Peripheral Nerve Development and the Pathogenesis of Peripheral Neuropathy: the Sorting Point.
Ontology highlight
ABSTRACT:
SUBMITTER: Previtali SC
PROVIDER: S-EPMC8804061 | biostudies-literature | 2021 Oct
REPOSITORIES: biostudies-literature
Publications
Peripheral Nerve Development and the Pathogenesis of Peripheral Neuropathy: the Sorting Point.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 20210709 4
Nerve development requires a coordinated sequence of events and steps to be accomplished for the generation of functional peripheral nerves to convey sensory and motor signals. Any abnormality during development may result in pathological structure and function of the nerve, which evolves in peripheral neuropathy. In this review, we will briefly describe different steps of nerve development while we will mostly focus on the molecular mechanisms involved in radial sorting of axons, one of these n ...[more]
Similar Datasets
Project description:BackgroundDiabetic peripheral neuropathy (DPN) is a prevalent and serious complication of diabetes mellitus, impacting the nerves in the limbs and leading to symptoms like pain, numbness, and diminished function. While the exact molecular and immune mechanisms underlying DPN remain incompletely understood, recent findings indicate that mitochondrial dysfunction may play a role in the advancement of this diabetic condition.MethodsTwo RNA transcriptome datasets (codes: GSE185011 and GSE95849), comprising samples from diabetic peripheral neuropathy (DPN) patients and healthy controls (HC), were retrieved from the Gene Expression Omnibus (GEO) database hosted by the National Center for Biotechnology Information (NCBI). Subsequently, differential expression analysis and gene set enrichment analysis were performed. Protein-protein interaction (PPI) networks were constructed to pinpoint key hub genes associated with DPN, with a specific emphasis on genes related to mitochondria and peripheral neuropathy disease (PND) that displayed differential expression. Additionally, the study estimated the levels of immune cell infiltration in both the HC and DPN samples. To validate the findings, quantitative polymerase chain reaction (qPCR) was employed to confirm the differential expression of selected genes in the DPN samples.ResultsThis research identifies four hub genes associated mitochondria or PN. Furthermore, the analysis revealed increased immune cell infiltration in DPN tissues, particularly notable for macrophages and T cells. Additionally, our investigation identified potential drug candidates capable of regulating the expression of the four hub genes. These findings were corroborated by qPCR results, reinforcing the credibility of our bioinformatics analysis.ConclusionsThis study provides a comprehensive overview of the molecular and immunological characteristics of DPN, based on both bioinformatics and experimental methods.
| S-EPMC10936109 | biostudies-literature
Project description:Bortezomib-induced peripheral neuropathy (BiPN) occurs in approximately 40% of patients with multiple myeloma. The induction of severe neuropathy entails the dose reduction or complete elimination of bortezomib (BTZ). Interestingly, discontinuation of BTZ mostly results in a reduction or complete resolution of peripheral neuropathy (PN) symptoms. Therefore, it is likely that the BiPN mechanisms are based on temporary/reversible changes such as epigenetic alterations. In this study, we examined the effect of treating nerve cells, differentiated from the Lund human mesencephalic (dLUHMES) cell line, with several low-dose BTZ (0.15 nM) applications. We showed a significant decrease in global histone H3 acetylation as well as histone H3 lysine 9 acetylation. Moreover, analysis of the genetic microarray showed changes mainly in epigenetic processes related to chromatin rearrangement, chromatin silencing, and gene silencing. GSEA analysis revealed three interesting signaling pathways (SIRT1, B-WICH and, b-Catenin) that may play a pivotal role in PN development. We also performed an analysis of the miRNA microarray which showed the interactions of miR-6810-5p with the genes MSN, FOXM1, TSPAN9, and SLC1A5, which are directly involved in neuroprotective processes, neuronal differentiation, and signal transduction. The study confirmed the existence of BTZ-induced complex epigenetic alterations in nerve cells. However, further studies are necessary to assess the reversibility of epigenetic changes and their potential impact on the induction/resolution of PN.
| S-EPMC8910765 | biostudies-literature
Project description:BackgroundChemotherapy-induced peripheral neuropathy is a severe side effect of chemotherapeutic agents. Vagus nerve stimulation attenuates neuroinflammation by activating the cholinergic anti-inflammatory pathway and thus may attenuate CIPN.MethodsAdult male Sprague-Dawley rats received intraperitoneal paclitaxel injection (2 mg/kg) every other day for a total of 4 injections. Three weeks later, the left cervical vagus nerve was exposed under general anesthesia, and the rats randomly received 20-min stimulation (1 V, 2 ms, 5 Hz, 30 s ON/5 min OFF) or sham stimulation. Heat and mechanical pain sensitivity was evaluated using Hargreaves and von Frey tests before and after treatment (n=12 per group per time point). Additionally, rats receiving paclitaxel or saline but no surgery were included. Expression of representative pro- and anti-inflammatory cytokines in dorsal root ganglia was assessed by Western blotting assays and immunohistochemistry.ResultsPaclitaxel significantly reduced the sensitivity for heat (withdrawal latency: paclitaxel 6.16 ± 0.54 s vs saline 9.93 ± 0.78 s, p<0.001) and mechanical pain (withdrawal frequency: paclitaxel 32.22 ± 15.51% vs saline 3.33 ± 4.92%, p<0.001). Compared with sham-stimulated rats, rats receiving vagus nerve stimulation had significantly higher sensitivity for heat (withdrawal latency: VNS 10.28 ± 1.15 s vs sham 6.27 ± 0.56 s, p<0.001) and mechanical pain (withdrawal frequency: VNS 10.00 ± 9.54% vs Sham 31.67 ± 18.99%, p=0.003) on +1 day, but not 7 days later (withdrawal latency: VNS 6.97 ± 1.13 s vs Sham 6.23 ± 0.79 s, p=0.080; withdrawal frequency: VNS 21.67 ± 11.93% vs Sham 23.33 ± 7.79%, p=0.689). Western blotting assays and immunohistochemistry revealed that interleukin-10 level was elevated in the dorsal root ganglia of rats receiving vagus nerve stimulation while no apparent changes in NF-κB or TNF-α levels were observed.ConclusionVagus nerve stimulation could transiently attenuate paclitaxel-induced hyperalgesia in rats. Future studies are needed to investigate whether stimulation with different protocols could achieve durable effects.
| S-EPMC7764936 | biostudies-literature
Project description:The peripheral nervous system has astonishing regenerative capabilities in that cut nerves are able to reconnect and re-establish their function. Schwann cells are important players in this process, during which they dedifferentiate to a progenitor/stem cell and promote axonal regrowth. Here, we report that fibroblasts also play a key role. Upon nerve cut, ephrin-B/EphB2 signaling between fibroblasts and Schwann cells results in cell sorting, followed by directional collective cell migration of Schwann cells out of the nerve stumps to guide regrowing axons across the wound. Mechanistically, we find that cell-sorting downstream of EphB2 is mediated by the stemness factor Sox2 through N-cadherin relocalization to Schwann cell-cell contacts. In vivo, loss of EphB2 signaling impaired organized migration of Schwann cells, resulting in misdirected axonal regrowth. Our results identify a link between Ephs and Sox proteins, providing a mechanism by which progenitor cells can translate environmental cues to orchestrate the formation of new tissue.
| S-EPMC3826531 | biostudies-literature
Project description:BackgroundOxaliplatin-induced peripheral neurotoxicity (OIPN) limits the dose of chemotherapy and seriously affects the quality of life. Huangqi Guizhi Wuwu Decoction (HGWD) is a classical Traditional Chinese Medicine (TCM) formula for the prevention of OIPN. However, its specific pharmacological mechanism of action remains unknown. Our study found that HGWD can effectively alleviate chronic OIPN and regulate intestinal flora. Therefore, we explored the mechanism of action of HGWD in alleviating chronic OIPN from the perspective of intestinal flora.MethodsIn this study, we established an OIPN model in C57BL/6 mice treated with different concentrations of HGWD. Mechanical pain and cold pain were assessed at certain time points, and samples of mice colon, dorsal root ganglion (DRG), serum, and feces were collected. Associated inflammation levels in the colon and DRG were detected using immunohistochemical techniques; the serum lipopolysaccharide (LPS) levels and associated inflammation were assessed using the appropriate kits; and 16S rRNA sequencing was used to examine the dynamic changes in gut microorganisms. Finally, established fecal microbiota transplantation (FMT) and antibiotic (ABX) pretreatment models were used to validate flora's role in HGWD for chronic OIPN by pain scoring and related pathological analysis.ResultsHGWD treatment significantly alleviated pain sensitivity in chronic OIPN mice. Pathological results showed that HGWD treatment improved intestinal ZO-1 expression and reduced serum LPS levels and associated inflammatory factors in the colon, serum, and DRG. The 16S rRNA results showed that HGWD restored the composition of the intestinal flora in a time-dependent manner to alleviate OIPN. FMT and ABX experiments demonstrated that HGWD can alleviate chronic OIPN by regulating intestinal flora homeostasis.ConclusionsHGWD prevents chronic OIPN by dynamically regulating intestinal flora homeostasis, thereby ameliorating intestinal barrier damage and reducing serum LPS and relevant inflammatory factor levels in the colon, serum, and DRG.
| S-EPMC10485938 | biostudies-literature
Project description:Diabetic peripheral neuropathy (DPN) occurs in up to half of individuals with type 1 or type 2 diabetes. DPN results from the distal-to-proximal loss of peripheral nerve function, leading to physical disability and sometimes pain, with the consequent lowering of quality of life. Early diagnosis improves clinical outcomes, but many patients still develop neuropathy. Hyperglycaemia is a risk factor and glycaemic control prevents DPN development in type 1 diabetes. However, glycaemic control has modest or no benefit in individuals with type 2 diabetes, probably because they usually have comorbidities. Among them, the metabolic syndrome is a major risk factor for DPN. The pathophysiology of DPN is complex, but mechanisms converge on a unifying theme of bioenergetic failure in the peripheral nerves due to their unique anatomy. Current clinical management focuses on controlling diabetes, the metabolic syndrome, and pain, but remains suboptimal for most patients. Thus, research is ongoing to improve early diagnosis and prognosis, to identify molecular mechanisms that could lead to therapeutic targets, and to investigate lifestyle interventions to improve clinical outcomes.
| S-EPMC10112836 | biostudies-literature
Project description:We aimed to assess DPNCheck's reliability for repeated sural nerve conduction (NC) parameters. This post hoc analysis used data from the randomized controlled ACUDPN trial assessing NC of the N. Suralis every eight weeks over a 6-month period in 62 patients receiving acupuncture against diabetic peripheral neuropathy (DPN) symptoms. The reliability of DPNCheck for nerve conduction velocity and amplitude was assessed using intraclass correlation coefficients (ICC) and was calculated using data from single time points and repeated measures design. The results of the NC measurements were correlated with the Total Neuropathy Score clinical (TNSc). Overall, for both nerve velocity and amplitude, the reliability at each measurement time point can be described as moderate to good and the reliability using repeated measures design can be described as moderate. Nerve velocity and amplitude showed weak correlation with TNSc. DPNCheck's reliability results question its suitability for monitoring DPN's progression. Given the limitation of our analysis, a long-term, pre-specified, fully crossed study should be carried out among patients with DPN to fully determine the suitability of the device for DPN progression monitoring. This was the first analysis assessing the reliability of the DPNCheck for DPN progression monitoring using data from multiple collection time points.
| S-EPMC10624654 | biostudies-literature
Project description:BackgroundWe have found that erbB receptor tyrosine kinases drive Ras hyperactivation and growth in NF1-null malignant peripheral nerve sheath tumors (MPNSTs). However, MPNSTs variably express multiple erbB receptors with distinct functional characteristics and it is not clear which of these receptors drive MPNST pathogenesis. Here, we test the hypothesis that altered erbB4 expression promotes MPNST pathogenesis by uniquely activating key cytoplasmic signaling cascades.MethodsErbB4 expression was assessed using immunohistochemistry, immunocytochemistry, immunoblotting and real-time PCR. To define erbB4 functions, we generated mice that develop MPNSTs with floxed Erbb4 alleles (P0-GGFβ3;Trp53+/-;Erbb4flox/flox mice) and ablated Erbb4 in these tumors. MPNST cell proliferation and survival was assessed using 3H-thymidine incorporation, MTT assays, Real-Time Glo and cell count assays. Control and Erbb4-null MPNST cells were orthotopically xenografted in immunodeficient mice and the growth, proliferation (Ki67 labeling), apoptosis (TUNEL labeling) and angiogenesis of these grafts was analyzed. Antibody arrays querying cytoplasmic kinases were used to identify erbB4-responsive kinases. Pharmacologic or genetic inhibition was used to identify erbB4-responsive kinases that drive proliferation.ResultsAberrant erbB4 expression was evident in 25/30 surgically resected human MPNSTs and in MPNSTs from genetically engineered mouse models (P0-GGFβ3 and P0-GGFβ3;Trp53+/- mice); multiple erbB4 splice variants that differ in their ability to activate PI3 kinase and nuclear signaling were present in MPNST-derived cell lines. Erbb4-null MPNST cells demonstrated decreased proliferation and survival and altered morphology relative to non-ablated controls. Orthotopic allografts of Erbb4-null cells were significantly smaller than controls, with reduced proliferation, survival and vascularization. ERBB4 knockdown in human MPNST cells similarly inhibited DNA synthesis and viability. Although we have previously shown that broad-spectrum erbB inhibitors inhibit Ras activation, Erbb4 ablation did not affect Ras activation, suggesting that erbB4 drives neoplasia via non-Ras dependent pathways. An analysis of 43 candidate kinases identified multiple NRG1β-responsive and erbB4-dependent signaling cascades including the PI3K, WNK1, STAT3, STAT5 and phospholipase-Cγ pathways. Although WNK1 inhibition did not alter proliferation, inhibition of STAT3, STAT5 and phospholipase-Cγ markedly reduced proliferation.ConclusionsErbB4 promotes MPNST growth by activating key non-Ras dependent signaling cascades including the STAT3, STAT5 and phospholipase-Cγ pathways. ErbB4 and its effector pathways are thus potentially useful therapeutic targets in MPNSTs.
| S-EPMC6621970 | biostudies-literature
Project description:IntroductionHansen's disease (HD) is the most common cause of treatable peripheral neuropathy in the world that may or may not involve skin manifestations, and physical examination based on simplified neurologic evaluation is a subjective and inaccurate procedure. High-resolution ultrasound (HRUS) can be used to evaluate peripheral nerves and is a validated technique of good reproducibility, permitting a detailed and precise examination.ObjectivesWe proposed to establish objective criteria for absolute values of the measurement of the CSA of peripheral nerves and their indices of the ΔCSA and ΔTpT in the diagnosis of Hansen's disease neuropathy as compared with healthy voluntaries.Materials and methodsIn municipalities from different regions of Brazil, we randomly selected 234 volunteer Brazilian patients diagnosed with leprosy to be submitted to peripheral nerve echography and compared with 49 healthy Brazilian volunteers.ResultsHansen Disease assessed by high resolution ultrasound is a primarily neural disease that leads to multiple hypertrophic mononeuropathy characterized by CSA values exceeding normal limits (Med CT = 10.2 mm2; UT = 9.8 mm2; UPT = 9.3 mm2; CFFH = 18.3 mm2; T = 9.6 mm2), and the pattern of asymmetry (ΔCSA>2.5 mm2 with RR 13) and focality (ΔTPT > 2.5 mm2 with RR 6.4) of this thickening has higher sensitivity (76,1%) and specificity (87,8 %) for its early diagnosis that laboratory tests. Analyzing each subject, the percentage of thickened nerves detected among the total number of nerves assessed was higher among patients with HD than among healthy individuals (p < 0.0001). Individuals with two or more thickened nerves were at 24.1 times higher relative risk (95% CI: 6.74-88.98) of HD.
| S-EPMC9504868 | biostudies-literature
Project description:ObjectivePeripheral nerve imaging by portable ultrasound (US) may serve as a noninvasive and lower-cost alternative to nerve conduction studies (NCS) for diagnosis and staging of diabetic sensorimotor polyneuropathy (DSP). We aimed to examine the association between the size of the posterior tibial nerve (PTN) and the presence and severity of DSP.Research design and methodsWe performed a cross-sectional study of 98 consecutive diabetic patients classified by NCS as subjects with DSP or control subjects. Severity was determined using the Toronto Clinical Neuropathy Score. A masked expert sonographer measured the cross-sectional area (CSA) of the PTN at 1, 3, and 5 cm proximal to the medial malleolus.ResultsFifty-five patients had DSP. The mean CSA of the PTN in DSP compared with control subjects at distances of 1 (23.03 vs. 17.72 mm(2); P = 0.004), 3 (22.59 vs. 17.69 mm(2); P < 0.0001), and 5 cm (22.05 vs. 17.25 mm(2); P = 0.0005) proximal to the medial malleolus was significantly larger. Although the area under the curve (AUC) for CSA measurements at all three anatomical levels was similar, the CSA measured at 3 cm above the medial malleolus had an optimal threshold value for identification of DSP (19.01 mm(2)) with a sensitivity of 0.69 and a specificity of 0.77 by AUC analysis.ConclusionsThis large study of diabetic patients confirms that the CSA of the PTN is larger in patients with DSP than in control subjects, and US is a promising point-of-care screening tool for DSP.
| S-EPMC3507587 | biostudies-literature