High Nerve Growth Factor Research Articles

Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression.

Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGF from CAFs directly enhances CRC cell growth via the PI3K/AKT pathway. Treatment with a tropomyosin receptor kinase (Trk) inhibitor decreased YAP and AKT activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk inhibitor may represent a potential therapeutic approach for CRC.

Genetic Engineering of Adipose-Derived Stem Cells Using Biodegradable and Lipid-Like Highly Branched Poly(β-amino ester)s.

Biodegradable and lipid-like highly branched poly(β-amino ester)s, HPAESA, were developed to enhance the biological functions of adipose-derived stem cells by gene transfection. Biodegradability reduces the cytotoxicity of HPAESA and enables controlled DNA release. Lipid mimicry enhances cellular uptake and endosomal escape of HPAESA/DNA polyplexes. HPAESA are able to transfect rat adipose-derived stem cells (rADSs) and human ADSCs (hADSCs) with orders of magnitude higher efficiency than commercial gene transfection reagents, with cell viability exceeding 90%. Most importantly, HPAESA can effectively transfer the nerve growth factor (NGF)-encoding plasmid to rADSCs and induce high NGF secretion, which significantly promotes neurite outgrowth of PC12 cells.

Bioprinted Constructs that Mimic the Ossification Center Microenvironment for Targeted Innervation in Bone Regeneration

AbstractAlthough great progress has been made in engineered bone tissues, delayed or ineffective bone regeneration remains an issue due to the lack of neural network reconstruction in their design. Therefore, an engineered bone tissue construct that mimics the ossification center microenvironment to promote innervation is proposed. Based on this, the NGF@Lap constructs are constructed through bioprinting technology, which can release nerve growth factor (NGF) for a long time and simulate the ossification center's microenvironment with high expression NGF. In vitro, NGF@Lap‐GA can promote axonal extension. Meanwhile, the NGF and Laponite from the constructs can respectively promote the expression and secretion of calcitonin gene‐related peptide (CGRP) in sensory neurons. Further, the constructs show a CGRP‐dependent osteogenic and inhibition of adipogenesis, which is mainly regulated by AMP‐activated protein kinase‐peroxisome proliferator activated receptor pathway. In vivo, the constructs increased neurovascular network density in the tissue surrounding the implant, promoted bone marrow mesenchymal stem cells osteogenic differentiation, and effectively improved bone regeneration in the cranial defect model. In conclusion, the novel tissue‐engineered bone simulates the ossification center microenvironment, promotes innervation, and has promising potential for future application in bone regeneration.

Elevated Level of Nerve Growth Factor (NGF) in Serum-Derived Exosomes Predicts Poor Survival in Patients with Breast Cancer Undergoing Neoadjuvant Chemotherapy.

Simple SummaryExosomes and cytokines play crucial roles in the process of tumor progression. Recent studies have reported that cytokines can be packaged into exosomes, leading to drug resistance. The aim of this study is to evaluate the potential value of cytokines in both serum and exosomes as prognostic biomarkers of long-term outcomes in patients with breast cancer treated with neoadjuvant chemotherapy. We observed significant differences in expression patterns between serum cytokines and exosomal cytokines. Elevated levels of serum IP-10, serum MMP-1, and exosomal NGF were associated with poor overall survival. In multivariate analysis, exosomal NGF was an independent prognostic factor for overall survival. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes.Neoadjuvant chemotherapy (NAC) is a standard treatment strategy for patients with locally advanced breast cancer (LABC). However, there are no established predictors of chemosensitivity and survival in LABC patients who undergo NAC. Many studies have demonstrated that exosomes and cytokines are important players in intercellular communication between tumors and their environments, and are involved in chemotherapy resistance. Recently, it was reported that cytokines can be packaged into exosomes, but whether exosomal cytokines serve as biomarkers in breast cancer patients is still unclear. In this study, we examined the roles of cytokines in both serum and exosomes as prognostic biomarkers for long-term outcomes in patients with breast cancer who undergo NAC. We isolated exosomes from the blood of 129 patients with early breast cancer who were receiving neoadjuvant chemotherapy between 2008 and 2011 at Samsung Medical Center. The levels of cytokines and growth factors in serum and exosomes were measured with ProcartaPlex immune-related panels. We investigated correlations between clinic-pathologic variables and patient survival, and Cox proportional hazards regression analysis was performed for prognostic evaluation. We detected significant differences in expression patterns between serum cytokines and exosomal cytokines. In both serum and exosomes, many cytokines were positively correlated with age. In univariate analysis, patients with high serum IP-10, serum MMP-1, and exosomal NGF had shorter overall survival. Exosomal NGF showed significantly poorer overall survival in multivariate analysis. These findings suggest that exosomal NGF is useful for identifying patients with poor survival outcomes.

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.

Effects of gender and age on protein secretion in saliva of transgenic mice expressing human nerve growth factor

Nerve growth factor (NGF) can promote the development, differentiation and regeneration of neurons. Recently, in order to efficiently produce human NGF (hNGF) drugs with better efficacy, we created transgenic mice expressing hNGF specifically in their salivary glands, and purified highly active hNGF protein from their saliva. Some studies reported that the NGF secretion in mouse saliva is affected by gender and age. Here, in order to select hNGF transgenic mice with high NGF secretion for saliva collection and hNGF purification, we divided transgenic mice into 4 groups, including 28-day-old young males and females, 63-day-old adult males and females. We compared their saliva volume, total salivary protein amount, salivary mNGF protein amount and salivary hNGF protein amount. The results showed that the saliva volume as well as amounts of total salivary protein, salivary mNGF protein and salivary hNGF protein secreted by 63-day-old transgenic mice were significantly higher than those secreted by sex-match 28-day-old transgenic mice, and the salivary hNGF protein amount secreted by male transgenic mice at the age of 63 days was significantly higher than that of female transgenic mice at the same age; Among 4 groups of mice, 63-day-old male transgenic mice secreted the highest salivary hNGF content, which was about 46 times higher than that secreted by the 28-day-old female transgenic mice. Therefore, 63-day-old male transgenic mice should be selected for saliva collection and hNGF purification.

The Correlation between Malondialdehyde and Nerve Growth Factor Serum Level with Diabetic Peripheral Neuropathy Score.

AIM:This study was conducted to identify malondialdehyde (MDA) serum level, nerve growth factor (NGF) serum level, diabetic peripheral neuropathy score and the correlation between MDA and NGF serum level with diabetic peripheral neuropathy score.METHODS:A cross-sectional study was conducted to observe diabetic patients in the internal medicine department in Dr M. Djamil Hospital, Padang, Indonesia. The MDA serum level was measured using Beuge method with thiobarbituric acid. The NGF serum level was analysed using ELISA method. Diabetic peripheral neuropathy score was defined when history score in Michigan Neuropathy Screening Instrument (MNSI) ≥ 7 and physical assessment score in MNSI > 2.RESULTS:Thirty subjects with diabetes has diabetic peripheral neuropathy score 3.53 (± 0.91), MDA serum level 2.16 (± 2.89) nmol/ml, and NGF serum level 10.56 (± 2.89) pg/dl. There were significant correlations between the MDA serum level and the diabetic peripheral neuropathy score (r = 0.364, p = 0.048), and between the NGF serum level with the diabetic peripheral neuropathy score (r = -0.59, p = 0.001).CONCLUSION:There are high MDA serum level and low NGF serum level in patients with diabetic peripheral neuropathy. Low NGF serum level plays a bigger role than high MDA serum level in diabetic peripheral neuropathy.

High serum nerve growth factor concentrations are associated with good functional outcome at 3 months following acute ischemic stroke

BackgroundPrevious studies in animal model have demonstrated that neurotrophins were associated with functional outcome following stroke. However, the relationship between serum nerve growth factor (NGF) and functional outcome in stroke patients has not been explored. Our objective was to investigate the association between serum NGF concentrations at admission and functional outcome of patients at 3 month after stroke. MethodsOne-hundred eight-five patients with acute ischaemic stroke were recruited in our study. Serum NGF concentrations were measured by ELISA at admission. The stroke severity at admission was assessed by the National Institute of Health Stroke Scale (NIHSS). The modified Rankin Scale (mRS) was used to assess the functional outcome of patients at 3 month after stroke. In addition, 100 healthy controls were recruited. ResultsSerum NGF concentrations were higher in good functional outcome group (mRS score of 0–2) than that in poor functional outcome group (mRS score of 3–6) (9.51 ± 2.33 vs. 8.12 ± 1.61, P < 0.001). Meanwhile, the serum NGF concentrations in healthy group were lower than that in acute ischemic stroke patients (7.17 ± 1.49 vs. 9.15 ± 2.24, P < 0.001). Moreover, our results demonstrated that high serum NGF concentrations (>9.21 ng/l) were independently associated with the better functional prognosis at 3 months following the occurrence of stroke (OR 0.048, 95% CI 0.012–0.185, P < 0.001). ConclusionsHigh concentrations of serum NGF at admission may predict good functional outcome of patients at 3 months after acute cerebral ischemia stroke.

New insights on a NGF-mediated pathway to induce ovulation in rabbits (Oryctolagus cuniculus)†

To investigate the ovulatory mechanisms triggered by raw semen (RS) in rabbits, we examined the expression of nerve growth factor (NGF)-a supposed ovulation-inducing factor (OIF)-and cognate receptors in anterior pituitary, ovary, and cervix as well as plasma NGF and luteinizing hormone (LH) concentrations. Six does/group were sham-inseminated with sterile saline (PBS), naturally mated (NM), inseminated with RS alone or after lumbar anesthesia (ARS), or treatment with COX inhibitors (CIRS). Immunohistochemistry revealed positive signals for NGF and receptors in all tissues. RT-PCR confirmed the presence of the target transcripts in the same tissues, except NTRK1 in the cervix. Circulating NGF concentrations rose 3- to 6-fold (P<0.01) 15 min after semen deposition into the genital tract of NM, RS, and ARS rabbits and remained sustained thereafter. Circulating NGF was 4-fold lower (P<0.01) in CIRS than in RS does indicating that NGF is mainly synthesized by the uterus. A concomitant rise of LH and NGF concentrations was found in 83.3%, 50.0%, and 16.7% of NM, RS, and CIRS does, respectively, but not in ARS (despite high NGF circulating levels). Seminal plasma NGF concentration was 151.9±9.25 μg/mL. The ovulatory responses were 0%, 83.3%, 66.7%, 16.7%, and 0% in PBS, NM, RS, ARS, and CIRS groups, respectively. Present data confirm that, although RS may induce ovulation via endocrine mechanisms through binding to NGF receptors in the ovary, a novel OIF-mediated neural mechanism facilitates ovulation in rabbits.

Multichanneled Nerve Guidance Conduit with Spatial Gradients of Neurotrophic Factors and Oriented Nanotopography for Repairing the Peripheral Nervous System.

Peripheral nerve injuries, causing sensory and motor impairment, affect a great number of patients annually. It is therefore important to incorporate different strategies to promote nerve healing. Among the treatment options, however, the efficacy of nerve conduits is often compromised by their lack of living cells, insufficient growth factors, and absence of the extracellular matrix (ECM)-like structure. To improve the functional recovery, we aimed to develop a natural biodegradable multichanneled scaffold characterized with aligned electrospun nanofibers and neurotrophic gradient (MC/AN/NG) to guide axon outgrowth. The gelatin-based conduits mimicked the fascicular architecture of natural nerve ECM. The multichanneled (MC) scaffolds, cross-linked with microbial transglutaminase, possessed sustainable mechanical stability. Meanwhile, the release profile of dual neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), exhibited a temporal-controlled manner. In vitro, the differentiated neural stem cells effectively extended their neurites along the aligned nanofibers. Besides, in the treated group, the cell density increased in high NGF concentration regions of the gradient membrane, and the BDNF significantly promoted myelination. In a rabbit sciatic nerve transection in vivo model, the MC/AN/NG scaffold showed superior nerve recovery and less muscle atrophy comparable to autograft. By integrating multiple strategies to promote peripheral nerve regeneration, the MC/AN/NG scaffolds as nerve guidance conduits showed promising results and efficacious treatment alternatives for autologous nerve grafts.

Nerve growth factor inhibitor with novel-binding domain demonstrates nanomolar efficacy in both cell-based and cell-free assay systems.

Nerve growth factor (NGF), a member of the neurotrophin family, is known to regulate the development and survival of a select population of neurons through the binding and activation of the TrkA receptor. Elevated levels of NGF have been associated with painful pathologies such as diabetic neuropathy and fibromyalgia. However, completely inhibiting the NGF signal could hold significant side effects, such as those observed in a genetic condition called congenital insensitivity to pain and anhidrosis (CIPA). Previous methods of screening for NGF‐inhibitors used labeling techniques which have the potential to alter molecular interactions. SPR spectroscopy and NGF‐dependent cellular assays were utilized to identify a novel NGF‐inhibitor, BVNP‐0197 (IC 50 = 90 nmol/L), the first NGF‐inhibitor described with a high nanomolar NGF inhibition efficiency. The present study utilizes molecular modeling flexible docking to identify a novel binding domain in the loop II/IV cleft of NGF.

Nogo-p4 Suppresses TrkA Signaling Induced by Low Concentrations of Nerve Growth Factor Through NgR1 in Differentiated PC12 Cells

Background: Regeneration of injured axons in adult mammalian central nervous system (CNS) is not spontaneous. Nogo is a major inhibitory molecule contributing to axon regeneration failure. The molecular mechanisms of Nogo inhibition of axon regeneration are not completely understood. To further investigate the underlying mechanisms, we studied the effects of Nogo-p4, a 25-amino acid core inhibitory fragment of Nogo, on nerve growth factor (NGF)-induced TrkA signaling. Methods: NGF-differentiated PC12 cells were used as cell models. The effects of Nogo-p4 on two key components of TrkA signaling, phosphorylated Erk1/2 and Akt, were analyzed by western blot. Co-immunoprecipitation experiments were performed to detect the formation of NgR1/p75 complexes. Neurite growth was quantified by measuring the neurite length. Results: Nogo-p4 did not significantly affect TrkA signaling induced by 100 ng/ml NGF, but signaling was suppressed when an NGF concentration of 5 ng/ml was used. Further investigation demonstrated that Nogo-p4 affected TrkA signaling in an NGF concentration-dependent manner. Nogo-p4 suppression of TrkA signaling was strong at low (1 and 5 ng/ml), moderate at intermediate (25 ng/ml), but absent at high (50 and 100 ng/ml) NGF concentrations. NEP1-40 attenuated, and NgR1 overexpression enhanced, Nogo-p4 suppression of TrkA signaling induced by low concentrations of NGF. High but not low concentrations of NGF reduced the formation of NgR1/p75 complexes triggered by Nogo-p4. Nogo-p4 strongly inhibited neurite growth induced by low rather than high concentrations of NGF. Conclusion: Nogo-p4 binding with NgR1 suppresses TrkA signaling induced by low concentrations of NGF in differentiated PC12 cells. Suppression of NGF-induced TrkA signaling may be another mechanism by which Nogo inhibits neurite growth.

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.

Anti-apoptotic role and clinical relevance of neurotrophins in diffuse large B-cell lymphomas.

Background:Diffuse large B-cell lymphoma (DLBCL) is a fatal malignancy that needs to identify new targets for additional therapeutic options. This study aimed to clarify the clinical and biological significance of endogenous neurotrophin (nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)) in DLBCL biopsy samples and cell lines.Methods:We analysed expression of NGF, BDNF, and their receptors (Trk, p75NTR) in 51 biopsies and cell lines by immunohistochemistry, immunofluorescence, and western blotting. To investigate the biological role of BDNF/TrkB/p75NTR axis, effects of neurotrophin signalling inhibition were determined on tumour cell survival and vascular endothelial growth factor (VEGF) secretion. The pharmacological pan-Trk inhibitor K252a was used for in vitro and in vivo studies.Results:A BDNF/TrkB axis was expressed in all biopsies, which was independent of the germinal centre B-cell (GCB)/non-GCB profile. p75NTR, TrkB, and BDNF tumour scores were significantly correlated and high NGF expression was significantly associated with MUM1/IRF4, and the non-GCB subtype. Diffuse large B-cell lymphoma cell lines co-expressed neurotrophins and their receptors. The full-length TrkB receptor was found in all cell lines, which was also phosphorylated at Tyr-817. p75NTR was associated to Trk and not to its cell death co-receptor sortilin. In vitro, inhibition of neurotrophin signalling induced cell apoptosis. K252a caused cell apoptosis, decreased VEGF secretion, and potentiated rituximab effect, notably in less rituximab-sensitive cells. In vivo, K252a significantly reduced tumour growth and potentiated the effects of rituximab in a GCB-DLBCL xenograft model.Conclusions:This work argues for a pro-survival role of endogenous neurotrophins in DLBCLs and inhibition of Trk signalling might be a potential treatment strategy for rituximab resistant subgroups.

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.

Clinical significance of NTRK family gene expression in neuroblastomas

Neuroblastomas (NBs) are characterized by clinical heterogeneity, from spontaneous regression to relentless progression. The pattern of NTRK family gene expression contributes to these disparate behaviors. TrkA/NTRK1 is expressed in favorable NBs that regress or differentiate, whereas TrkB/NTRK2 and its ligand brain-derived neurotrophic factor (BDNF) are co-expressed in unfavorable NBs, representing an autocrine survival pathway. We determined the significance of NTRK family gene expression in a large, representative set of primary NBs. We analyzed the expression of the following genes in 814 NBs using quantitative real-time reverse transcriptase polymerase chain reaction (RT-PCR): NTRK1, NTRK2, NTRK3, P75/NGFR, nerve growth factor (NGF), BDNF, IGFR1, and EGFR. Expression (high vs. low) was dichotomized by median expression value and compared to clinical and biological variables as well as outcome. High NTRK1 expression was strongly correlated with favorable age, stage, MYCN status, histology, ploidy, risk group, and outcome (P < 0.0001 for all). However, it did not add significantly to the panel of prognostic variables currently used for cooperative group trials. NTRK2 expression was associated with risk factors but not with outcome. High NGF expression was also associated with most risk factors and weakly with unfavorable outcome. High expression of NTRK1 is strongly associated with favorable risk factors and outcome in a large, representative population of NB patients. It did not add significantly to the current risk prediction algorithm, but it may contribute to future expression classifiers. Indeed, prospective assessment of NTRK1 and NTRK2 expression will identify tumors that would be candidates for NTRK-targeted therapy, either alone or in combination with conventional agents.

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.

Dose and duration of nerve growth factor (NGF) administration determine the extent of behavioral recovery following peripheral nerve injury in the rat

Nerve growth factor (NGF) has been previously shown to support neuron survival and direct neurite outgrowth in vitro, and to enhance axonal regeneration in vivo. However, a systematic analysis of NGF dose and dose duration on behavioral recovery following peripheral nerve injury in rodents has not been previously investigated. Here, we show that NGF promotes a bell shaped dose–response, with an optimal threshold effect occurring at 800 pg/μl. High dose NGF inhibited regeneration. However, this effect could be reversed through functional blockade of p75 receptors, thus implicating these receptors as mediators of the inhibitory response. Longer term evaluation showed that animals administered NGF at 80 ng/day for 3 weeks had greater sensorimotor recovery compared to all other treatment groups. These animals made significantly fewer errors during skilled locomotion, and displayed both increased vertical and fore-aft ground reaction forces during flat surface locomotion. Furthermore, terminal electrophysiological and myological assessments (EMG, wet gastrocnemius muscle weights) corroborated the behavioral data. Overall, these data support the hypothesis that both appropriate dose and duration of NGF are important determinants of behavioral recovery following nerve injury in the rat.

Urinary Nerve Growth Factor Levels in Urinary Tract Diseases With or Without Frequency Urgency Symptoms.

To measure urinary nerve growth factor (NGF) levels in patients with several urinary tract diseases under different conditions and compare with NGF levels in patients with overactive bladder (OAB) and interstitial cystitis/painful bladder syndrome (IC/PBS). Urinary NGF levels were measured using enzyme-linked immunosorbent assay (ELISA) and normalized by urinary creatinine concentration. Patients with acute bacterial cystitis, urinary tract stone, urothelial cell carcinoma, and OAB patients after antimuscarinic therapy were evaluated. The urinary NGF levels of OAB, IC/PBS and controls from previous studies were used for comparison. NGF levels were compared among subgroups and between urinary tract diseases with or without associated OAB symptoms. The urinary NGF levels were also compared among natural filling, after normal saline filling and after potassium chloride test in a group of OAB and IC/PBS patients. Patients with acute bacterial cystitis, urinary tract stones or urothelial cell carcinoma had elevated NGF levels that were not associated with the presence of OAB symptoms. Symptomatic cystitis patients who had resolved OAB symptoms after antibiotic treatment had a significant decrease in urinary NGF levels. The urinary NGF levels decreased significantly in OAB patients with effective antimuscarinic treatment for 6 months, but remained stationary and higher than the controls for up to 12 months after treatment. Urinary NGF is not produced solely in patients with OAB or IC/PBS. Acute bacterial cystitis, urinary tract stones and urothelial cell carcinoma can have high urinary NGF production.

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.