Peripheral nerve stimulation is commonly used for nerve localization in regional anaesthesia, but recommended stimulation currents of 0.3-0.5 mA do not reliably produce motor activity in the absence of intraneural needle placement. As this may be particularly true in patients with diabetic neuropathy, we examined the stimulation threshold in patients with and without diabetes.

To examine the effects of Cerebrolysin on the treatment of diabetic peripheral neuropathy, we first established a mouse model of type 2 diabetes mellitus by administering a high-glucose, high-fat diet and a single intraperitoneal injection of streptozotocin. Mice defined as diabetic in this model were then treated with 1.80, 5.39 or 8.98 mL/kg of Cerebrolysin via intraperitoneal injections for 10 consecutive days. Our results demonstrated that the number, diameter and area of myelinated nerve fibers increased in the sciatic nerves of these mice after administration of Cerebrolysin. The results of several behavioral tests showed that Cerebrolysin dose-dependently increased the slope angle in the inclined plane test (indicating an improved ability to maintain body position), prolonged tail-flick latency and foot-licking time (indicating enhanced sensitivity to thermal and chemical pain, respectively, and reduced pain thresholds), and increased an index of sciatic nerve function in diabetic mice compared with those behavioral results in untreated diabetic mice. Taken together, the anatomical and functional results suggest that Cerebrolysin ameliorated peripheral neuropathy in a mouse model of type 2 diabetes mellitus.

Clinical and histological studies have found evidence that nerve ischemia is a major contributor to diabetic neuropathy (DN) in type 2 diabetes (T2D). The aim of this study was to investigate peripheral nerve microvascular permeability using dynamic contrast enhanced (DCE) magnetic resonance neurography (MRN) to analyze potential correlations with clinical, electrophysiological, and demographic data.

The present study aimed to explore novel target genes that regulate the development of diabetic neuropathy (DN) by analyzing gene expression profiles in the sciatic nerve of infected mice. The GSE11343 microarray dataset, which was downloaded from Gene Expression Omnibus, included data on 4 control samples and 5 samples from mice with diabetes induced by streptozotocin (STZ), 5 samples from normal mice treated with rosiglitazone (Rosi) and 5 samples from mice with diabetes induced by STZ and treated with Rosi. Differentially expressed genes (DEGs) between the different groups were identified using the substitution augmentation modification redefinition (SAMR) model. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID). Regulatory and protein‑protein interaction networks were searched using BioCarta and STRING, respectively. The protein structures of potential regulatory genes were predicted using the SYBYL program. Compared with the controls, 1,384 DEGs were identified in the mice with STZ-induced diabetes and 7 DEGs were identified in the mice treated with Rosi. There were 518 DEGs identified between the mice in the STZ + Rosi and STZ groups. We identified 45 GO items, and the calmodulin nerve phosphatase and chemokine signaling pathways were identified as the main pathways. Three genes [myristoylated alanine-rich protein kinase C substrate (Marcks), GLI pathogenesis-related 2 (Glipr2) and centrosomal protein 170 kDa (Cep170)] were found to be co-regulated by both STZ and Rosi, the protein structure of which was predicted and certain binding activity to Rosi was docked. Our study demonstrates that the Marcks, Glipr2 and Cep170 genes may be underlying drug targets in the treatment of DN.

Compressive neuropathy is a recurring and challenging disease for patients, regardless of medical or surgical treatment. Neuropathological severity is associated with the force of mechanical compression. Available animal models do not address mechanical issues with reproducible outcomes. We used a chronic constriction injury model to analyze tension-controlled compressive neuropathy and achieve reproducible functional outcomes.

To investigate the candidate biomarkers and molecular mechanisms involved in the early phase of experimental diabetic peripheral neuropathy (DPN).

Background: Peripheral nerve block (PNB) under echo guidance may not prevent intrafascicular anesthetic injection-induced nerve injury. This study investigated whether unintended needle piercing alone, or the intrafascicular nerve injectant could induce neuropathy. Methods: 120 adult male Sprague-Dawley rats were divided into four groups: 1) group S, only the left sciatic nerve was exposed; 2) group InF-P, the left sciatic nerve was exposed and pierced with a 30 G needle; 3) group InF-S, left sciatic nerve was exposed and injected with saline (0.9% NaCl 30 µL); 4) group InF-R, left sciatic nerve was exposed and injected with 0.5% (5 mg/mL, 30 µL) ropivacaine. Behaviors of thermal and mechanical stimuli responses from hindpaws, sciatic nerve vascular permeability and tight junction protein expression, and macrophage infiltration were assessed. Pro-inflammatory cytokine expression and TIMP-1 and MMP-9 activation at the injection site and the swollen, and distal sites of the sciatic nerve were measured by cytokine array, western blotting, and immunofluorescence of POh14 and POD3. Results: Intrafascicular saline and ropivacaine into the sciatic nerve, but not needle piercing alone, significantly induced mechanical allodynia that lasted for seven days. In addition, the prior groups increased vascular permeability and macrophage infiltration, especially in the swollen site of the sciatic nerve. Thermal hypersensitivity was induced and lasted for only 3 days after intrafascicular saline injection. Obvious upregulation of TIMP-1 and MMP-9 on POh6 and POh14 occurred regardless of intrafascicular injection or needle piercing. Compared to the needle piercing group, the ratio of MMP-9/TIMP-1 was significantly higher in the intrafascicular injectant groups at the injected and swollen sites of the sciatic nerve. Although no gross changes in the expressions of tight junction proteins (TJPs) claudin-5 and ZO-1, the TJPs turned to apparent fragmentation and fenestration-like degenerative change in swollen endothelial cells and thickened microvessels. Conclusion: Intrafascicular nerve injection is a distinct mechanism that induces neuropathy. It is likely that the InF nerve injection-induced neuropathy was largely due to dramatic, but transient, increases in enzymatic activities of MMP-9 and activating TIMP-1 in the operated nerves. The changes in enzymatic activities then contributed to certain levels of extracellular matrix degradation, which leads to increases in endoneurial vascular permeability.

Leptin-deficient ob/ob mice are a model of type 2 diabetes induced peripheral neuropathy. Ob/ob mice exhibit obesity, insulin resistance, hyperglycaemia, and alterations of peripheral nerve fibres and endoneural microvessels. Here we test the hypothesis that cartilage oligomeric matrix protein (COMP)-Ang-1, a soluble and stabile form of Ang-1 which promotes angiogenesis and nerve growth, improves regeneration of nerve fibres and endoneural microvessels in ob/ob mice.

Chemotherapy-induced peripheral neuropathy is a neurological complication that frequently occurs during chemotherapeutic intervention, resulting in damaged myelin sheath, motor weakness and/or sensory impairment. This study aims to investigate the therapeutic efficiency of low-intensity pulsed low-frequency ultrasound on cisplatin-induced peripheral neuropathy. Rats were randomly divided into five experimental groups as control, cisplatin administration, 10 mg/kg melatonin treatment after cisplatin administration, 1 MHz frequency 0.5 W/cm2 pulsed ultrasound treatment after cisplatin administration and 1 MHz frequency 1.5 W/cm2 pulsed ultrasound treatment after cisplatin administration. Chemical neuropathy was induced by the injection of 3 mg/kg/week of cisplatin (i.p.) for 5 weeks. Afterwards, melatonin and pulsed ultrasound treatments were applied for 15 consecutive days. Cisplatin administration resulted in a decrease in nociceptive pain perception and nerve conduction velocities together with a decrease in myelin thickness and diameters of axons and myelinated fibers, indicating a dysfunction and degeneration in sciatic nerves. In addition, cisplatin administration led to a decrease, in superoxide dismutase activity, and an increase in malondialdehyde and IL-1β levels together with an increase in caspase-3 protein expression levels and a decrease in Bcl-2 and Parkin levels. The ultrasound treatments resulted in an increase in nociceptive pain perception and sciatic nerve conduction; led to a decrease in oxidative stress and inflammation, restored nerve degeneration and regulated apoptosis and mitophagy. Taken together, low-intensity pulsed low-frequency ultrasound was efficient in restoring the alterations attributable to cisplatin-induced peripheral neuropathy, and warrants further investigations.

Diabetic neuropathy (DN) is one of the chronic complications of diabetes which can cause severe harm to patients. In order to determine the key genes and pathways related to the pathogenesis of DN, we downloaded the microarray data set GSE27382 from Gene Expression Omnibus (GEO) and adopted bioinformatics methods for comprehensive analysis, including functional enrichment, construction of PPI networks, central genes screening, TFs-target interaction analysis, and evaluation of immune infiltration characteristics. Finally, we examined quantitative real- time PCR (qPCR) to validate the expression of hub genes. A total of 318 differentially expressed genes (DEGs) were identified, among which 125 upregulated DEGs were enriched in the mitotic nuclear division, extracellular region, immunoglobulin receptor binding, and p53 signaling pathway, while 193 downregulated DEGs were enriched in ion transport, membrane, synapse, sodium channel activity, and retrograde endocannabinoid signaling. GSEA plots showed that condensed nuclear chromosome kinetochore were the most significant enriched gene set positively correlated with the DN group. Importantly, we identified five central genes (Birc5, Bub1, Cdk1, Ccnb2, and Ccnb1), and KEGG pathway analysis showed that the five hub genes were focused on progesterone-mediated oocyte maturation, cell cycle, and p53 signaling pathway. The proportion of immune cells from DN tissue and normal group showed significant individual differences. In DN samples, T cells CD4 memory resting and dendritic cells resting accounted for a higher proportion, and macrophage M2 accounted for a lower proportion. In addition, all five central genes showed consistent correlation with immune cell infiltration levels. qPCR showed the same expression trend of five central genes as in our analysis. Our research identified key genes related to differential genes and immune infiltration related to the pathogenesis of DN and provided new diagnostic and potential therapeutic targets for DN.

Painful peripheral neuropathy is a significant clinical problem; however, its pathological mechanism and effective treatments remain elusive. Increased peripheral expression of tetrodotoxin-resistant voltage-gated sodium channel 1.8 (NaV1.8) has been shown to associate with chronic pain symptoms in humans and experimental animals. Sciatic nerve entrapment (SNE) injury was used to develop neuropathic pain symptoms in rats, resulting in increased NaV1.8 mRNA in the injured nerve but not in dorsal root ganglia (DRG). To study the role of NaV1.8 mRNA in the pathogenesis of SNE-induced painful neuropathy, NaV1.8 shRNA vector was delivered by subcutaneous injection of cationized gelatin/plasmid DNA polyplex into the rat hindpaw and its subsequent retrograde transport via sciatic nerve to DRG. This in vivo NaV1.8 shRNA treatment reversibly and repeatedly attenuated the SNE-induced pain symptoms, an effect that became apparent following a distinct lag period of 3-4 days and lasted for 4-6 days before returning to pretreatment levels. Surprisingly, apparent knockdown of NaV1.8 mRNA occurred only in the injured nerve, not in the DRG, during the pain alleviation period. Levels of heteronuclear NaV1.8 RNA were unaffected by SNE or shRNA treatments, suggesting that transcription of the Scn10a gene encoding NaV1.8 was unchanged. Based on these data, we postulate that increased axonal mRNA transport results in accumulation of functional NaV1.8 protein in the injured nerve and the development of painful neuropathy symptoms. Thus, targeted delivery of agents that interfere with axonal NaV1.8 mRNA may represent effective neuropathic pain treatments.

Ischemia and hypoxia are important physiological changes in diabetic peripheral neuropathy (DPN). Chinese herbal medicine prescription Tangkuei Decoction for Frigid Extremities (TDFE) is useful for increasing blood flow. To help determine whether TDFE could protect the peripheral nerves of diabetic patients from the degeneration caused by high blood glucose, TDFE was administered to streptozotocin-induced diabetic rats for 6 or 12 weeks. Plantar thermal stimulation reaction time thresholds, sciatic nerve conduction velocities, and the levels of HIF-1α mRNA, HIF-1α protein, VEGF protein, and the endothelial marker vWF in sciatic nerves were measured at the end of the sixth and twelfth weeks. The thermal thresholds and sciatic nerve conduction velocities of the rats differed after 12 weeks, and the sciatic nerves of the diabetic rats that were given TDFE displayed higher levels of HIF-1α protein, VEGF protein, and HIF-1α mRNA than those of the diabetic model rats. The results at 6 weeks differed from those at 12 weeks. These results suggest that the early preventive application of TDFE effectively delayed the development of DPN and that TDFE increased HIF-1α mRNA levels in the sciatic nerves of diabetic rats through 12 weeks of treatment.

Ischemia-reperfusion (IR) in the rat femoral artery has been proposed as an experimental model of vasculitic peripheral neuropathy (VPN) which presents neuropathic pain and peripheral nerve injury patterns observed clinically. This study investigates the involvement of the proinflammatory signaling pathway underlying the peripheral mechanisms of VPN. Male Sprague-Dawley rats were allocated to receive either a sham operation or IR. IR was induced by occluding the right femoral artery for 4h followed by reperfusion periods from 0 to 72h. The behavioral parameters were assessed at baseline as well as at days 1, 2 and 3 after reperfusion. The time-course analyses of proinflammatory mediators in the sciatic nerves were also performed on rats of the sham group or IR groups with reperfusion periods of 0, 2, 4, 24 and 72h, respectively. The behavioral data confirmed that this VPN model induced hindpaw mechano-allodynia and heat hyperalgesia as well as impaired hindpaw grip strength. The molecular data revealed that IR in the femoral artery activated the expression of nuclear factor-κB (NF-κB) in the sciatic nerve indicating a neuroinflammatory response. Moreover, IR in the femoral artery increased the expression of proinflammatory cytokines TNF-α and IL-1β in the sciatic nerve. This study elucidated the novel time-course expression profiles of NF-κB and proinflammatory cytokines in VPN induced by IR which may be involved in the development of neuropathic pain. Since NF-κB is a key element during neuroinflammation, strategies targeting the NF-κB signaling pathway may provide therapeutic potential against VPN induced by IR.

Diabetic neuropathy is the most common complication of diabetes mellitus affecting the nervous system. In this study, we investigated the in vivo effects of combined administration of 4-methylcatechol (4-MC) and progesterone (P) as a potential therapeutic tool for sciatic nerve function improvement and its role in histomorphological alterations in diabetic neuropathy in rats.

Diabetes mellitus is the most common metabolic disease with a high prevalence rate in human society that eventually leads to the peripheral nervous system complications in a great number of patients. In the present study, the effects of Angipars on nerve conduction velocity, histological alterations, and behavioral indices were investigated. Diabetes was induced in male rats by intraperitoneal injection of streptozotocin (STZ). Six weeks after STZ injection, animals were divided into five groups control, vehicle, and 3 experimental groups. The vehicle group received 1 mL distilled water daily for two weeks and three experimental groups received, respectively, intraperitoneal injection of 5, 10, and 20 mg/kg Angipars daily for two weeks. Intraperitoneal injection of Angipars, in some extent, could significantly improve behavioral indices of the experimental groups as compared to the vehicle group. Furthermore, mean nerve conduction velocity in the vehicle group showed significant difference with that in the control and the 2nd experimental groups; therefore, Angipars could increase nerve conduction velocity in neuropathic rats. Overall, Angipars exerted positive effects on the treatment and reduction of physiologic symptoms and improvement of sciatic morphological injuries in neuropathic rats.

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.

The effect of glycemic variability (GV) on diabetic neuropathy, including diabetic central neuropathy and diabetic peripheral neuropathy (DPN), and the involved mechanism are not fully understood. In this study, a fluctuant hyperglycemia rat model was induced by alternate intraperitoneal injections of glucose and insulin. To assess diabetic central neuropathy, step-down type passive avoidance tests were conducted, and the expression levels of p-Tau, T-Tau, p-GSK3β, GSK3β, p-Akt, and Akt in the hippocampus were measured. To assess DPN, the motor nerve conduction velocity (MNCV) was measured, and the microstructure of the sciatic nerve was observed. Additionally, the expression levels of oxidative stress and inflammation indicators were detected in the sciatic nerve. We observed that both learning and memory abilities were disrupted by GV. GV promoted Tau phosphorylation and inhibited the Akt/GSK3β pathway in the hippocampus. Additionally, GV weakened the MNCV of the sciatic nerve, and the structures of both the myelin sheath and the axons in the sciatic nerve were disrupted. GV also significantly reduced the expression of superoxide dismutase (SOD) and increased the expression levels of malondialdehyde (MDA), of proinflammatory cytokines (TNF-α and IL-6) and of NF-κB. In conclusion, the present study highlighted that GV might induce diabetic central neuropathy through the hyperphosphorylation of Tau in the hippocampus by inhibiting the Akt/GSK3β pathway and that it may cause DPN through oxidative stress and inflammatory responses by activating the NF-κB pathway.

Immune-mediated small fiber neuropathy (SFN) is increasingly recognized. Acute-onset SFN (AOSFN) remains poorly described. Herein, we report a series of AOSFN cases in which immune origins are debatable.

We hypothesized that intranasal insulin (I-I) delivery targets the nervous system while avoiding potential adverse systemic effects when compared with subcutaneous insulin (S-I) for experimental streptozotocin-induced diabetic peripheral neuropathy (DPN).

Alcoholic neuropathy (AN), a debilitating condition that mainly affects chronic alcohol drinkers, is thought to cause lesions in the peripheral nervous system leading to sensory, autonomic, and motor dysfunctions. Despite many studies, the pathogenesis of these lesions is still not completely understood. We investigated few aspects on the development of alcohol-induced peripheral neuropathy, by assessing sensory, motor and autonomic functions, as well as stereological analysis of axonal fibers and myelin sheath of the sciatic nerve. Twelve male Wistar rats were divided into Control group and Alcohol group that was submitted to Two Bottle-Choice Paradigm of intermittent and voluntary alcohol solution intake (20%; v/v) during eight weeks. At the end of treatment, three different sensorium-motor tests were applied - Tactile Sensitivity, Thermal Sensitivity, and Functional Observational Battery (FOB). Quantitative morphometric analysis of sciatic nerve structures was performed by stereological method. Alcohol concentration in the blood was measured to analyze possible correlation between availability of alcohol in the blood and the magnitude of the peripheral nerve lesion. Our data showed a peripheral effect of chronic alcohol intake associated with hyperalgesia and a process of demyelination with a strong correlation with alcohol consumption. This process was associated with increased tactile sensitivity, with behavioral reflexes such as locomotor hyperactivity, changes in gait and balance, and autonomic reflexes such as piloerection.