Articulating the "stem cell niche" paradigm through the lens of non-model aquatic invertebrates.

Stem cells (SCs) in vertebrates typically reside in "stem cell niches" (SCNs), morphologically restricted tissue microenvironments that are important for SC survival and proliferation. SCNs are broadly defined by properties including physical location, but in contrast to vertebrates and other "model" organisms, aquatic invertebrate SCs do not have clearly documented niche outlines or properties. Life strategies such as regeneration or asexual reproduction may have conditioned the niche architectural variability in aquatic or marine animal groups. By both establishing the invertebrates SCNs as independent types, yet allowing inclusiveness among them, the comparative analysis will allow the future functional characterization of SCNs.

Increased serum levels of proNGF, mature NGF and interleukins in burn-injured children.

OBJECTIVE: Burns are among the most common injuries in children. In burns of more than 20% of the total body surface area, a systemic inflammatory response involving several chemical mediators occurs. Among them, nerve growth factor (NGF) regulates the inflammatory response related to wound healing and promotes keratinocyte proliferation and angiogenesis. The aim of our study was to investigate the physiological response to injury in children with moderate-severe burns, assaying proNGF, mature NGF (mNGF), interleukins (IL)-1ß, and Il-10 serum levels. PATIENTS AND METHODS: This is a prospective observational study, including twelve children hospitalized for moderate-severe burns at the Gemelli Hospital (Rome). Their laboratory features were compared to those of patients with obstructive hydrocephalus who underwent surgery. RESULTS: Our results showed an increase in proNGF and mNGF serum levels. In burn patients, proNGF levels increased before mNGF, and serum concentrations of both were not correlated with burn extension and depth. The most significant levels of mNGF and proNGF were reported in scalds involving the face. Serum IL-1ß and IL-10 peak levels were reached with a time-course pattern similar to proNGF. CONCLUSIONS: Our preliminary results validate the hypothesis that serum levels of proNGF and mNGF may represent inflammatory biomarkers useful for monitoring burn patients and defining new strategies for their treatment.

Electroacupuncture counteracts the development of thermal hyperalgesia and the alteration of nerve growth factor and sensory neuromodulators induced by streptozotocin in adult rats.

AIMS/HYPOTHESIS: Diabetes is considered the leading cause of neuropathies in developed countries. Dysfunction of nerve growth factor (NGF) production and/or utilisation may lead to the establishment of diabetic neuropathies. Electroacupuncture has been proved effective in the treatment of human neuropathic pain as well as in modulating NGF production/activity. We aimed at using electroacupuncture to correct the development of thermal hyperalgesia and the tissue alteration of NGF and sensory neuromodulators in a rat model of type 1 diabetes. METHODS: Adult rats were injected with streptozotocin to induce diabetes and subsequently treated with low-frequency electroacupuncture for 3 weeks. Variation in thermal sensitivity was studied during the experimental course. Hindpaw skin and spinal cord protein content of NGF, NGF receptor tyrosine kinase A (TrkA), substance P (SP), transient receptor potential vanilloid 1 (TRPV1) receptor and glutamic acid decarboxylase-67 (GAD-67) were measured after electroacupuncture treatments. The skin and spinal cord cellular distribution of TrkA was analysed to explore NGF signalling. RESULTS: Early after streptozotocin treatment, thermal hyperalgesia developed that was corrected by electroacupuncture. The parallel increases in NGF and TrkA in the spinal cord were counteracted by electroacupuncture. Streptozotocin also induced variation in skin/spinal TrkA phosphorylation, increases in skin SP and spinal TRPV1 and a decrease in spinal GAD-67. These changes were counteracted by electroacupuncture. CONCLUSIONS/INTERPRETATION: Our results point to the potential of electroacupuncture as a supportive therapy for the treatment of diabetic neuropathies. The efficacy of electroacupuncture might depend on its actions on spinal/peripheral NGF synthesis/utilisation and normalisation of the levels of several sensory neuromodulators.

Acupuncture in clinical and experimental reproductive medicine: a review.

BACKGROUND: Acupuncture has been used as treatment for infertility for hundreds of years, and recently it has been studied in male and female infertility and in assisted reproductive technologies, although its role in reproductive medicine is still debated. AIM: To review studies on acupuncture in reproductive medicine, in experimental and clinical settings. METHODS: Papers were retrieved on PubMed and Google Scholar and were included in the review if at least the abstract was in English. RESULTS: There is evidence of benefit mainly when acupuncture is performed on the day of embryo transfer (ET) in the live birth rate. Benefit is also evident when acupuncture is performed for female infertility due to polycystic ovary syndrome (PCOS). There is some evidence of sperm quality improvement when acupuncture is performed on males affected by idiopathic infertility. Experimental studies suggest that acupuncture effects are mediated by changes in activity of the autonomic nervous system and stimulation of neuropeptides/neurotransmitters which may be involved in the pathogenesis of infertility. CONCLUSIONS: Acupuncture seems to have beneficial effects on live birth rate when performed on the day of ET, and to be useful also in PCOS as well as in male idiopathic infertility, with very low incidence of side effects. However, further studies are necessary to confirm the clinical results and to expand our knowledge of the mechanisms involved.

Muscarinic receptors modulate Nerve Growth Factor production in rat Schwann-like adipose-derived stem cells and in Schwann cells.

Regenerative capability of the peripheral nervous system after injury is enhanced by Schwann cells (SCs) producing several growth factors. The clinical use of SCs in nerve regeneration strategies is hindered by the necessity of removing a healthy nerve to obtain the therapeutic cells. Adipose-derived stem cells (ASCs) can be chemically differentiated towards a SC-like phenotype (dASCs), and represent a promising alternative to SCs. Their physiology can be further modulated pharmacologically by targeting receptors for neurotransmitters such as acetylcholine (ACh). In this study, we compare the ability of rat dASCs and native SCs to produce NGF in vitro. We also evaluate the ability of muscarinic receptors, in particular the M2 subtype, to modulate NGF production and maturation from the precursor (proNGF) to the mature (mNGF) form. For the first time, we demonstrate that dASCs produce higher basal levels of proNGF and mature NGF compared to SCs. Moreover, muscarinic receptor activation, and in particular M2 subtype stimulation, modulates NGF production and maturation in both SCs and dASCs. Indeed, both cell types express both proNGF A and B isoforms, as well as mNGF. After M2 receptor stimulation, proNGF-B (25 kDa), which is involved in apoptotic processes, is strongly reduced at transcript and protein level. Thus, we demonstrate that dASCs possess a stronger neurotrophic potential compared to SCs. ACh, via M2 muscarinic receptors, contributes to the modulation and maturation of NGF, improving the regenerative properties of dASCs.

Hair cells in an ascidian (Tunicata) and their evolution in chordates.

In ascidians, mechanoreceptors of the oral area are involved in monitoring the incoming water flow. Sensory cells are represented by scattered, ciliated primary cells (sending their own axons to the cerebral ganglion) or secondary sensory cells (axonless cells forming afferent and efferent synapses with neurons, whose somata are located in the ganglion) of the coronal organ. Coronal cells have varying morphologies: in species of the Enterogona order, they are multiciliate, whereas those of Pleurogona possess an apical apparatus composed of one or two cilia accompanied by stereovilli, in some cases also graded in length. The coronal organ has been proposed as a homologue to the vertebrate octavo-lateralis system, because coronal cells resemble vertebrate hair cells for morphology, embryonic origin and arrangement. In the ascidian Molgula socialis (Pleurogona), we now describe the morphology of the coronal organ, which contains a few associated rows of sensory cells that run the whole length of the oral velum and the branched tentacles. Three kinds of sensory cells, accompanied by specialised supporting cells, are present. Comparisons between the coronal organ and other chordate mechanosensory structures suggest that hair cells originated in the common ancestor of chordates.

Streptozotocin-induced diabetes is associated with changes in NGF levels in pancreas and brain.

Type 1 diabetes mellitus (DM), a "classical" result of a pancreatic-beta cell damage, is associated with various metabolic, neuronal, endocrine and immune alterations at cellular, tissue and organ levels. Nerve growth factor (NGF) is one of the most extensively studied neurotrophic factors, which is produced and released by numerous cells including the pancreatic beta cells. NGF plays an important role during brain development and may be able to delay or even reverse damaged forebrain cholinergic neurons that undergo degeneration in aged animals and in Alzheimer's disease (AD). Recent reports indicate that experimentally induced DM in rodents can cause brain biochemical and molecular alterations similar to those observed in sporadic AD. Given the importance of NGF in the pathophysiology of brain cholinergic neurons, we looked for NGF changes in the pancreas and brain of diabetic rats. The aim of this study was, therefore, to investigate the effect of streptozotocin-induced DM on NGF and NGF receptor expression in pancreas and brain. The results showed that DM is associated with altered NGF, NGF-receptor expression in both pancreas and brain.

Changes in HbA1c and circulating and adipose tissue androgen levels in overweight-obese women with polycystic ovary syndrome in response to electroacupuncture.

AIM: Insulin sensitivity is ~40% lower in women with polycystic ovary syndrome (PCOS) than in controls. We tested the hypothesis that 5 weeks of electroacupuncture treatment improves glucose regulation and androgen levels in overweight/obese women with PCOS. MATERIAL AND METHODS: Seventeen women with PCOS, aged 18 to 38 years, with a body mass index (BMI) ≥25 kg/m2 and diagnosed with PCOS were included in this experimental and feasibility study and subjected to five weeks of electroacupuncture treatments three times/week. The primary outcome was changes in whole-body glucose homeostasis measured by euglycemic hyperinsulinemic clamp before and after the intervention. Secondary outcome were changes in HbA1c, circulating catecholamines, adipocyte size and adipose tissue expression of sex steroids and nerve growth factor (NGF). RESULTS: No significant change in glucose homeostasis was observed, but HbA1c decreased by 9.5% (p = 0.004), circulating testosterone decreased by 22% (p = 0.0007) and dihydrotestosterone decreased by 12% (p = 0.007). The two vagal activity markers of plasma serotonin levels and the dopamine metabolite homovanillic acid decreased by 21% (p = 0.027) and 20% (p = 0.011), respectively. Adipose tissue concentrations of testosterone decreased by 18% (p = 0.049), and androstenedione decreased by 13% (p = 0.035), and mature NGF/proNGF ratio, a marker of sympathetic activity, increased (p = 0.04). These changes occurred without changes in anthropometrics. CONCLUSION: Five weeks of electroacupuncture treatment improves HbA1c and circulating and adipose tissue androgens in women with PCOS. This effect is mediated, at least in part, via modulation of vagal activity and adipose tissue sympathetic activity. Based on these findings, we have recently initiated a randomized controlled study (NTC02647827).

Effect of exercise on ovarian morphology and expression of nerve growth factor and alpha(1)- and beta(2)-adrenergic receptors in rats with steroid-induced polycystic ovaries.

Oestadiol valerate (EV)-induced polycystic ovaries (PCO) in rats cause anovulation and cystic ovarian morphology. Denervation of ovarian sympathetic nerves restores ovulatory disruption. In the present study, we determined whether 5 weeks of voluntary exercise influence ovarian morphology and the expression of sympathetic markers in the EV-induced PCO rat model. The effect of exercise on (i) ovarian morphology; (ii) mRNA and protein expression of nerve growth factor (NGF); and (iii) mRNA and number of ovarian-expressing cells for the NGF receptor (p75 neurotrophin receptor) and the alpha(1a)-, alpha(1b)-, alpha(1d)- and beta(2)-adrenergic receptors (ARs) in rats with EV-induced PCO was evaluated. PCO was induced by a single i.m. injection of EV, and controls were injected with oil alone in adult cycling rats. The rats were divided into four groups: (i) control (oil); (ii) exercise group (oil + exercise); (iii) a PCO group (EV); and (iv) a PCO exercise group (EV + exercise). The exercise and PCO exercise groups ran voluntarily for 5 weeks in computer-monitored wheels placed in the cages where they were housed. The results obtained indicated that ovarian morphology was almost normalised in the PCO exercise group; NGF mRNA and protein concentrations were normalised in the PCO exercise group; high numbers of NGF receptor expressing cells in PCO ovaries were lowered by exercise; and the number of immunopositive cells of the different AR subtypes were all reduced after exercise in the PCO group, except for the alpha(1b)- and beta(2)-AR whereas the mRNA levels were unaffected, indicating transcriptional regulation. In conclusion, our data indicate a beneficial effect of regular exercise, as a modulator of ovarian sympathetic innervation, in the prevention and treatment of human PCOS.

Mechanism of neurogenesis during the embryonic development of a tunicate.

Ascidian and vertebrate nervous systems share basic characteristics, such as their origin from a neural plate, a tripartite regionalization of the brain, and the expression of similar genes during development. In ascidians, the larval chordate-like nervous system regresses during metamorphosis, and the adult's neural complex, composed of the cerebral ganglion and the associated neural gland is formed. Classically, the homology of the neural gland with the vertebrate hypophysis has long been debated. We show that in the colonial ascidian Botryllus schlosseri, the primordium of the neural complex consists of the ectodermal neurohypophysial duct, which forms from the left side of the anterior end of the embryonal neural tube. The duct contacts and fuses with the ciliated duct rudiment, a pharyngeal dorsal evagination whose cells exhibit ectodermic markers being covered by a tunic. The neurohypophysial duct then differentiates into the neural gland rudiment whereas its ventral wall begins to proliferate pioneer nerve cells which migrate and converge to make up the cerebral ganglion. The most posterior part of the neural gland differentiates into the dorsal organ, homologous to the dorsal strand. Neurogenetic mechanisms in embryogenesis and vegetative reproduction of B. schlosseri are compared, and the possible homology of the neurohypophysial duct with the olfactory/adenohypophysial/hypothalamic placodes of vertebrates is discussed. In particular, the evidence that neurohypophysial duct cells are able to delaminate and migrate as neuronal cells suggests that the common ancestor of all chordates possessed the precursor of vertebrate neural crest/placode cells.

Neurogenic role of the neural gland in the development of the ascidian, Botryllus schlosseri (Tunicata, Urochordata).

In adult ascidians, the neural complex consists of a cerebral ganglion (the brain) and the associated neural gland. We have studied the development of the neural complex during the vegetative reproduction of the colonial ascidian Botryllus schlosseri, the buds of which arise from the atrial mantle of the parental zooid. Each bud develops into a new organism within which a neural complex becomes differentiated. We found that the presumptive (pioneer) nerve cells that ultimately form the cerebral ganglion of the adult arise as migratory cells from a primordial cluster of rudimentary gland cells. Hence, the neural gland appears to be neurogenic in that it serves as the cellular source of components that differentiate into conventional nerve cells. In the adult, these cells take on the form of a typical invertebrate ganglion with an outer cortex of nerve cell bodies and an internal medulla. This medulla consists of a neuropile of neuronal processes making classical synaptic contacts. The adult neural gland differentiates into a structure with a ciliated duct that opens into the branchial chamber, the body of the gland, and the dorsal organ, which is quite distinct from the dorsal strand of other ascidians. The rudimentary neural gland cells, therefore, differentiate into one of two distinct pathways: the first, glandular, is possibly involved in the evaluation of environmental signals, and the other, nervous, leads to brain formation. This compares with the vertebrate situation in which the olfactory-pituitary placodes are thought to originate from a common cellular source. Thus, these data support the earlier contention of a homology between the tunicate neural gland and the vertebrate adenohypophysis.

Cholecystokinin-8 and nerve growth factor: two endogenous molecules working for the upkeep and repair of the nervous system.

Cholecystokinin-8 (CCK-8), the small peptide initially described as a gastric factor involved in the regulation of feeding behavior, is today recognized as one of the most abundant neurotransmitters/ neuropeptides in brain and is an important signal factor for the peripheral and central nervous systems. In the past twenty years, many studies have focused on possible clinical applications of this peptide and its receptor ligands in psychiatric diseases and gastrointestinal pathologies. Recently it has been suggested that CCK-8 may also have a neuroprotective role, thus opening a new field of interest around the physiology and the pharmacology of this neuropeptide and its receptors. It has been demonstrated that CCK-8 counteracts neuronal deficit following chemical or surgical lesions in both the central and peripheral nervous systems and that Nerve Growth factor (NGF) is involved in the CCK-induced recovery process. By using selective CCK receptor antagonists it has been demonstrated that CCK-8, when injected intraperitoneally, has the ability to stimulate NGF synthesis in brain and peripheral organs by a mechanism that involves the activation of CCK receptors. As has been widely reported, NGF is an essential survival and differentiative factor for selective neuronal populations of the PNS and CNS and plays a role in the events of degeneration and repair of the nervous system in diseases with different etiologies, e.g. neurodegenerative and autoimmune diseases as well as diabetes-associated pathologies. The possibility of using NGF in therapy has been evaluated and systemic and intracerebral NGF treatment have been tested in patients and animal models. Although the results of these studies are encouraging, the difficulty to predict and/or eliminate the side effects of NGF/NGF antibody treatment has made it difficult to fully evaluate the potential of the beneficial effects. In this context recent results obtained in our laboratories may offer a new prospective for the pharmacological approaches to the diseases associated with altered NGF production and functions. The data of our recent observations on NGF and CCK-8 is covered in this review.

Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas.

PURPOSE: A recent clinical report demonstrated that topical nerve growth factor (NGF) treatment in patients affected by corneal neurotrophic ulcers induced epithelial and stromal healing restoring corneal integrity. Mechanisms(s) undergoing these clinical NGF actions are still unclear. The aim of this study was to investigate the role of NGF in human and rat cornea physiopathology. METHODS: Expression of high-affinity NGF receptors, NGF-mRNA, and NGF protein was evaluated in human and rat normal corneas, in human and rat corneal epithelial cell cultures, in human corneal organ culture, and in the rat cornea after an experimental model of epithelial injury, by means of immunohistochemistry, in situ hybridization reverse transcription-polymerase chain reaction, and enzyme-linked immunosorbent assay. RESULTS: The resultant data demonstrated that NGF is a constitutive molecule present and produced in normal human and rat corneas. In vitro human and rat corneal epithelial cells produce, store, and release NGF and also express high-affinity NGF receptors (TrkA). In human organ culture, epithelium, keratocytes, and endothelium have been shown to bind exogenous radiolabeled NGF, and the epithelial cells' binding was increased after epithelium injury. In vivo, after rat corneal epithelial injury, a transient increase of corneal NGF levels was observed. Inhibition of endogenous NGF activity by neutralizing anti-NGF antibodies delayed the corneal epithelial healing rate, whereas exogenous administration of NGF accelerated healing. CONCLUSIONS: Taken together, the above findings show that NGF plays an important role in corneal physiopathology and suggest that this neurotrophin may exert therapeutic action in wide-spectrum corneal diseases.

Cholecystokinin-8 enhances nerve growth factor synthesis and promotes recovery of capsaicin-induced sensory deficit.

Alterations of nerve growth factor (NGF) expression have been demonstrated during peripheral nerve disease and the impaired expression or synthesis and transportation of NGF has been correlated with the pathogenesis of several peripheral neuropathies. Since exogenous NGF administration seems to cause undesired side-effects, therapeutical strategies based on the regulation of endogenous synthesis of NGF could prove useful in the clinical treatment of these disorders. The aim of the present study was to analyse the effects of exogenous peripheral administration of the neuropeptide cholecystokinin-8 (CCK-8) on endogenous NGF synthesis, NGF mRNA and distribution of peripheral neuropeptides which are known to be regulated by this neurotrophin. To address these questions we studied the effects of capsaicin (CAPS) before and after the administration of CCK-8 on NGF levels, NGF mRNA expression and localization, and the concentration of substance P (SP) and calcitonin gene-related peptide (CGRP) in peripheral tissue These studies demonstrate that administration of the CCK-8 induces an increase of NGF protein and mRNA in peripheral tissue. NGF level in paw skin of CAPS/CCK-8-treated mice is 3 fold higher than in controls (1241+/-110 pg gr(-1) of tissue wet weight versus 414+/-110 pg gr(-1) of controls) and nearly 6 fold higher than in CAPS-treated mice (1241+/-110 pg gr(-1) versus 248+/-27 pg gr(-1)). The increase of NGF is correlated with the recovery of impaired nocifensive behaviour and with an overexpression of SP and CGRP. The evidence that CCK-8 promotes the recovery of sensory deficits suggests a potential clinical use for this neuropeptide in peripheral neuropathies.

Cholecystokinin-8 promotes recovery of sympathectomy induced by 6-hydroxydopamine in adult mice.

We used an experimental model of sympathetic neuropathy to investigate the effects of intraperitoneal cholecystokinin-8 (CCK-8) administration on the recovery of injured peripheral neurones. After treatment of adult mice with 6-hydroxydopamine (6-OHDA), which known to induce peripheral sympathectomy, nerve growth factor (NGF) in peripheral tissue first increased and then rapidly decreased to baseline levels. Following this observation, sympathectomised mice were treated with CCK-8 starting when the NGF levels lowered toward the control value. Our results show that injections with 8 nmol/kg of CCK-8 promote not only recovery of noradrenergic innervation but also NGF and neuropeptide Y (NPY) synthesis in peripheral tissue. This latter observation suggests that the effect of CCK-8 might be mediated through the stimulation of NGF synthesis.

Neonatal handling in EAE-susceptible rats alters NGF levels and mast cell distribution in the brain.

Maternal separation in neonatal rodents causes a wide range of behavioural and metabolic alterations, affecting the physiological response of the neuro-immune-endocrine system. For example, interference with the normal mother-infant interactions leads to an increased susceptibility to experimentally-induced allergic encephalomyelitis (EAE) in adult life. Since it has been reported that mast cells (MCs) participate in the pathophysiology of the autoimmune inflammatory disease multiple sclerosis (MS) and also EAE and that brain nerve growth factor (NGF) levels are altered in EAE, studied whether maternal separation and gentle manipulation (gentling) of neonatal Lewis rats perturb NGF levels or MC distribution in the brain. EAE-induction susceptibility in adult life was also evaluated and NGF levels and mast cell distribution within the hippocampus and thalamus were measured at 0, 10, 20 and 60 postnatal days. Our results show an exacerbation of clinical signs in rats separated from mothers where EAE was induced, a general decrease in NGF protein levels and MC number in the hippocampus during the first developmental period and significant increase in the number of MC in the hippocampus and the thalamus at young-adulthood (60 days of age). These results indicate that disruption of the maternal bond during early infancy may produce long-lasting alterations in the brain cellular and molecular environment, leading to increased susceptibility to EAE in adult life.

RT-PCR ELISA method for the analysis of neurotrophin mRNA expression in brain and peripheral tissues.

The levels of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in brain and periphery are susceptible to changes during development and as result of different physiopathological conditions, such as stress and aging and during the onset and progression of neurological and autoimmune diseases. Despite the sensitive methods for measurement of neurotrophin protein levels in different tissues, no easily applicable methods to evaluate changes in the level of NGF and BDNF mRNA expression within physiological range have been described. This study reports the development of a reproducible and simple procedure for measurement of neurotrophin mRNA expression in brain and peripheral tissues based upon an enzyme linked immunosorbent assay (ELISA) detection system of reverse transcriptase-polymerase chain reaction (RT-PCR) products. The major advantages of this RT-PCR ELISA procedure is to allow the co-amplification of diverse mRNAs starting from small amounts of tissues; to contemporaneously test a large number of samples; to be rapid and to use only commercial reagents and widely available equipment. The procedure could also be useful in studies addressed to measure the pattern of expression of molecules involved in the pathogenesis of neurodegenerative and inflammatory diseases, such as neuropeptides and cytokines.

Nerve growth factor release by human synovial fibroblasts prior to and following exposure to tumor necrosis factor-alpha, interleukin-1 beta and cholecystokinin-8: the possible role of NGF in the inflammatory response.

OBJECTIVE: Aim of this study was to investigate the synthesis, release and effects of nerve growth factor (NGF) in human synovial cells isolated from synovial tissue specimen from healthy and osteoarthritis (OA) patients. METHODS: Human synovial fibroblasts cultures were established starting from healthy and osteoarthritis patients. NGF protein levels in the culture medium, NGFmRNA and high-affinity NGF receptor (Tyrosine kinase A: TrkA) expression in the cells were evaluated in basal conditions and after stimulation with pro-inflammatory cytokines or with the neuropeptide cholecystokinin-8 (CCK-8). The effect of NGF supplement to culture medium on cell proliferation, TrkA expression, and tumour necrosis factor-alpha (TNF-alpha) and inducible-nitric oxide synthase (iNOS) production was investigated. RESULTS: Under basal conditions human synovial cells produce and release NGF. Both interleukin-1-beta (IL-1 beta) and TNF-alpha, but not CCK-8 promote NGF synthesis and release from OA cells. TrkA NGF receptors are also expressed in both normal and OA synovial cells. NGF, but not IL-1 beta, TNF-alpha and CCK-8, enhances the expression of TrkA in isolated synovial cells. NGF down-regulates IL-1 beta-induced TNF-alpha and iNOS production by OA synovial fibroblasts. CONCLUSIONS: NGF is produced and released and TrkA receptors are expressed in synovial inflammation. Overexpression of NGF in inflammed joints might be involved in the modulation rather than in the induction of the joint inflammatory response.

Topical application of nerve growth factor in human diabetic foot ulcers. A study of three cases.

Three diabetic patients with leg or foot ulcers unresponsive to conventional therapies were treated with topical application of Nerve Growth Factor (NGF). The results showed that NGF promotes healing after 5-14 weeks of treatment. This study suggests that the use of topical application of NGF may represent a new useful tool for the management of difficult diabetic ulcers.

Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis.

In this study we investigate the neurotoxic action of Cisplatin (6 micrograms/g body weight for 5 treatment cycles during 15 weeks with a total dose of 30 micrograms/g), an antitumor drug, and its effect on the level of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in peripheral tissues. We found that Cisplatin in adult rodents impairs peripheral sensory function and both sympathetic and sensory peripheral innervation as shown by the hot-plate response, catecholamine distribution and substance P immunoreactivity respectively. These changes are associated with decreased NGF in intestine, paws, and bladder while NGF increased in the spinal cord. Also BDNF decreased in bladder and paws and increased in spinal cord and intestine. To further investigate the role of NGF in the pathogenesis of Cisplatin-induced peripheral neuropathies a group of animals was injected with NGF (1 microgram/g every 4 days for 4 times) following Cisplatin treatment and evaluated for sensory function, sympathetic and sensory innervation and BDNF levels. Data demonstrated that exogenous NGF administration is able to restore biochemical, structural and functional changes induced by Cisplatin. These findings suggest that the reduction of NGF availability could be a cause of Cisplatin-induced peripheral neuropathies and that NGF exogenous administration could prevent or reduce Cisplatin neurotoxicity also in cancer patients, reducing the side effects of chemotherapy.