Nerve Fiber Injury Research Articles

LncRNA Kcnq1ot1relieves neuropathic pain through downregulation of Myd88.

Long non-coding RNAs (lncRNAs) have already been documented to become the therapeutic targets for neuropathic pain. Here, this work focused on exploring the specific mechanism underlying Kcnq1 overlapping transcript 1 (kcnq1ot1) in neuropathic pain. Sciatic nerve chronic constriction injury (CCI) in vivo and LPS-stimulated microglia BV2 cell injury in vitro were adopted to construct neuropathic pain models. Expressions of kcnq1ot1, MyD88, and microglia activation marker Iba-1 were measured. In this study, we carried out fluorescence in-situ Hybridization (FISH) and immunofluorescence for examining Kcnq1ot1 localization within microglial cells in mouse spinal dorsal horn. Subsequently, we evaluated binding between Kcnq1ot1 and Myd88, together with the expressions of IL-1β, IL-6, TNF-α, and Myd88 ubiquitination. Kcnq1ot1 levels decreased within CCI mice and LPS-induced BV2 cells. According to the results of FISH and immunofluorescence, Kcnq1ot1 is located in microglia. Overexpression of Kcnq1ot1 suppressed Iba-1, IL-1β, IL-6 together with TNF-α expression. RNA pull-down and RIP assay confirmed that Kcnq1ot1 bound to Myd88. In addition, Kcnq1ot1 overexpression promoted the degradation, enhanced the ubiquitination, and reduced protein level of Myd88. Overexpression of Myd88 eliminated the effects of Kcnq1ot1 overexpression on Iba-1level and production of pro-inflammatory cytokines. Further in vivo results revealed that increased Kcnq1ot1 level alleviated neuropathic pain and myelinated nerve fiber injury of CCI mice. Kcnq1ot1 downregulated Myd88 protein expression by binding to Myd88 and promoting its ubiquitination, which in turn suppressed microglia activation, pro-inflammatory cytokine production, and relieved neuropathic pain.

Corneal nerve loss and increased Langerhans cells are associated with disease severity in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a multisystem autoimmune disorder characterized by articular and extra-articular manifestations. Neuropathy is a poorly studied manifestation of RA. The aim of this study was to utilize the rapid non-invasive ophthalmic imaging technique of corneal confocal microscopy to identify whether there is evidence of small nerve fibre injury and immune cell activation in patients with RA. Fifty consecutive patients with RA and 35 healthy control participants were enrolled in this single-centre, cross-sectional study conducted at a university hospital. Disease activity was assessed with the 28-Joint Disease Activity Score and erythrocyte sedimentation rate (DAS28-ESR). Central corneal sensitivity was measured with a Cochet-Bonnet contact corneal esthesiometer. A laser scanning in vivo corneal confocal microscope was used to quantify corneal nerve fibre density (CNFD), nerve branch density (CNBD), nerve fibre length (CNFL), and Langerhans cell (LC) density. Corneal sensitivity (P = 0.01), CNFD (P = 0.02), CNBD (P < 0.001), and CNFL (P < 0.001) were lower, and mature (P = 0.001) and immature LC densities (P = 0.011) were higher in patients with RA compared to control subjects. CNFD (P = 0.016) and CNFL (P = 0.028) were significantly lower in patients with moderate to high (DAS28-ESR > 3.2) compared to mild (DAS28-ESR ≤ 3.2) disease activity. Furthermore, the DAS28-ESR score correlated with CNFD (r = -0.425; P = 0.002), CNBD (ρ = -0.362; P = 0.010), CNFL (r = -0.464; P = 0.001), total LC density (ρ = 0.362; P = 0.010) and immature LC density (ρ = 0.343; P = 0.015). This study demonstrates reduced corneal sensitivity, corneal nerve fibre loss and increased LCs which were associated with the severity of disease activity in patients with RA.

TRPV4-induced Neurofilament Injury Contributes to Memory Impairment after High Intensity and Low Frequency Noise Exposures

ObjectiveExposure to high intensity, low frequency noise (HI-LFN) causes vibroacoustic disease (VAD), with memory deficit as a primary non-auditory symptomatic effect of VAD. However, the underlying mechanism of the memory deficit is unknown. This study aimed to characterize potential mechanisms involving morphological changes of neurons and nerve fibers in the hippocampus, after exposure to HI-LFN. MethodsAdult wild-type and transient receptor potential vanilloid subtype 4 knockout (TRPV4-/-) mice were used for construction of the HI-LFN injury model. The new object recognition task and the Morris water maze test were used to measure the memory of these animals. Hemoxylin and eosin and immunofluorescence staining were used to examine morphological changes of the hippocampus after exposure to HI-LFN. ResultsThe expression of TRPV4 was significantly upregulated in the hippocampus after HI-LFN exposure. Furthermore, memory deficits correlated with lower densities of neurons and neurofilament-positive nerve fibers in the cornu ammonis 1 (CA1) and dentate gyrus (DG) hippocampal areas in wild-type mice. However, TRPV4-/- mice showed better performance in memory tests and more integrated neurofilament-positive nerve fibers in the CA1 and DG areas after HI-LFN exposure. ConclusionTRPV4 up-regulation induced neurofilament positive nerve fiber injury in the hippocampus, which was a possible mechanism for memory impairment and cognitive decline resulting from HI-LFN exposure. Together, these results identified a promising therapeutic target for treating cognitive dysfunction in VAD patients.

Considering the protective effect of exendin-4 against oxidative stress in spiral ganglion neurons.

The protection of spiral ganglion neurons (SGNs) is crucial for hearing loss. Exendin-4 has been shown to have neuroprotective effects in several neurological disorders. Therefore, this study aimed to investigate the effect of the glucagon-like protein-1 receptor (GLP-1R) agonist exendin-4 on kanamycin-induced injury in mouse SGNs in vitro. In this study, GLP-1R expression in SGNs was verified by immunofluorescence and immunohistochemical staining. In vitro-cultured SGNs and the organ of Corti were exposed to kanamycin with or without exendin-4 treatment. The cell survival rate was measured using the cell counting kit-8 assay, and the damage to auditory nerve fibers (ANF) projecting radially from the SGNs was evaluated using immunofluorescence staining. Reactive oxygen species (ROS) content was determined by flow cytometry, and glutathione peroxidase (GSH-Px) content, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) content were determined by spectrophotometry. Protein expression of nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) was detected using western blotting. GLP-1R was expressed in SGNs. Treatment with 1 mM kanamycin for 24 hr induced SGN damage. Exendin-4 (100 nM) had a protective effect against kanamycin-induced SGN cell injury, improved cell survival rate, reduced nerve fiber injury, increased SOD activity and GSH-Px level, and reduced MDA and ROS contents. The Nrf2/HO-1 pathway was activated. Exendin-4 alleviates oxidative damage and exerts neuroprotective effects in kanamycin-induced SGN injury through the Nrf2/HO-1 signaling pathway. Exendin-4 has the potential to prevent or treat hearing loss due to SGN damage.

Continuous glucose monitoring reveals a novel association between duration and severity of hypoglycemia, and small nerve fiber injury in patients with diabetes.

Continuous glucose monitoring (CGM) has revealed that glycemic variability and low time in range are associated with albuminuria and retinopathy. We have investigated the relationship between glucose metrics derived from CGM and a highly sensitive measure of neuropathy using corneal confocal microscopy in participants with type 1 and type 2 diabetes. A total of 40 participants with diabetes and 28 healthy controls underwent quantification of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) and inferior whorl length (IWL) and those with diabetes underwent CGM for four consecutive days. CNBD was significantly lower in patients with high glycemic variability (GV) compared to low GV (median (range) (25.0 (19.0-37.5) vs 38.6 (29.2-46.9); P = 0.007); in patients who spent >4% compared to <4% time in level 1 hypoglycemia (54-69 mg/dL) (25.0 (22.9-37.5) vs 37.5 (29.2-46.9); P = 0.045) and in patients who spent >1% compared to <1% time in level 2 hypoglycemia (<54 mg/dL) (25.0 (19.8-41.7) vs 35.4 (28.1-44.8); P = 0.04). Duration in level 1 hypoglycemia correlated with CNBD (r = -0.342, P = 0.031). Duration in level 1 (181-250 mg/dL) and level 2 (>250 mg/dL) hyperglycemia did not correlate with CNFD (P > 0.05), CNBD (P > 0.05), CNFL (P > 0.05) or IWL (P > 0.05). Greater GV and duration in hypoglycemia, rather than hyperglycemia, are associated with nerve fiber loss in diabetes.

Clinical presentation and surgical anatomy of sympathetic nerve injury during lumbar spine surgery: a narrative review.

To highlight the surgical anatomy, procedural variations, presentation, and management of sympathetic nerve injury after surgery of the lumbar spine. PubMed and Google Scholar were searched for publications that were completed between 1951 and 2021. Relevant full-text articles published in the English language were selected and critically reviewed. Sympathetic injury is a highly variable postsurgical complication with a greater incidence after an anterior or oblique approach to the lumbar spine compared to posterior and lateral approaches. The direct and extreme lateral approaches reduce the need to disturb sympathetic nerves thus reducing the risk of complications. It can present in multiple manners, including complex regional pain syndrome (CRPS) and retrograde ejaculation. These complications can be transient and resolve spontaneously or be treated with medications, physical therapy, and spinal blocks. The severity of the conditions and extent of recovery can vary drastically, with some patients never fully recovering. To access the lumbar spine, there are operational approaches and techniques that should be used to decrease the risk of intraoperative injury. It is crucial to understand the advantages and risks to different approaches and take the necessary steps to minimize complications. Early identification of dysfunction and adequate management of symptoms are imperative to effectively manage patients with lumbar sympathetic trunk and sympathetic nerve fiber injuries.

Effect of moxibustion on colonic mucosal injury and expression of CGRP positive nerve fibers of distal colonic mucosa in ulcerative colitis mice

To observe the effect of moxibustion at "Zusanli" (ST 36) on distal, middle and proximal colonic mucosal injury and expression of calcitonin gene-related peptide (CGRP) positive nerve fibers of distal colonic mucosa in ulcerative colitis (UC) mice at different time points. A total of 51 C57BL/6N mice were randomized into a 7-day control group (n=8), a 7-day model group (n=7), a 7-day moxibustion group (n=7), a 14-day control group (n=6), a 14-day model group (n=14) and a 14-day moxibustion group (n=9). In the model groups and the moxibustion groups, 2% dextran sulfate sodium (DSS) was given for 7-day free drinking to establish the UC model. Three days into modeling, moxibustion was applied at "Zusanli" (ST 36) in the 7-day moxibustion group and the 14-day moxibustion group, once a day, 10 min a time for 5 days and 12 days respectively. HE staining was used to observe the morphology of colonic tissue, the percentages of distal, middle and proximal colonic mucosal injury were calculated. Immunofluorescence staining was used to detected the expressions of positive nerve fibers of distal, middle and proximal colonic mucosa and CGRP positive nerve fibers of distal colonic mucosa. Mucosal injury can be observed in mice after modeling, displaying epithelial layer disappearance, abnormal crypt structure or crypt disappearance. Compared with the 7-day control group, colon length was shortened (P<0.001), percentages of overall, distal, middle colonic mucosal injury were increased (P<0.001), the expressions of positive nerve fibers of distal, middle and proximal colonic mucosa and CGRP positive nerve fibers of distal colonic mucosa were increased (P<0.001, P<0.05, P<0.01) in the 7-day model group. Compared with the 7-day model group, the expressions of positive nerve fibers of middle and distal colonic mucosa and CGRP positive nerve fibers of distal colonic mucosa were decreased in the 7-day moxibustion group (P<0.05). Compared with the 14-day control group, the colon length was shortened (P<0.01), percentage of overall colonic mucosal injury was increased (P<0.001) in the 14-day model group. Compared with the 14-day model group, colon length was lengthened (P<0.05), percentage of overall colonic mucosal injury was decreased (P<0.05) in the 14-day moxibustion group. Moxibustion at "Zusanli" (ST 36) can reduce the expressions of positive nerve fibers of colonic mucosa and CGRP positive nerve fibers of distal colonic mucosa, thus, improve the colonic mucosal injury.

Clipless Robotic-assisted Radical Prostatectomy and Impact on Outcomes

BackgroundThe use of surgical clips for athermal dissection of the lateral prostatic pedicles and ligation during pelvic lymph node dissection (PLND) while performing robotic-assisted radical prostatectomy (RARP) has been the gold standard. Clips are used to prevent thermal injury of the unmyelinated nerve fibers and lymphceles, respectively. ObjectiveTo compare oncological and functional outcomes of a new technique of clipless, lateral pedicle control and PLND with RARP with bipolar energy (RARP-bi) versus the standard RARP technique with clips (RARP-c). Design, setting, and participantsA retrospective study was conducted among 338 men who underwent RARP between July 2018 and March 2020. Surgical procedureRARP-c versus RARP-bi. MeasurementsWe prospectively collected data and retrospectively compared demographic, clinicopathological, and functional outcome data. Urinary as well as sexual function was assessed using the Expanded Prostate Cancer Index for Clinical Practice, and complications were assessed using Clavien-Dindo grading. Multivariable regression modeling was used to examine whether the technical approach of RARP-bi versus RARP-c was associated with positive surgical margins (PSMs) or sexual and urinary function scores. Results and limitationsA total of 144 (43%) and 194 (57%) men underwent RARP-bi and RARP-c, respectively. Overall, there were no differences in functional and oncological outcomes between the two approaches. On multivariable regression analysis, the RARP-bi technique was not associated with significant differences in PSMs (odds ratio [OR] = 1.04, 95% confidence interval [CI] 0.6–1.8; p = 0.9), sexual function (OR = 0.4, 95% CI 0.1–1.5; p = 0.8), or urinary function (OR = 0.5, 95% CI 0.2–1.4; p = 0.2). The overall 30-d complication rates (12% vs 16%, p = 0.5) and bladder neck contracture rates (2.1% vs 3.6%, p = 0.5) were similar between the two groups. There was no difference in lymphocele complications (1.4% vs 0.52%, p = 0.58). All complications were of Clavien-Dindo grade I–II. ConclusionsDespite the concerns for an increased risk of nerve injury secondary to the use of bipolar energy for prostatic pedicle dissection, we demonstrate that this technique is oncologically and functionally similar to the standard approach with surgical clips. There was no difference in complications or lymphocele formation for techniques with versus without clips. Patient summaryWe describe a modified technique for prostatic pedicle dissection during robotic-assisted radical prostatectomy, which utilizes bipolar energy and is associated with shorter operative time, without compromising functional or oncological outcomes.

The relationship and significance between lipoprotein abnormalities and HDL dysfunction in severely obese people

Obesity and dyslipidemia may have a role in the development of cardiovascular disease. Neuropathy has also been linked to obesity. The existence of peripheral nerve injury and the presence of metabolic syndrome and lipoprotein abnormalities were evaluated in patients with severe obesity who did not have type 2 diabetes. Detailed proteomics of neuropathic and an evaluation of lipoproteins and HDL-functionality were performed on 49 patients with extreme obesity and 35 age-matched healthy controls. Compared to healthy controls, participants with extreme obesity exhibited a more excellent neuropathy symptom portfolio, lower sural and peroneal nerve impedance, aberrant temperature thresholds, heart rate with controlled breathing, and corneal nerve characteristics. People with significant obesity suffer from little nerve fiber injury. In comparison to controls, obese patients have abnormal lipoproteins and impaired HDL activity. Obese patients with minor nerve fiber injury showed significantly higher serum triglycerides, decreased PON-1 activity, and a higher frequency of obesity than those without.

Measurement of corneal nerve fiber parameters in patients with Parkinson's disease

Objective: To analyze the characteristic changes of corneal nerve fibers in patients with Parkinson's disease (PD) by corneal confocal microscopy (CCM) and investigate the association of corneal nerve fiber parameters with disease severity and motor symptoms. Methods: Forty-two patients with PD were recruited from the Department of Neurology, Henan University People's Hospital from June 2018 to October 2019. Meanwhile, 40 healthy controls who visited the hospital for physical examination at the same period were enrolled. Corneal nerve fibers in both eyes of all participants were detected by using CCM. The differences of corneal nerve fibers were comparatively analyzed between PD group and healthy controls. Associations of corneal nerve parameters with clinical characteristics such as course of disease, Hoehn and Yahr stage (H-Y stage), unified Parkinson disease rating scale (UPDRS), levodopa equivalent daily dosage (LEDD) were analyzed by using partial correlations. The receiver operating characteristic (ROC) curve was used to analyze the capability of corneal nerve fibers for distinguishing patients with PD from healthy controls. Results: Corneal nerve fiber density (CNFD) in PD group ((19±3)/mm2) was significantly decreased compared with healthy controls ((28±4)/mm2) (t=10.798, P<0.001). However, corneal nerve branch density (CNBD) was significantly increased in PD group ((25±11)/mm2) compared with healthy controls ((18±6)/mm2) (t=-3.427, P=0.001). Meanwhile, corneal nerve fiber length (CNFL) was decreased in PD group ((11.0±2.5) mm/mm2) in comparison with healthy controls ((12.5±1.6) mm/mm2) (t=3.139, P=0.002). ROC curve analysis revealed that CNFD could discriminate PD patients from healthy controls, with an area under the curve of 0.961 3 (95%CI: 92.42-99.84, P<0.000 1). CNFD was negatively correlated with H-Y stage and UPDRS-Ⅲ (r=-0.501 and -0.399, both P<0.05). CNBD was significantly negatively associated with H-Y stage, UPDRS-Ⅲ and UPDRS-Total (r=-0.622, -0.394 and -0.354, respectively, all P<0.05). CNFL was negatively correlated with H-Y stage, UPDRS-Ⅲ and UPDRS-total (r=-0.574, -0.484 and -0.422, respectively, all P<0.05). Conclusion: Small nerve fiber injuries exist in PD patients. Corneal nerve fibers negatively correlates with motor symptoms. CNFD have a good discriminative power to distinguish PD patients from healthy controls and may serve as a marker for PD.

PCA Atrophy and Synkinesis as the Main Factors for Persistent Vocal Fold Immobility in RLN Paralysis.

An immobile vocal fold due to recurrent laryngeal nerve (RLN) injury usually shows no gross signs of atrophy and lies near the midline. In 1881, Felix Semon proposed that this phenomenon was due to a selective injury of nerve fibers supplying the posterior cricoarytenoid muscle (PCA) and supported this with postmortem proof of selective PCA atrophy. In recent decades, evidence has emerged that the RLN regenerates after injury but does not always result in useful motion of the vocal folds. It has been proposed that this is caused by laryngeal synkinesis. Laryngeal synkinesis describes a random distribution of regenerated nerve fibers to opposing vocal fold muscles. This study was conducted to clarify the relative contribution of these two potential pathomechanisms in our patient population. Retrospective case analysis. Retrospective analysis of laryngeal EMG results from cases with RLN paralysis of at least 6 months duration seen at our neurolaryngology clinic. Out of 118 PCA EMGs, there was not a single normal or near-normal tracing, whilst 33.3% of TA EMGs indicated normal or near normal innervation. PCA EMGs showed signs of persistent high-grade partial denervation (41.5%) as a sign of atrophy, moderate or strong synkinesis (21.2%), or a combination of both (37.3%). In chronic RLN paralysis the intrinsic laryngeal muscles are affected to different extents either by atrophy or synkinesis or a combination of both. The PCA is always affected. The lesser damage to TA innervation explains the commonly seen maintenance of vocal fold muscle bulk. 4 Laryngoscope, 131:E1244-E1248, 2021.

Diagnostic utility of corneal confocal microscopy in type2 diabetic peripheral neuropathy.

Aims/IntroductionThe early pathological changes of diabetic peripheral neuropathy (DPN) are mainly small nerve fiber injuries. Corneal confocal microscopy (CCM) is an easy, rapid, non‐invasive and repeatable technique to detect the damage of small nerve fibers. The purpose of this study was to explore the application of CCM in DPN and other chronic complications of type 2 diabetes mellitus.Materials and MethodsA total of 220 individuals (48 normal healthy control participants and 172 patients with type 2 diabetes mellitus) were included in the study. All participants were assessed and scored for neurological symptoms and neurological deficits, quantitative sensory test, neuroelectrophysiological test, and CCM.ResultsCorneal nerve fiber density, corneal nerve fiber length and corneal nerve branch density were significantly reduced in patients with type 2 diabetes mellitus compared with normal healthy control subjects (P < 0.001, P < 0.001 and P < 0.001, respectively). In the DPN group, corneal nerve fiber density, corneal nerve branch density and corneal nerve fiber length were significantly lower than for patients without DPN (P < 0.001, P < 0.001 and P < 0.001, respectively). Receiver operating characteristic analysis showed that the optimal cut‐off values were 24.68, 39 and 15.315, respectively, in which corneal nerve fiber density and corneal nerve fiber length had moderate sensitivity and specificity.ConclusionThis study provides more support for the clinical use of CCM to diagnose type 2 diabetes mellitus‐related complications, especially DPN.

Bu-Shen-Yi-Sui Capsule, an Herbal Medicine Formula, Promotes Remyelination by Modulating the Molecular Signals via Exosomes in Mice with Experimental Autoimmune Encephalomyelitis.

Multiple sclerosis (MS) is a common inflammatory demyelinating disorder of the central nervous system. Bu-shen-yi-sui capsule (BSYSC) could significantly reduce the relapse rate, prevent the progression of MS, and enhance remyelination following neurological injury in experimental autoimmune encephalomyelitis (EAE), an established model of MS; however, the mechanism underlying the effect of BSYSC on remyelination has not been well elucidated. This study showed that exosomes carrying biological information are involved in the pathological process of MS and that modified exosomes can promote remyelination by modulating related proteins and microRNAs (miRs). Here, the mechanism by which BSYSC promoted remyelination via exosome-mediated molecular signals was investigated in EAE mice and oligodendrocyte progenitor cells (OPCs) in vitro. The results showed that BSYSC treatment significantly improved the body weight and clinical scores of EAE mice, alleviated inflammatory infiltration and nerve fiber injury, protected the ultrastructural integrity of the myelin sheath, and significantly increased the expression of myelin basic protein (MBP) in EAE mice. In an in vitro OPC study, BSYSC-containing serum, especially 20% BSYSC, promoted the proliferation and migration of OPCs and induced OPCs to differentiate into mature oligodendrocytes that expressed MBP. Furthermore, BSYSC treatment regulated the expression of neuropilin- (NRP-) 1 and GTX, downregulated the expression of miR-16, let-7, miR-15, miR-98, miR-486, and miR-182, and upregulated the level of miR-146 in serum exosomes of EAE mice. In conclusion, these results suggested that BSYSC has a neuroprotective effect and facilitates remyelination and that the mechanism underlying the effect of BSYSC on remyelination probably involves regulation of the NRP-1 and GTX proteins and miRs in serum exosomes, which drive promyelination.

Epimedium flavonoids improve cognitive impairment and white matter lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/NRG1/PI3K pathway in rats

Chronic cerebral hypoperfusion is a common cause of cerebral small vascular disease (CSVD). White matter (WM) lesions are the typical pathological manifestation of CSVD and contribute to cognitive decline. Epimedium flavonoids (EF) are the main component in Epimedium brevicornu Maxim., which is commonly used in traditional Chinese medicine. The purpose of this study was to investigate the effects of EF on cognitive impairment and the underlying mechanisms in a CSVD rat model induced with chronic cerebral hypoperfusion. The model was established by permanent bilateral common carotid artery occlusion (2VO) in rats. EF (50, 100, and 200 mg/kg) was intragastrically administered once a day for 12 weeks starting 2 weeks after 2VO surgery. The learning and memory capacity of the rats were measured using the Morris water maze and step-through tests. WM lesions were observed by MRI-diffusion tensor imaging, transmission electron microscopy, and LFB staining. Oligodendrocytes were detected by immunohistochemistry. Western blotting assay was used to determine the level of protein expression. The results showed that EF significantly improved learning and memory impairment, alleviated WM nerve fiber injuries and demyelination, and increased the number of mature oligodendrocytes in the corpus callosum, subcortical WM, and periventricular WM in 2VO rats. Mechanistically, EF reduced the expression of Lingo-1 and ROCK2 and increased the levels of phosphorylated (p-) Fyn, brain-derived neurotrophic factor (BDNF), TrkB, neuregulin-1 (NRG-1), p-ErbB4, PI3K p85 and p110α, p-Akt, and p-CREB in the corpus callosum of 2VO rats. These results suggest that EF may improve cognitive impairment and WM lesions induced by chronic cerebral hypoperfusion through inhibiting the Lingo-1/Fyn/ROCK pathway and activating the BDNF/TrkB, NRG-1/ErbB4, and the downstream PI3K/Akt/CREB pathways in WM. Thus, EF can be used as a potential neuroprotective agent in CSVD therapy.

Role of TRPM8 Channels in Altered Cold Sensitivity of Corneal Primary Sensory Neurons Induced by Axonal Damage.

The cornea is extensively innervated by trigeminal ganglion cold thermoreceptor neurons expressing TRPM8 (transient receptor potential cation channel subfamily M member 8). These neurons respond to cooling, hyperosmolarity and wetness of the corneal surface. Surgical injury of corneal nerve fibers alters tear production and often causes dry eye sensation. The contribution of TRPM8-expressing corneal cold-sensitive neurons (CCSNs) to these symptoms is unclear. Using extracellular recording of CCSNs nerve terminals combined with in vivo confocal tracking of reinnervation, Ca2+ imaging and patch-clamp recordings of fluorescent retrogradely labeled corneal neurons in culture, we analyzed the functional modifications of CCSNs induced by peripheral axonal damage in male mice. After injury, the percentage of CCSNs, the cold- and menthol-evoked intracellular [Ca2+] rises and the TRPM8 current density in CCSNs were larger than in sham animals, with no differences in the brake K+ current IKD Active and passive membrane properties of CCSNs from both groups were alike and corresponded mainly to those of canonical low- and high-threshold cold thermoreceptor neurons. Ongoing firing activity and menthol sensitivity were higher in CCSN terminals of injured mice, an observation accounted for by mathematical modeling. These functional changes developed in parallel with a partial reinnervation of the cornea by TRPM8(+) fibers and with an increase in basal tearing in injured animals compared with sham mice. Our results unveil key TRPM8-dependent functional changes in CCSNs in response to injury, suggesting that increased tearing rate and ocular dryness sensation derived from deep surgical ablation of corneal nerves are due to enhanced functional expression of TRPM8 channels in these injured trigeminal primary sensory neurons.SIGNIFICANCE STATEMENT We unveil a key role of TRPM8 channels in the sensory and autonomic disturbances associated with surgical damage of eye surface nerves. We studied the damage-induced functional alterations of corneal cold-sensitive neurons using confocal tracking of reinnervation, extracellular corneal nerve terminal recordings, tearing measurements in vivo, Ca2+ imaging and patch-clamp recordings of cultured corneal neurons, and mathematical modeling. Corneal nerve ablation upregulates TRPM8 mainly in canonical cold thermoreceptors, enhancing their cold and menthol sensitivity, inducing a rise in the ongoing firing activity of TRPM8(+) nerve endings and an increase in basal tearing. Our results suggest that unpleasant dryness sensations, together with augmented tearing rate after corneal nerve injury, are largely due to upregulation of TRPM8 in cold thermoreceptor neurons.

Characteristics of Diffusion Tensor Imaging and Language Dysfunction Based on Nerve Fiber Injury in Patients with Acute Hemorrhagic Stroke

Characteristics of Diffusion Tensor Imaging and Language Dysfunction Based on Nerve Fiber Injury in Patients with Acute Hemorrhagic Stroke

Knockdown the P2X3 receptor in the stellate ganglia of rats relieved the diabetic cardiac autonomic neuropathy

Diabetic cardiac autonomic neuropathy (DCAN) is a common and serious complication of diabetes mellitus (DM), is manifested by nerve fiber injury in the sympathetic and parasympathetic nerve of the autonomic nervous system, and causes hypertension, cardiac arrhythmias, silent myocardial infarction, and sudden death. Our previous study observed that P2X3 receptor in superior cervical ganglia in rat was associated with sympathetic neuropathy caused by myocardial ischemia. However, whether the P2X3 receptor is involved in the diabetic cardiac autonomic neuropathy and the underlying mechanisms remain unclear. The aim of this research was explored the effect of P2X3 short hairpin RNA (shRNA) on information transmission of sympathetic nerve induced by DCAN. Sprague-Dawley (SD) male rats were randomly divided into four groups: Control, DM, DM treated with P2X3 shRNA and DM treated with scramble shRNA. Blood pressure, heart rate and heart rate variability were measured in each group. The expression of P2X3 in stellate ganglion (SG) was detected by immunohistochemistry, western blotting and QPCR. Results showed that P2X3 shRNA alleviated blood pressure and heart rate, improved heart rate variability, decreased the up-regulated expression levels of P2X3, interleukin-1beta and tumor necrosis factor alpha in stellate ganglion (SG) of diabetic rats. P2X3 shRNA also reduced the incremental concentration of serum epinephrine and the phosphorylation level of extracellular regulated protein kinases1/2 in diabetic rats. These results indicated that P2X3 shRNA could decrease sympathetic activity via inhibiting P2X3 receptor in the SG to alleviate DCAN.

Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis

Ethnopharmacological relevanceBu Shen Yi Sui capsule (BSYSC), based on traditional Chinese formula Liu Wei Di Huang pill, is effective for the treatment of multiple sclerosis (MS) in clinical experience and trials. Our previous studies confirmed that BSYSC had the neuroprotective effect in MS and its animal model, experimental autoimmune encephalomyelitis (EAE); however, its mechanism of action was not clear. Thus, the effect of BSYSC on remyelination and the underlying mechanisms were investigated in the EAE mice. Materials and methodsThe EAE model was established by injecting subcutaneously myelin oligodendrocyte protein (MOG) 35–55 in mice. Mice were treated with BSYSC (3.02 g/kg) or vehicle daily by oral gavage for 40 days. The body weight and clinical score of mice were evaluated. Brain was observed by magnetic resonance imaging. The inflammation infiltrate of brain and spinal cord was determined by hematoxylin-eosin staining, while the structure of myelin sheath was visualized by transmission electron microscopy on days 23 and 40 post immunization (dpi), respectively. The protein and mRNA levels of platelets-derived growth factor receptor (PDGFR) α and 2′, 3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) were measured by immunohistochemistry, western blot and quantitative real-time polymerase chain reaction. The protein expressions of semaphorins (Sema) 3A, Neuropilin (NRP) − 1, leukemia inhibitory factor (LIF), LIF receptor (LIFR) and Nkx6.2 were further investigated by western blot. ResultsBSYSC treatment improved the body weight and clinical score of EAE mice, alleviated inflammatory infiltration and nerve fiber injuries. It also protected the ultrastructural integrity of myelin sheath. BSYSC significantly increased expressions of PDGFRα and CNPase in mice with EAE on 40 dpi. Furthermore, BSYSC treatment increased the expressions of LIF, LIFR and Nkx6.2 and reduced Sema3A and NRP-1 in EAE mice on 40 dpi. ConclusionsThe data demonstrated that BSYSC exhibited the neuroprotective effect against EAE by promoting oligodendrocyte progenitor cells (OPCs) proliferation and differentiation, thus facilitating remyelination. Sema3A/NRP-1, LIF/LIFR and Nkx6.2 are likely contributed to the effects of BSYSC on OPCs.

Retinal Nerve Fiber Layer Thickness in Chronic Obstructive Pulmonary Disease: An Optical Coherence Tomography Study

Background: To evaluate changes in the retinal nerve fiber layer (RNFL) thickness in patients with chronic obstructive pulmonary disease (COPD) using optical coherence tomography (OCT).Methods: In this case-controlled study, COPD subjectswith various disease durations andseverity were recruited. The standard global initiative for chronic obstructive lung disease (GOLD) criteria was used to determine the severity of COPD in the subjects.Healthy individuals were recruited as the control group. Peripapillary RNFL thickness was measured using spectral domain OCT.Results: Seventy oneeyes of71 COPD patients and 71 eyes ofhealthy controls were examined. The RNFL in all quadrants and the average RNFL were significantly thinner in patients with COPD compared to the control group (p&lt;0.05). There were significant correlationsbetween severity of COPD and RNFL thickness (p&lt;0.05) for the average RNFL (r=0.831) and RNFL in all quadrants(superior RNFLr=0.736, inferior RNFL r=0.681, nasal RNFL r=0.600, andtemporal RNFL r=0.353). Similar significant correlations were found between RNFL thickness and duration of COPD (p&lt;0.005) for the average RNFL(r=-0.674) and RNFL in all quadrants (superior r=-0.615, inferior r=-0.472, nasal r=-0.484, and temporal r=-0.323). The risk of having a thin RNFL (odds ratio) was 13 fold higher in patients with COPD.Conclusions: These results suggest that COPD causes thinning of the RNFL, and severe retinal nerve fiber injury occurs more frequently in advanced COPD.

Association of Electroencephalography (EEG) Power Spectra with Corneal Nerve Fiber Injury in Retinoblastoma Patients.

BackgroundIn our clinical experience we discovered that EEG band power may be correlated with corneal nerve injury in retinoblastoma patients. This study aimed to investigate biomarkers obtained from electroencephalography (EEG) recordings to reflect corneal nerve injury in retinoblastoma patients.Material/MethodsOur study included 20 retinoblastoma patients treated at the Department of Ophthalmology, Affiliated Hospital of Weifang Medical University between 2010 and 2014. Twenty normal individuals were included in the control group. EEG activity was recorded continuously with 32 electrodes using standard EEG electrode placement for detecting EEG power. A cornea confocal microscope was used to examine corneal nerve injury in retinoblastoma patients and normal individuals. Spearman rank correlation analysis was used to analyze the correlation between corneal nerve injury and EEG power changes. The sensitivity and specificity of changed EEG power in diagnosis of corneal nerve injury were also analyzed.ResultsThe predominantly slow EEG oscillations changed gradually into faster waves in retinoblastoma patients. The EEG pattern in retinoblastoma patients was characterized by a distinct increase of delta (P<0.01) and significant decrease of theta power P<0.05). Corneal nerves were damaged in corneas of retinoblastoma patients. Corneal nerve injury was positively correlated with delta EEG spectra power and negatively correlated with theta EEG spectra power. The diagnostic sensitivity and specificity by compounding in the series were 60% and 67%, respectively.ConclusionsChanges in delta and theta of EEG appear to be associated with occurrence of corneal nerve injury. Useful information can be provided for evaluating corneal nerve damage in retinoblastoma patients through analyzing EEG power bands.