therapeutic potential of metformin in the management of nerve injuries during diabetes mellitus.

Glycyrrhizic acid promotes sciatic nerves recovery in type 1 diabetic rats and protects Schwann cells from high glucose-induced cytotoxicity.

The present study aims to investigate the therapeutic effect and mechanism of glycyrrhizic acid (GA) in diabetic peripheral neuropathy (DPN). GA significantly mitigated nerve conduction velocity (NCV) deficit and morphological abnormality and reduced high-mobility group box-1 (HMGB1) expression in the sciatic nerves of diabetic rats independent of blood glucose and body weight. Notably, GA alleviated the increase of HMGB1 and the decrease of cell viability in high glucose-stimulated RSC96 cells. Furthermore, GA obviously reduced the concentration of inflammatory cytokines in the sciatic nerves of diabetic rats and supernatants of high glucose-exposed RSC96 cells, then restored the decreased expression levels of nerve growth factor (NGF) and neuritin-1, and the increased expression levels of cleaved caspase-3 and neuron-specific enolase. Additionally, GA markedly inhibited receptor for advanced glycation end products (RAGE) expression, p38MAPK phosphorylation, and the nuclear translocation of NF-κBp65 in diabetic rats and high glucose-exposed RSC96 cells. The promotional effect of high glucose in RSC96 cells was diminished following Hmgb1 siRNA treatment. Our findings indicate that GA may exert neuroprotection on DPN by suppressing HMGB1, which lead to extenuation of inflammation response, balance of NGF, neuritin-1 and caspase-3, as well as inactivation of RAGE/p38MAPK/NF-κBp65 signaling pathway.

Taurine ameliorates axonal damage in sciatic nerve of diabetic rats and high glucose exposed DRG neuron by PI3K/Akt/mTOR-dependent pathway.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes and axonopathy is its main pathological feature. Previous studies suggested an advantage of taurine against diabetes. However, there are few reports which study the effect of taurine against axonopathy. In this study, we confirmed that taurine significantly decreased blood glucose level, mitigated insulin resistance and improved dysfunctional nerve conduction in diabetic rats. Taurine corrected damaged axonal morphology of sciatic nerve in diabetic rats and induced axon outgrowth of Dorsal root ganglion (DRG) neurons exposed to high glucose. Taurine up-regulated phosphorylation levels of PI3K, Akt, and mTOR in sciatic nerve of diabetic rats and DRG neurons exposed to high glucose. However, Akt and mTOR inhibitors (MK-2206 and Rapamycin) blocked the effect of taurine on improving axonal damage. These results indicate that taurine ameliorates axonal damage in sciatic nerve of diabetic rats by activating PI3K/Akt/mTOR signal pathway. Our findings provide taurine as a potential candidate for axonopathy and a new evidence for elucidating protective mechanism of taurine on DPN.

The Effect of Endurance Training on Fibronectin Gene Expression of the Sciatic Nerve in Diabetic Rats

- Diabetic neuropathy can cause disorders in axon transmission, changes in the extracellular matrix, and peripheral nerve damages. However, its mechanism, along with the beneficial effects of exercise on these disorders is not entirely clear. The aim of the current study was to assess changes in fibronectin mRNA gene expression level of the sciatic nerve in rats with streptozotocin-induced diabetes after endurance training. Eighteen male Wistar rats (10 weeks old with 250±20 gr weight) were randomly assigned to three groups, including healthy, induced diabetes and induced diabetes plus endurance training. Induction of diabetes was conducted using an intraperitoneal injection of a single dose of streptozotocin (STZ). Neuropathy was confirmed using the behavioral tests. Rats in induced diabetes plus training group had 8 weeks of moderate and increasing intensity endurance training on the treadmill. The Fibronectin mRNA gene expression level of the sciatic nerve was assessed using Real-time-PCR. Changes in fibronectin protein and myelin thickness were measured by immunohistochemistry and luxol fast blue staining. The mean and standard deviation was used to report descriptive data. Data were entered into SPSS 22. Fibronectin mRNA gene expression level (1.90) of sciatic nerve fibronectin protein and myelin thickness reduced significantly due to diabetes (P<0.05). Eight weeks of endurance training increased fibronectin gene expression of sciatic nerve fibronectin protein and prevented further destruction of myelin, which was statistically significant. The results showed that diabetes leads to changes in the extracellular matrix and the reduction of the sciatic nerve myelin thickness. Endurance training as a non-drug strategy is effective in preventing these damages.

Effects of Insulin on Fibronectin Alterations in Sciatic Nerve of Diabetic Rats-A Brief Report

Objective: Alteration in the basement membrane proteins maybe associated with diabetic neuropathy. Fibronectin is one of the most important components of peripheral nerves basement membrane. In this study we investigated the effects of insulin administration on prevention of alteration in fibronectin contents of sciatic nerve in diabetic rats.
 Materials and Methods: Twenty-four wistar rats were divided into control, diabetic and diabetic with insulin treatment groups. Three months after diabetes induction, we measured blood glucose level, body weight and then expression of fibronectin in sciatic nerves of rats were evaluated by real time polymerase chain reaction (PCR) and immunohistochemical study.
 Results: Intensity of fibronectin immunoreactivity in the perineurium and endoneurium of sciatic nerves significantly increased in diabetic without treatment group compared to control group (P-value< 0.001).
 Conclusion: This finding suggested that diabetic neuropathy resulted in increased of fibronectin contents in sciatic nerves of rats.

The Effect of Aerobic Exercise on Collagen Type I and IV Gene Expression and Collagen Type I Protein Changes in the Sciatic Nerve of Diabetic Rats

Background: Neuropathy is one of the complications of diabetes, probably due to the destruction of the extracellular matrix and the thickening of the peripheral nerve basement membrane. However, its mechanisms and the impact of exercise on these disorders has not fully understood. The purpose of the present study was to investigate the effect of aerobic exercise on collagen levels of type I and IV and collagen type I protein changes in the sciatic nerve of diabetic rats. Materials and Methods: Eighteen 10-week-old Wistar male rats weighing 250 ± 20 g were randomly divided into three groups of healthy control (n=6), diabetic (n=6) and diabetic + aerobic exercise (n=6). For this purpose, after introduction and adaptation of rats to new environment, diabetes was induced by single dose injection of dissolved streptozotocin in sodium citrate buffer at pH=4.5 at 45 mg/kg intraperitoneal. After confirming neuropathic conditions (with behavioral tests), diabetic+exercise rats underwent moderate-intensity aerobic exercise on the treadmill for 8 week. At the beginning and at the end of the period, blood glucose of all rats was measured by glucometer and the mean of each group was measured separately. Changes in collagen type I and IV gene expression, and collagen type I protein levels in sciatic nerve of rats were evaluated by real-time PCR technique and immunohistochemistry, respectively. Results: Diabetes increased collagen type I and IV gene expression and collagen type I protein levels in the sciatic nerve samples of rats. However, exercise reduced blood sugar levels and expression of collagen type I and IV genes (p=0.05) and collagen type I protein significantly reduced in sciatic nerve (p=0.001). Conclusion: The results of the present study showed that aerobic exercise as a non-pharmacological strategy by negative regulating type I and IV collagen factors at the gene and protein level, was able to control and inhibit the effects of diabetes on extracellular matrix components in the sciatic nerve.

Exercise and insulin-like growth factor1 supplementation improve angiogenesis and angiogenic cytokines in a rat model of diabetes-induced neuropathy.

What is the central question of this study? Do changes in levels of angiogenesis-related mediators [vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1) and nuclear factor-κB (NF-κB)] in the sciatic nerve mediate diabetic neuropathy in the streptozotocin-induced type1 diabetic male rat? Can exercise and insulin-like growth factor1 (IGF-I) treatment improve the diabetes-related decrease in angiogenesis in sciatic nerve in these animals? What is the main finding and its importance? Levels of VEGF-A, TSP-1 and NF-κB change in the sciatic nerve of diabetic rats and might mediate diabetic neuropathy. Treatment with IGF-I and exercise could increase angiogenesis in the diabetic rats by increasing VEGF-A and decreasing TSP-1 and NF-κB expression in the sciatic nerve. Diabetic neuropathy is a severe complication of diabetes that affects 40-50% of diabetic people in the world. The aim of this study was to characterize alterations in angiogenesis and related molecular mediators in the sciatic nerve in diabetic conditions alone or in diabetes in combination withexercise and/or administration of insulin-like growth factor1 (IGF-I). Forty male Wistar rats were assigned into one of five groups, namely control, diabetes, diabetes+exercise, diabetes+IGF-I and diabetes+exercise+IGF-I. Type1 diabetes was induced by i.p. injection of streptozotocin (60mgkg-1 ). After 30 days of treatment with exercise or IGF-I alone or in combination, diabetic neuropathy was evaluated with a hotplate, glycated haemoglobin was measured, angiogenesis was determined by immunostaining for PECAM-1/CD31, and expressions of vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1) and nuclear factor-κB (NF-κB) were determined by enzyme-linked immunosorbent assay.After 4weeks, the diabetes group showed a significant decrease in capillary density and VEGF-A levels, but a significant increasein glycated haemoglobin in blood, TSP-1 and NF-κB levels in the sciatic nerve compared with the control group, and these effects were ameliorated by exercise and IGF-I. However, simultaneous treatment of diabetic rats with IGF-I and exercise did not have any synergistic effects. These findings indicate that diabetes-induced neuropathy may be associated, in part, with decreasedangiogenesis mediated by overproduction of TSP-1 and NF-κB, in addition to reduced production of VEGF-A. The findings also showed that exercise and IGF-I can reduce neuropathy, followed by increased angiogenesis, by changes in TSP-1, NF-κB and VEGF-A production levels.

Expressions of Thioredoxin Interacting Protein/Nucleotide-binding Oligomerization Domain-like Receptor Protein 3 Inflammasome in the Sciatic Nerve of Streptozotocin-induced Diabetic Rats

Objective To investigate the role of thioredoxin interacting protein(TXNIP)/ nucleotides-binding oligomerization domain-like receptor protein(NLRP)3 inflammasome in the sciatic nerve of streptozotocin(STZ)-induced diabetic rats. Methods The diabetic rat model was established by single intraperitoneal injection of STZ.The rats with matched sex and age were taken as normal control group.The blood glucose and body weight were monitored.The mechanical withdrawal threshold was measured by von Frey filaments at 12 weeks after the model was established.At 12 weeks,the rats were sacrificed and the sciatic nerves were separated for Luxol fast blue staining,the expressions of TXNIP,NLRP3,caspase-1,and interleukin(IL)-1β were detected by immunohistochemistry and Western blot method,and the levels of IL-1β and IL-18 in serum were measured by enzyme-linked immunosorbent assay(ELISA). Results The expression of TXNIP protein in the sciatic nerve of diabetic rats was 3.78±0.08,which significantly increased than that in the normal control group(0.99±0.06)(t=26.980,P<0.0001).Compared with the normal control group(0.97±0.05),the expression of NLRP3 protein in the diabetic group(2.44±0.16)was significantly higher(t=8.885,P<0.0001).The expression of cleaved caspase-1 was 4.45±0.19 in the diabetic group and 1.08±0.06 in the normal control group,and the difference was significant(t=16.900,P<0.0001).The expression of IL-1β protein in the diabetic group(4.50±0.16)was significantly higher than that(1.19±0.08)in the normal control group(t=18.630,P<0.0001).Compared with the normal control group,the levels of IL-1β [(110.50±8.80)pg/ml vs.(17.97±3.18)pg/ml,t=9.892,P<0.0001] and IL-18 [(591.70±8.78)pg/ml vs.(160.70±8.33)pg/ml,t=35.620,P<0.0001] in the serum of diabetic rats significantly increased. Conclusion The pathogenesis of diabetic peripheral neuropathy may be related to increased expression of TXNIP,activation of NLRP3 inflammasome,and downstream inflammation,which may provide a new target for diabetic peripheral neuropathy therapy.

Therapeutic efficacy of arginine-rich exenatide on diabetic neuropathy in rats

Diabetes mellitus is characterized by metabolic dysregulation associated with a number of health complications. More than 50% of patients with diabetes mellitus suffer from diabetic polyneuropathy, which involves the presence of peripheral nerve dysfunction symptoms. The aim of this study was to evaluate the potential of a new synthetic arginine-rich exendin-4 (Peptide D) in the treatment of complications caused by diabetes, including peripheral neuropathy, in rats. Diabetes was induced by administering streptozotocin (STZ). Three groups of diabetic rats were treated with Peptide D (0.1, 1, and 10 μg/kg). One group of diabetic rats was treated with Byetta® (1 μg/kg) for 80 days. Neuropathic pain development was assessed by tactile allodynia. STZ-treated rats showed an increased level of tactile allodynia unlike naïve animals. A histological study revealed that the diameter of the sciatic nerve fibers in STZ-treated rats was smaller than that of the naïve animals. An IHC study demonstrated decreased expression of myelin basic protein (MBP) in the sciatic nerve of diabetic rats compared to that in the naïve animals. Peptide D reduced the severity of tactile allodynia. This effect was more pronounced in the Peptide D treated groups than in the group treated with Byetta®. Peptide D and Byetta® treatment resulted in increased MBP expression in the sciatic nerve and increased diameter of myelinated nerve fibers. These findings suggest that poly-arginine peptides are promising agents for the treatment of peripheral polyneuropathies.

Taurine protects against myelin damage of sciatic nerve in diabetic peripheral neuropathy rats by controlling apoptosis of schwann cells via NGF/Akt/GSK3β pathway

Diabetic peripheral neuropathy is a common complications of Type 2 Diabetes and its main pathological feature is myelin sheath damage of peripheral nerve that was induced by Schwann cells (SCs) apoptosis. Increasing evidence suggested that taurine might play a role in improving DPN because of its ability to prevent SCs apoptosis. In this study, we explore the effect of taurine on preventing SCs apoptosis and its underlying mechanism. Sprague Dawley rats were treated with streptozotocin to establish the diabetes model. Rats were randomly divided into control, diabetes, taurine treatment (as giving 0.5%, 1% and 2% taurine in drinking water) groups. RSC96 cell (a rat SCs line) was used for intervention experiments in vitro. Results showed that taurine significantly corrected morphology of damaged myelin sheath and inhibited SCs apoptosis in sciatic nerve of diabetic rats. Moreover, taurine prevented apoptosis of RSC96 cells exposed to high glucose. Mechanistically, taurine up-regulated NGF expression and phosphorylation levels of Akt and GSK3β, while, blocking activation of NGF and phosphorylation of Akt and GSK3β increased apoptosis of high glucose-exposed RSC96 cells with taurine supplement. These results revealed taurine improved the myelin sheath damage of sciatic nerve in diabetic rats by controlling SCs apoptosis via NGF/Akt/GSK3β signaling pathways, which provides some clues that taurine might be effective and feasible candidate for the treatment of DPN.

EFFECTS OF DIABETES MELLITUS ON VISCOELASTICITY OF ULTRASTRUCTURES OF PERIPHERAL NERVES: THREE-DIMENSIONAL FINITE ELEMENT ANALYSES

Diabetes mellitus induces a variety of neuropathies and causes various symptoms. Understanding how diabetes affects mechanical properties of nerves is useful for preventing complications of diabetes mellitus such as the carpal tunnel syndrome. In a previous study, a two-dimensional hyper-viscoelastic finite element model (FEM) of the ultra-structures of normal rat sciatic nerves was developed using an optical coherence tomography (OCT) microscope and in vitro parallel compression tests. The main goal of this study was to extend the FEM from two to three dimensions and use it to explore hyper-viscoelasticity of ultra-structures of sciatic nerves of diabetic rats. A modification of the compression testing system to enhance OCT cross-sectional images of the nerve samples was also conducted. The results showed that the instantaneous shear moduli of the perineurium, epineurium, and endoneurium of the diabetic rat were all greater than those of the normal rats. Due to high instantaneous shear moduli and low percentage of relaxation, the diabetic nerve is prone to damage when subjected to prolonged mechanical loads.

Conditioned media from dental pulp stem cells improved diabetic polyneuropathy through anti-inflammatory, neuroprotective and angiogenic actions: Cell-free regenerative medicine for diabetic polyneuropathy.

Aims/IntroductionDental pulp stem cells (DPSCs) can be easily obtained from teeth for general orthodontic reasons. We have previously reported the therapeutic effects of DPSC transplantation for diabetic polyneuropathy. As abundant secretomes from DPSCs are considered to play a central role in the improvement of diabetic polyneuropathy, we investigated whether direct injection of DPSC‐conditioned media (DPSC‐CM) into hindlimb skeletal muscles ameliorates diabetic polyneuropathy in diabetic rats.Materials and MethodsDPSCs were isolated from the dental pulp of Sprague–Dawley rats. Eight weeks after the induction of diabetes, DPSC‐CM was injected into the unilateral hindlimb skeletal muscles in both normal and diabetic rats. The effects of DPSC‐CM on diabetic polyneuropathy were assessed 4 weeks after DPSC‐CM injection. To confirm the angiogenic effect of DPSC‐CM, the effect of DPSC‐CM on cultured human umbilical vascular endothelial cell proliferation was investigated.ResultsThe administration of DPSC‐CM into the hindlimb skeletal muscles significantly ameliorated sciatic motor/sensory nerve conduction velocity, sciatic nerve blood flow and intraepidermal nerve fiber density in the footpads of diabetic rats. We also showed that DPSC‐CM injection significantly increased the capillary density of the skeletal muscles, and suppressed pro‐inflammatory reactions in the sciatic nerves of diabetic rats. Furthermore, an in vitro study showed that DPSC‐CM significantly increased the proliferation of umbilical vascular endothelial cells.ConclusionsWe showed that DPSC‐CM injection into hindlimb skeletal muscles has a therapeutic effect on diabetic polyneuropathy through neuroprotective, angiogenic and anti‐inflammatory actions. DPSC‐CM could be a novel cell‐free regenerative medicine treatment for diabetic polyneuropathy.

Jinmaitong, a Traditional Chinese Compound Prescription, Ameliorates the Streptozocin-Induced Diabetic Peripheral Neuropathy Rats by Increasing Sciatic Nerve IGF-1 and IGF-1R Expression.

Jinmaitong (JMT) is a Traditional Chinese Compound Prescription for the treatment of diabetic peripheral neuropathy (DPN). This study aims to investigate the effect of JMT on the insulin-like growth factor 1 (IGF-1) and the insulin like growth factor 1 receptor (IGF-1R) expression in sciatic nerves of diabetic rats. Firstly, the chemical profile of JMT was characterized by UPLC/Q-TOF-MS analysis. A total of 72 compounds were putatively identified. Secondly, streptozotocin (STZ)-induced diabetic rats were treated with neurotropin (NTP, 2.67 NU/kg/day) or JMT at low-dosage (0.4375 g/kg/day), medium-dosage (0.875 g/kg/day), and high-dosage (1.75 g/kg/day) for continuous 16 weeks. Blood glucose and body weight were detected every 4 weeks during the experiment. The mechanical pain and morphological change on sciatic nerves were detected by pain measurement instrument and microscopy. The IGF-1 level in serum and tissues were measured though ELISA and immunohistochemistry. The mRNA and protein expressions of IGF-1, IGF-1R, peripheral myelin protein zero (P0), and peripheral myelin protein 22 (PMP22) in the tissues were measured by qRT-PCR and western blot. As a result, JMT had no significant effect on body weight, but reduced the fasting blood glucose levels of diabetic rats. Besides, the pathological morphology, mechanical pain thresholds, serum level and tissue expression of IGF-1, mRNA, and protein levels of IGF-1R, P0, and PMP22 were significantly improved in JMT group at middle dosage. In conclusion, JMT could ameliorate the behavioristics and morphology changes in DPN rats by promoting IGF-1 and IGF-1R gene and protein expressions in sciatic nerves, as well as regulating the peripheral nerve remyelination genes P0 and PMP22 expressions, which provides scientific evidence for the clinical application of JMT in DPN patients.

GLP‑1R agonists ameliorate peripheral nerve dysfunction and inflammation via p38 MAPK/NF‑κB signaling pathways in streptozotocin‑induced diabetic rats.

The present study aimed to investigate the mechanism of glucagon‑like peptide‑1 receptor (GLP‑1R) agonists in the progression of diabetic peripheral neuropathy (DPN) in streptozotocin (STZ)‑induced diabetic rats, through inflammatory signaling pathways. The DPN rat model was generated by intraperitoneal injection of STZ and then treated with the GLP‑1R agonist liraglutide or saline for 8 weeks. These animals were randomly divided into 4groups (10rats in each): The normal control+saline group, the normal control+liraglutide group, the diabetic+saline (DM) group and the diabetic+liraglutide (DML) group. The nerve conduction velocity (NCV) in the sciatic nerves of the rats was monitored over a period of 8weeks. Peripheral serum was obtained for the measurement of blood glucose, tumor necrosis factor‑α (TNF‑α), interleukin‑6 (IL‑6) and IL‑1β level. The protein levels of phosphorylated (p‑) and total extracellular signal‑regulated kinase, c‑Jun NH2‑terminal kinases, p38mitogen‑activated protein kinases (MAPK), and nuclear and cytoplasmic nuclear factor‑κB (NF‑κB) were measured through western blot analysis. Sciatic nerve mRNA expression levels of proinflammatory chemokines (TNF‑α, IL‑6 and IL‑1β), chemokines [monocyte chemoattractant protein‑1 (MCP‑1)], adhesion molecules [intercellular adhesion molecule1 (ICAM‑1)], neurotrophic factors [neuritin, nerve growth factor (NGF) and neuron‑specific enolase(NSE)] and NADPH oxidase4 (NOX4) were evaluated by reverse transcription-quantitative polymerase chain reaction. Subsequent to 8weeks of treatment with liraglutide, the density of myelin nerve fibers was partially restored in the DML group. The delayed motor NCV and sensory NCV in the DML group were improved. The IOD value of NOX4 staining in the DML group (24.43±9.01) was reduced compared with that in the DM group (56.60±6.91). The levels of TNF‑α, IL‑1β and IL‑6 in the peripheral serum of the DML group were significantly suppressed compared with those of the DM group. It was also observed that the mRNA expression levels of TNF‑α, IL‑6, IL‑1β, MCP‑1, ICAM‑1 and NOX4 in the sciatic nerve were attenuated in the DML group. The mRNA expression of neuritin and NGF was significantly increased in the DML group compared with that of the DM group; NSE was reduced in the sciatic nerves of the DML group compared with that of the DM group. Additionally, the protein expression of p‑p38MAPK and NF‑κB in the DML group was significantly suppressed. These data demonstrated that GLP‑1R agonists may prevent nerve dysfunction in the sciatic nerves of diabetic rats via p38MAPK/NF‑κB signaling pathways independent of glycemic control. GLP‑1R agonists may be a useful therapeutic strategy for slowing the progression of DPN.

Potential utility of aldose reductase-deficient Schwann cells IKARS1 for the study of axonal degeneration and regeneration.

Potential utility of aldose reductase-deficient Schwann cells IKARS1 for the study of axonal degeneration and regeneration.

The correlation between insulin and OCT-6 transcription factor in Schwann cells and sciatic nerve of diabetic rats

Insulin signal is one of the vital signaling cascade required for Schwann cells to myelinate the axons of peripheral nervous system (PNS). Myelin formation of peripheral nerve is a complex molecular event controlled by different neurotrophic and transcription factors. The altered or failure in this signaling progression is one of the reasons behind the demyelination of peripheral neurons in diabetic peripheral neuropathy (DPN). The Schwann cell in PNS includes POU domain transcription factor OCT-6 expression. This factor is considered as crucial for the initiation and enhancement of myelination during nerve regeneration. To know the importance of OCT-6 gene, here we studied the long term expression of OCT-6 nuclear protein in sciatic nerve of normal and diabetic neuropathic rats. Also for the first time we elucidated the role of insulin in controlling the expression of OCT-6 in hyperglycemic Schwann cells and sciatic nerve of diabetic neuropathic rats. The results shows that, there will be long term OCT-6 expression in sciatic nerve of adult rats and also their significant decrease is observed in the diabetic condition. But, addition of Insulin for primary Schwann cells and diabetic rats shows the increased OCT-6 expression in both invivo and invitro. Together these results indicate the failure of OCT-6 support in neuropathy and also the importance of insulin signaling cascade in the expression of OCT-6 transcription factor.

Protective effects of methanolic extract of Juglans regia L. leaf on streptozotocin-induced diabetic peripheral neuropathy in rats

BackgroundOxidative stress has a pivotal role in the pathogenesis and development of diabetic peripheral neuropathy (DPN), the most common and debilitating complications of diabetes mellitus. There is accumulating evidence that Juglans regia L. (GRL) leaf extract, a rich source of phenolic components, has hypoglycemic and antioxidative properties. This study aimed to determine the protective effects of Juglans regia L. leaf extract against streptozotocin-induced diabetic neuropathy in rat.MethodsThe DPN rat model was generated by intraperitoneal injection of a single 55 mg/kg dose of streptozotocin (STZ). A subset of the STZ-induced diabetic rats intragastically administered with GRL leaf extract (200 mg/kg/day) before or after the onset of neuropathy, whereas other diabetic rats received only isotonic saline as the same volume of GRL leaf extract. To evaluate the effects of GRL leaf extract on the diabetic neuropathy various parameters, including histopathology and immunohistochemistry of apoptotic and inflammatory factors were assessed along with nociceptive and biochemical assessments.ResultsDegeneration of the sciatic nerves which was detected in the STZ-diabetic rats attenuated after GRL leaf extract administration. Greater caspase-3, COX-2, and iNOS expression could be detected in the STZ-diabetic rats, which were significantly attenuated after GRL leaf extract administration. Also, attenuation of lipid peroxidation and nociceptive response along with improved antioxidant status in the sciatic nerve of diabetic rats were detected after GRL leaf extract administration. In other word, GRL leaf extract ameliorated the behavioral and structural indices of diabetic neuropathy even after the onset of neuropathy, in addition to blood sugar reduction.ConclusionOur results suggest that GRL leaf extract exert preventive and curative effects against STZ-induced diabetic neuropathy in rats which might be due to its antioxidant, anti-inflammatory, and antiapoptotic properties.Graphical abstractProtection against neuropathy

The protective effect of the active components of ERPC on diabetic peripheral neuropathy in rats

Ethnopharmacological relevanceEuonymus alatus, Radix trichosanthis, Panax notoginseng and Coptis chinensis are popular plants used in traditional Chinese medicine to treat diabetes. Aim of the studyThe aim of the study is to investigate the therapeutic effect of the active components of Euonymus alatus, Radix trichosanthis, Panax notoginseng and Coptis chinensis (cERPC) on diabetic peripheral neuropathy in the rats and explore the underlying mechanism involved. MethodsAfter diabetes was induced in rats for 20 weeks, cERPC or water was administered for 12 weeks. After a hot plate test, motor nerve conduction velocity and sciatic nerve blood flow were determined; the sciatic nerves were isolated for toluidine blue staining; and the fibre area, fibre diameter, axon area, axon diameter and myelin thickness were evaluated. The levels of the myelin basic protein, myelin protein zero, Oct6 and Krox20 were measured by western blot or immunofluorescence. ResultscERPC was efficient in reducing the response latency, increasing motor nerve conduction velocity, enhancing sciatic nerve blood flow and ameliorating the pathological changes in diabetic rats. cERPC also had a role in increasing the levels of myelin basic protein and myelin protein zero and improving the expression of Oct6 and Krox20 in sciatic nerves of diabetic rats. ConclusionscERPC ameliorates diabetic peripheral neuropathy by attenuating electrophysiological, circulatory and morphological alterations, which is mediated by the Oct6-Krox20 pathway.