High Levels Of Nerve Growth Factor Research Articles

FNDC5/irisin mediates the protective effects of Innovative theta-shaking exercise on mouse memory

As a passive motion and non-invasive treatment, theta-shaking exercise is considered an alternative to traditional active exercise for slowing down brain ageing. Here, we studied the influence of theta-shaking exercise on fibronectin type III domain containing 5/irisin (FNDC5/irisin) in the anterior nucleus of the thalamus, hippocampus, and medial prefrontal cortex (ATN–HPC–MPFC). Further, we assessed memory in senescence-accelerated prone mice (SAMP-10 mice) using a behavioural test to confirm the protective effect of theta-shaking exercise against age-related memory decline. SAMP-10 mice were subjected to theta-shaking exercise for 9–30 weeks. Mice then performed the T-maze test and passive avoidance task. Immunohistochemical analysis and ELISA were used to assess FNDC5/irisin, nerve growth factor (NGF), and neurotrophin 4/5 (NT4/5) expression in the ATN–HPC–MPFC. In the shaking group, FNDC5 was locally upregulated within the hippocampus and MPFC area rather than exhibiting even distribution throughout brain tissue. Irisin levels were generally higher in the control group. Meanwhile, hippocampal NGF levels were significantly higher in the shaking group, with no differences noted in neurotrophin levels. Theta-shaking preserved normal neurons in certain sub-regions. However, no beneficial changes in neuronal density were noted in the ATN. Theta-shaking exercise positively affects memory function in SAMP-10 mice. FNDC5 upregulation and higher levels of NGF, along with the potential involvement of irisin, may have contributed to the preservation of normal neuronal density in the hippocampus and MPFC subregions.

Analysis of Global and Local DNA Methylation Patterns in Blood Samples of Patients With Autism Spectrum Disorder.

The goal of this investigation was to determine whether there are alterations in DNA methylation patterns in children with autism spectrum disorder (ASD).Material and Methods: Controlled prospective observational case-control study. Within the ASD group, children were sub-classified based on the presence (AMR subgroup) or absence (ANMR subgroup) of neurodevelopmental regression during the first 2 years of life. We analyzed the global levels of DNA methylation, reflected in LINE-1, and the local DNA methylation pattern in two candidate genes, Neural Cell Adhesion Molecule (NCAM1) and Nerve Growth Factor (NGF) that, according to our previous studies, might be associated to an increased risk for ASD. For this purpose, we utilized blood samples from pediatric patients with ASD (n = 53) and their corresponding controls (n = 45).Results: We observed a slight decrease in methylation levels of LINE-1 in the ASD group, compared to the control group. One of the CpG in LINE-1 (GenBank accession no.X58075, nucleotide position 329) was the main responsible for such reduction, highly significant in the ASD subgroup of children with AMR (p < 0.05). Furthermore, we detected higher NCAM1 methylation levels in ASD children, compared to healthy children (p < 0.001). The data, moreover, showed higher NGF methylation levels in the AMR subgroup, compared to the control group and the ANMR subgroup. These results are consistent with our prior study, in which lower plasma levels of NCAM1 and higher levels of NGF were found in the ANMR subgroup, compared to the subgroup that comprised neurotypically developing children.Conclusions: We have provided new clues about the epigenetic changes that occur in ASD, and suggest two potential epigenetic biomarkers that would facilitate the diagnosis of the disorder. We similarly present with evidence of a clear differentiation in DNA methylation between the ASD subgroups, with or without mental regression.

Relationship of Pain Catastrophizing With Urinary Biomarkers in Women With Bladder Pain Syndrome.

Brain-derived neurotrophic factor (BDNF) has been implicated in central neurological processes. We hypothesize that greater pain catastrophizing is associated with higher urinary BDNF levels in women with bladder pain syndrome. A secondary analysis of a database of women with urinary urgency was conducted. We identified women who met AUA criteria of bladder pain syndrome. Urinary symptoms, pain catastrophizing, and neuropathic pain were measured using the Female Genitourinary Pain Index, Pain Catastrophizing Scale and painDETECT questionnaires respectively. The relationship of the catastrophizing score with urinary BDNF (primary outcome) and other urinary biomarkers, including nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and osteopontin, was evaluated using univariable and multivariable analyses. In 62 women with bladder pain syndrome, 15 (24%) reported pain catastrophizing symptoms (Pain Catastrophizing Scale score >30). Higher catastrophizing scores were associated with worse urinary symptoms, greater pelvic pain, greater neuropathic pain, and worse quality of life scores (all P < 0.01). On multivariable analysis, after controlling for age, body mass index and urinary symptoms, a higher pain catastrophizing score was associated with lower BDNF (P = 0.04) and lower VEGF levels (P = 0.03). Urinary urgency was associated with a higher NGF level (P = 0.04) while bladder pain was associated with higher levels of NGF (P = 0.03) and VEGF (P = 0.01). Neuroinflammatory mechanisms contribute to the central processing of pain in women with bladder pain syndrome. Worse urinary symptoms are associated with higher NGF and VEGF levels, but worse pain catastrophizing is associated with lower BDNF and VEGF levels. Urinary BDNF levels may be useful in phenotyping women who have central augmentation of pain processing.

Gender differences in ultradian serum levels of NGF and BDNF correlate with psychophysical traits in healthy humans.

We aimed at investigating the gender and/or ultradian pattern of serum levels of the Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF). Blood samples were collected at the 8.00, 13.00 and 20.00 hours of the day in healthy men and women, and the neurotrophins concentration was measured in the serum by ELISA. A further aim of the study was to evaluate whether or not the NGF/BDNF variations might be related to specific physiological or psychological traits as mood, feeling good and feeling rested, sexual desire and energy. Heart rate and blood pressure were also monitored at the same hours in each enrolled subject. The anxiety (STAI-T and STAI-S score) and sleeping quality were once evaluated in the morning too. We found that serum BDNF increases in men and decreases in women from morning to evening, while NGF shows a similar ultradian profile between men and women, but with higher concentrations in women. Both neurotrophins also show gender-related associations with psychophysiological variables. High NGF levels correlated with a high score for all the psychological variables in men, but with a low score in women. An inverse correlation was found between BDNF and energy and sexual desire in women, while no correlations were found in men. These data disclose that the condition of well-being (or activity/arousal status) is featured by an increasing NGF profile in men and a negative BDNF/NGF trend in women. The clinical relevance of the present data is discussed.

Nerve growth factor is closely related to glucose metabolism, insulin sensitivity and insulin secretion in the second trimester: a case\u2013control study in Chinese

ObjectiveInflammation-related factors have been shown to play a significant role throughout pregnancy. In this study, we aimed to explore the relationships between selected inflammatory cytokines and gestational diabetes (GDM) in Chinese pregnant women.Design and methodsThis was a 1:1 matched case–control study that included 200 pairs of subjects in the second trimester and 130 pairs of subjects in the third trimester. Serum levels of nerve growth factor (NGF), Interleukin-6 (IL-6), leptin, Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α) and Interleukin-1beta (IL-1β) were measured by enzyme immunoassay. The associations of these inflammatory factors with metabolic parameters were analysed.ResultsIn the second trimester, GDM patients had higher NGF levels and lower IL-8 levels than did normal controls (P < 0.001 and P = 0.015, respectively). However, in the third trimester, only lower leptin levels were observed in the GDM group (P = 0.031). Additionally, in the second trimester, NGF levels were not only positively associated with fasting, 1-h and 2-h glucose levels and the area under curve of glucose, but also positively related to insulin sensitivity and secretion, as suggested by fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment index of β-cell secretion (HOMA-β) (all P < 0.05). Moreover, IL-6 and leptin levels were positively correlated with HOMA-IR and HOMA-β, and TNF-α levels were positively related to HOMA-IR (all P < 0.05). Except for the relationships between NGF and HOMA-β and TNF-α and HOMA-IR, the other correlations still existed even after adjusting for confounding factors (all P < 0.05).ConclusionIn addition to the positive associations of IL-6 and leptin with insulin resistance and secretion, NGF was higher in the GDM patients and strongly linked to glucose metabolism, insulin resistance and pancreatic β cell function in Chinese pregnant women in the second trimester.

Targeted Immune and Growth Factor Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension Reveals a Potential Role of the Hepatic Growth Factor

Although inflammatory features have been reported in the pressure-overloaded right ventricle, prior proteomic studies of pulmonary arterial hypertension (PAH) have mainly focused on identifying circulating biomarkers associated with pulmonary vascular disease severity or outcomes. This study sought to determine the circulating proteomic immune profile associated with right heart maladaptive phenotype (RHMP) in PAH. In this observational study of PAH patients enrolled at Stanford University from 2008-2011 (n=121, discovery cohort) and from 2011-2014 (n=76, validation cohort), we carried out plasma proteomic profiling using Luminex® multiplex immunoassay (48-plex of interleukins, chemokines and growth factors). RHMP was defined by the Mayo right heart score (based on echocardiographic right ventricular RV strain, NYHA class and NT-proBNP) and Stanford right heart score (based on RV end-systolic remodeling index, NYHA class and NT-proBNP). The association between cytokines and RHMP was assessed by partial least square regression (PLS-R). To further validate the circulating markers associated with RHMP, we confirmed tissue-level expression in RV biopsies from PAH patients. Median age was 50 [39-59] years in the discovery cohort, where the majority of patients was female (74%) and PAH was most commonly associated with connective tissue disease (33%). Patients from the validation cohort had more severe features (lower six minute walk test distance, lower cardiac index and higher levels of NT-proBNP) than patients from the discovery cohort, with similar resistance levels and right heart echocardiography metrics. High levels of hepatic growth factor (HGF), stem cell growth factor beta (SCGFβ), nerve growth factor (NGF) and SDF1 were significantly associated with worst Mayo and Stanford scores but not with pulmonary vascular resistance or mean pulmonary arterial pressure, in both cohorts. In the right ventricle of deceased PAH patients, we confirmed expression of HGF and its receptor cMet using immunofluorescence. High plasma levels of HGF, SCGFβ, NGF and SDF1 are associated with RHMP in PAH, independent of pulmonary vascular disease severity. The HGF-cMet pathway warrants further exploration to investigate a potential RV specific therapeutic target.

Effect of vitamin B12 and omega-3 fatty acid supplementation on brain neurotrophins and cognition in rats: A multigeneration study.

Vitamin B12 and omega-3 fatty acids are important nutrients required for neuronal functioning. We have demonstrated the beneficial effects of vitamin B12 and omega-3 fatty acid supplementation on brain neurotrophins and cognition in the first and second generation offspring. However, there is a need to examine if the effects are sustained in the third generation offspring. This study reports the effects of vitamin B12 and omega-3 fatty acid supplementation across three consecutive generations on brain neurotrophins like brain derived neurotrophic factor (BDNF); nerve growth factor (NGF) and cognitive performance in the third generation male offspring. Three successive generations of Wistar rats were assigned the following groups throughout pregnancy, lactation and adulthood: i) Control, ii) vitamin B12 deficient (BD), iii) vitamin B12 deficient+omega-3 fatty acid (BDO), iv) vitamin B12 supplemented (BS) and v) vitamin B12 supplemented+omega-3 fatty acid (BSO). The BD group demonstrated lower (p<0.01) NGF in the cortex but not BDNF levels although the cognition was impaired (p<0.01). In contrast, in the BDO group, higher NGF levels were observed in the hippocampus and animals demonstrated improved (p<0.01) cognitive performance. Vitamin B12 supplementation showed comparable BDNF levels in the hippocampus while their levels were lower in the cortex as compared to the control (p<0.05). These animals showed more reference and working memory errors (p<0.01) as compared to the control group. A combined supplementation of vitamin B12 and omega-3 fatty acid showed higher (p<0.01) levels of DHA and NGF in the hippocampus, higher BDNF in both hippocampus and cortex and improved cognitive performance. Our findings have implications for fortification of foods with vitamin B12 and omega-3 fatty acids in improving brain development.

NGF Modulates trkANGFR/p75NTR in αSMA-Expressing Conjunctival Fibroblasts from Human Ocular Cicatricial Pemphigoid (OCP).

ObjectiveIn a previous study, we reported the upregulation of Nerve Growth Factor (NGF) and trkANGFR expression in Ocular Cicatricial Pemphigoid (OCP), an inflammatory and remodeling eye disease. Herein, we hypothesize a potential NGF-driven mechanism on fibroblasts (FBs) during OCP remodeling events. To verify, human derived OCP-FBs were isolated and characterized either at baseline or after NGF exposure.Materials and MethodsConjunctival biopsies were obtained from 7 patients having OCP and 6 control subjects (cataract surgery). Both conjunctivas and primary FB cultures were characterised for αSMA, NGF and trkANGFR/p75NTR expression. Subcultures were exposed to NGF and evaluated for αSMA, NGF, trkANGFR/p75NTR expression as well as TGFβ1/IL4 release. For analysis, early and advanced subgroups were defined according to clinical parameters.ResultsOCP-conjunctivas showed αSMA-expressing FBs and high NGF levels. Advanced OCP-FBs showed higher αSMA expression associated with higher p75NTR and lower trkANGFR expression, as compared to early counterparts. αSMA expression was in keeping with disease severity and correlated to p75NTR. NGF exposure did not affect trkANGFR levels in early OCP-FBs while decreased both αSMA/p75NTR expression and TGFβ1/IL4 release. These effects were not observed in advanced OCP-FBs.ConclusionsTaken together, these data are suggestive for a NGF/p75NTR task in the potential modulation of OCP fibrosis and encourages further studies to fully understand the underlying mechanism occurring in fibrosis. NGF/p75NTR might be viewed as a potential therapeutic target.

Neurotrophin levels in different regions of the placenta and their association with birth outcome and blood pressure

IntroductionOur recent study in preeclampsia indicates differential oxidative stress in various regions of the placenta. Oxidative stress is known to influence neurotrophin levels. We therefore hypothesize that placental regional differences in oxidative stress will also lead to differences in neurotrophin levels. MethodsThe current study examines the levels of neurotrophins, brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in different regions of the placenta in 50 normotensive control women and 47 women with preeclampsia (21 delivering at term and 26 delivering preterm). Placentae were collected from four different regions: central maternal (CM), central fetal (CF), peripheral maternal (PM) and peripheral fetal (PF). ResultsBDNF levels were higher in CF region as compared to CM (p < 0.01), PM (p < 0.01) and PF (p < 0.05) regions of the placenta in the control group. There was no regional change in NGF levels in any of the groups. Analysis between groups indicated higher NGF levels in CM (p < 0.01), PM (p < 0.05) and PF (p < 0.01) regions of preterm preeclampsia group as compared to control. Negative association of NGF levels in CM, CF and PM regions with baby weight and in CF, PM and PF regions with baby length was observed. NGF levels in all four regions were positively associated with systolic blood pressure. DiscussionOur data indicates regional differences in levels of BDNF only in normotensive control but not in preeclampsia group. Higher NGF levels in preterm preeclampsia may be a response to increased oxidative stress. This may have implications for altered placental development in preeclampsia.

Nerve growth factor exposure promotes tubular epithelial–mesenchymal transition via TGF-β1 signaling activation

Clinical studies showed that renal expression and serum levels of nerve growth factor (NGF) are increased in renal diseases characterized by progressive fibrosis, a pathologic process in which TGF-β1 mediates most of the key events leading to tubular epithelial–mesenchymal transition (EMT). However, the pathogenic role of high NGF levels has not yet been elucidated. In this study, we found that in tubular renal cells, HK-2, NGF transcriptionally up-regulated TGF-β1 expression and secretion and enhanced cell motility by activating EMT markers via its receptors, TrkA and p75NTR. Interestingly, we observed that TGF-β1–SMAD pathway activation and the up-regulation of EMT markers NGF-induced were both prevented when knockdown of TGF-β1 gene occurred and that the pretreatment with an antibody anti-NGF reversed the nuclear translocation of pSMAD3/SMAD4 complex. Collectively, our results demonstrated that NGF promotes renal fibrosis via TGF-β1-signaling activation, suggesting that in kidney diseases high NGF serum levels could contribute to worsen renal fibrosis.

Regulation of Autocrine Signaling in Subsets of Sympathetic Neurons Has Regional Effects on Tissue Innervation.

SummaryThe regulation of innervation by target-derived factors like nerve growth factor (NGF) is the cornerstone of neurotrophic theory. Whereas autocrine signaling in neurons affecting survival and axon growth has been described, it is difficult to reconcile autocrine signaling with the idea that targets control their innervation. Here, we report that an autocrine signaling loop in developing mouse sympathetic neurons involving CD40L (TNFSF5) and CD40 (TNFRSF5) selectively enhances NGF-promoted axon growth and branching, but not survival, via CD40L reverse signaling. Because NGF negatively regulates CD40L and CD40 expression, this signaling loop operates only in neurons exposed to low levels of NGF. Consequently, the sympathetic innervation density of tissues expressing low NGF is significantly reduced in CD40-deficient mice, whereas the innervation density of tissues expressing high levels of NGF is unaffected. Our findings reveal how differential regulation of autocrine signaling in neurons has region-specific effects on axon growth and tissue innervation.

Increased Severity of Inflammation Correlates with Elevated Expression of TRPV1 Nerve Fibers and Nerve Growth Factor on Interstitial Cystitis/Bladder Pain Syndrome

Objectives: Although evidence supports a role for inflammation in interstitial cystitis/bladder pain syndrome (IC/BPS), the mechanism remains unknown. We determined whether inflammation causes an elevated expression of nerve growth factor (NGF) and transient receptor potential vanilloid receptor subtype 1 (TRPV1) and correlated them with the symptoms. Methods: Bladder biopsies were obtained from 53 IC/BPS patients and 27 controls, and hematoxylin and eosin staining, immunostaining and Western blotting were performed to detect inflammation, TRPV1-immunoreactive and PGP9.5-immunoreactive nerve fibers, and NGF, respectively. Symptoms were assessed using the Pelvic Pain/Urgency/Frequency (PUF) questionnaire and pain visual analogue scale scores. Suburothelial nerve fiber density was quantified and correlated with PUF scores. Results: Increased severity of inflammation was correlated with a higher TRPV1-immunoreactive nerve fiber density (r = 0.4113, p = 0.0024) and higher NGF levels (r = 0.3775, p = 0.0052). Suburothelial TRPV1-immunoreactive nerve fiber density was significantly correlated with pain scores and urgency scores (r = 0.3320, p = 0.0145 and r = 0.3823, p = 0.0039, respectively). PGP9.5-immunoreactive nerve fibers were significantly increased in IC/BPS (p = 0.0193) and had a positive relationship with inflammation severity (r = 0.6138, p < 0.0001). Conclusions: Our study revealed increased severity of inflammation correlated with a higher expression of TRPV1-immunoreactive nerve fibers and NGF in IC/BPS and correlated with clinical symptoms.

Urinary nerve growth factor: a biomarker of detrusor overactivity? A systematic review

Nerve growth factor (NGF) is a signalling protein that interacts with specific receptors in autocrine, paracrine and endocrine modes. It is produced by bladder smooth muscle and urothelium. Patients with overactive bladder and detrusor overactivity (DO) have been found to have increased urinary NGF levels in several small studies. The objective of the review was to assess the accuracy of NGF as a biomarker in the diagnosis of DO by a systematic review of the literature. A systematic search of MEDLINE, Embase, CINAHL, MEDION and LILACS databases was conducted (inception till December 2012). Selection criteria included studies where NGF (as a biomarker for DO) and urodynamics were performed in humans with symptoms of overactive bladder. Two reviewers independently selected articles and extracted data on study characteristics, quality and results. All the eight included studies were of case-control design. A meta-analysis was not performed as there were variations in the quality, methods of performing the NGF assay, different NGF cut-offs used and the format of reporting findings. Two studies used a cut-off of 0.05 for NGF levels. Six studies observed a trend towards higher NGF levels in patients with DO. There was a trend towards higher NGF in patients with DO. However, the data are imprecise and hence cannot be recommended for use in current clinical practice.

Low levels of the nerve growth factor receptor TrkA in JIA: a possible defect in a novel anti-inflammatory mechanism

High levels of Nerve Growth Factor (NGF) are found in chronic inflammatory diseases, including synovial fluids (SF) of juvenile idiopathic arthritis (JIA) patients. The effects of high NGF levels on immune cell activity and inflammatory process are unknown. Objective To evaluate the effects of NGF and the role of its receptor TrkA on cytokine production in monocytes, which express TrkA and are key players of inflammation. To investigate in JIA patients the expression of the NGF receptor, TrkA, in blood and SF mononuclear cells (MC). Methods Using real time PCR we evaluated the expression of TrkA in JIA patients (n=25; mean age 8.93 years) and controls comparable (n=17; mean age 8.93 years). In human monocytes stimulated with LPS, the effect of TrkA activation or inhibition on signalling and cytokine release was evaluated using real-time PCR, western blot and ELISA. Results Compared to controls, TrkA mRNA expression was markedly lower in blood MC of JIA patients (p<0.001). TrkA mRNA levels were similarlv low in SF MC of JIA patients. In vitro, we show that addition of NGF down-regulates IL-6 and IL-1 production and increases IL-10. Blocking the receptor TrkA resulted in enhanced activation of the NF-kB pathway, in increased inflammatory cytokine production and in decreased IL-10. Conclusions We show for the first time that NGF, through TrkA, has anti-inflammatory effects on monocytes, suggesting that the well-known NGF increase found in chronic inflammatory diseases represents an endogenous mechanisms limiting inflammatory response. Defective TrkA expression, as found in JIA patients, may lead to an imbalance between pro-inflammatory and antiinflammatory pathways contributing to chronic inflammation.

Involvement of nerve growth factor (NGF) and its receptors in respiratory diseases

Beside its classical role in nervous system, NGF plays a crucial role also in inflammatory processes. In fact, B and T lymphocytes, as well as mast cells, monocytes, dendritic cells and macrophages, produce high levels of NGF and express its receptors TrKA and p75. Previous studies have shown an involvement of NGF in some respiratory diseases, but its role is still unclear. The aim of our study was to investigate the expression and the levels of TrKA and p75 on innate and adaptative immune response cells in patients with asthmatic and Chronic Obstructive Pulmonary (COPD) diseases, by cytofluorimetric analysis. Blood samples of 15 control subjects, 10 asthmatic and 10 COPD patients were analyzed. Our results showed that, in adaptative immune response cells, TrKA expression was significantly decreased in asthmatic but not in COPD patients, while p75 was not expressed. Furthermore, analysis of innate immune response cells showed a significant increase in TrKA, but not in p75 in the asthmatic group and an increase of both TrKA and p75 in the COPD group. In conclusion, our data show that, beside the release of NGF, there is an important involvement of NGF receptors during the innate and adaptative immune response in respiratory diseases. In clinical practice, evaluation of these two receptors may be a further parameter for a better definition of the severity in respiratory diseases. Acknowledgements This work was supported by CARIT Foundation, Terni.

Functional significance of nerve growth factor and its receptor (TrkA) in inflammatory arthritis

We read the article by Barthel and colleagues [1] in this is sue of Arthritis Research & Th erapy with great interest. Th ey reported that neurotrophin receptors/ligands and specifi cally nerve growth factor (NGF) and NGF receptor (NGF-R) (TrkA and p75) are expressed in synovial fl uid (SF) cells and synovial tissue (ST) of patients with rheuma toid arthritis (RA) or spondyloarthritis (SpA). Th e authors also looked for the cellular source of NGF and demonstrated that the T cells and monocytes/macrophages derived from SF of patients with RA/SpA are enriched with NGF. Furthermore, they reported that STderived fi broblast-like synoviocytes (FLSs) did not produce NGF in vitro. In a recent publication, we observed similarly that NGF levels in SF were signifi cantly higher in patients with psoriatic arthritis (PsA) (365.5 ± 85.2 pg/ mL) or RA (120 ± 35 pg/mL) than in patients with osteoarthritis (OA) (30 ± 6 pg/mL) [2]. However, in regard to the source of NGF, we observed that FLSs produced a signifi cant amount of NGF. Here, we would like to share our observations about the NGF/TrkA system in human FLSs and its function. Synovial biopsies from patients with meniscal injury without any other joint diseases or PsA, OA, or RA were collected. FLSs were isolated and examined for NGF/ NGF-R expression in accordance with our standardized protocols [2]. Using a highly sensitive enzyme-linked immuno sorbent assay (ELISA) for human NGF (NGFEmax assay; Promega Corporation, Madison, WI, USA) and Hi-D fl uorescence-activated cell sorting analyses, we observed that under basal conditions FLSs from healthy individuals express low levels of NGF/TrkA. However, there was a marked upregulation of NGF and TrkA in these FLSs following stimulation with tumor necrosis factor-alpha and interleukin-1-beta (Table 1). A critical observation was that FLSs from patients with PsA or RA produced spontaneously higher levels of NGF and had increased expression of TrkA compared with FLSs of patients with OA (Table 1). Furthermore, we observed that NGF signifi cantly stimulated the proliferation of FLSs derived from PsA synovial tissue (Figure 1). Barthel and colleagues [1] cultured FLSs from only one patient with RA and one patient with SpA and noticed that FLSs did not produce NGF, but the authors do mention that they can’t rule out the production of NGF by FLS. We cultured FLSs from 15 subjects (Table 1), and it is also possible that the NGF ELISA kit that we used is more sensitive. A fully formed pannus is characterized by proliferation of FLSs, infl ammatory infi ltrates, and a marked angiogenesis. NGF and its receptor system are known to

Neurotrophins in chronic cough: association with asthma but not with cough severity

Chronic cough is associated with an enhanced excitability of airway cough receptors, possibly due to action of neurotrophins. The present study aimed to compare the neurotrophin levels between healthy subjects and patients with chronic cough and to analyze the factors associated with these levels. Serum and sputum levels of nerve growth factor (NGF), serum levels of brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) were analyzed by enzyme immunoassay in 19 healthy subjects and 47 patients with chronic cough. In addition, cough sensitivity to hypertonic saline was assessed, cough diary was kept, Leicester Cough Questionnaire was filled in, peak flow was monitored and spirometry, skin prick tests, exhaled nitric oxide measurement and histamine challenge were performed. The NGF levels did not differ between the healthy subjects and the patients with chronic cough and were not associated with any index describing cough severity. However, these levels in both serum (P = 0.01) and sputum (P = 0.025) samples were associated with asthma. There was a statistically significant association between serum and sputum NGF levels (R = 0.45, P = 0.026). The serum BDNF levels did not differ between the groups and were not associated with any of the background characteristics. The serum NT-3 levels were below the detection limit in most subjects and therefore these data were not analyzed. Neither chronic cough nor its severity is associated with abnormal neurotrophin levels. High NGF levels among some patients with chronic cough may indicate a presence of asthma.

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Mammalian dorsal root ganglia (DRG) contain a diverse collection of sensory neuronal subtypes specialized to detect different sensory stimuli. Most of these cells respond to mechanical stimulation of some sort, be they proprioceptors detecting body movements, receptors for gentle touch or nociceptors activated by painful levels of pressure, and yet the proteins that detect mechanical stimuli remain unknown. In this issue of The EMBO Journal, Gary Lewin and colleagues give insights into the developmental acquisition of mechanosensitivity by different classes of sensory neurons and in doing so, they offer a new approach for determining the molecular basis of this sensory modality.

Urinary nerve growth factor is a better biomarker than detrusor wall thickness for the assessment of overactive bladder with incontinence

To compare the differences in urinary nerve growth factor (NGF) and detrusor wall thickness (DWT) between patients with overactive bladder (OAB) and controls to evaluate their suitability as biomarkers in OAB. A total of 81 patients including normal controls (n = 28), patients with OAB dry (n = 28) and OAB wet (n = 25) were enrolled in this study. Videourodynamic study was performed in 79 patients after confirmation of symptomatic classification by 3-day voiding diary. Urine NGF and DWT measurements were performed at full bladder and urge to void after natural-filling or catheter-filling during videourodynamic study. Urinary NGF level was measured by the ELISA method and DWT was measured by trans-abdominal ultrasound. These two parameters were compared among different symptomatic and urodynamic subgroups. DWT was not significantly different among subgroups at 250 ml bladder volume. Although patients with OAB wet had a significantly greater DWT at the maximal bladder volume, this difference was not significant from controls after correction of the volume factor. By contrast, urinary NGF levels were significantly increased in patients with OAB wet and those with urodynamic detrusor overactivity. However, elevated NGF levels in OAB wet were found only after natural-filling and not after catheter-filling. Urinary NGF level in natural-filling urine sample is a better biomarker for assessment of OAB wet compared to DWT. Patients with OAB dry or hypersensitive bladder did not have an elevated urinary NGF level. Urine samples from catheter-filling do not have a detectably high NGF levels.

Stress, anxiety and schizophrenia and neurotrophic factors: the pioneer studies with nerve growth factor.

The aim of this review is to highlight past and ongoing studies on neurotrophin (NT) role, in particular focusing on nerve growth factor (NGF), on behavioral response to stress, agonistic and emotional behavior, anxiety, and schizophrenia. One of the first evidences of NGF involvement in behavioral response to a social challenge was published in 1986. In male mice, agonistic encounters caused a massive NGF release into the bloodstream and in the hypothalamus. Subsequent studies revealed that this NGF release was not strictly linked to agonistic behavior, but to mice hierarchical status, with subordinates having higher NGF levels than dominants. This observation led to the hypothesis and later to the demonstration that NGF release is associated to anxiety-related behaviors. Later studies provided evidence for the involvement of NTs, including NGF, in the development of neuropsychiatric disorders. Interestingly, pharmacological treatment can reduce the effects of the maldevelopment and neuropathology due to NT imbalance during early periods of life crucial for development. Further understanding of the core pathophysiological mechanism for neurodegenerative and psychiatric disorders will eventually provide tools for amelioration of symptoms of those psychiatric disorders characterized by an NT imbalance.