Nerve growth factor

Nerve growth factor (NGF) is widely recognized as a target-derived factor responsible for the survival and maintenance of the phenotype of specific subsets of peripheral neurons and basal forebrain cholinergic nuclei during development and maturation. Other NGF-responsive cells are now known to belong to the hemopoietic-immune system and to populations in the brain involved in neuroendocrine functions. The concentration of NGF is elevated in a number of inflammatory and autoimmune states in conjunction with increased accumulation of mast cells. Mast cells and NGF appear to be involved in neuroimmune interactions and tissue inflammation. Mast cells themselves are capable of producing and responding to NGF, suggesting that alterations in mast cell behavior may trigger maladaptive neuroimmune tissue responses, including those of an autoimmune nature. Moreover, NGF exerts a modulatory role on sensory nociceptive nerve physiology in the adult, and appears to correlate with hyperalgesic phenomena occurring in tissue inflammation. NGF can thus be viewed as a multifactorial modulator of neuroimmune-endocrine functions.     

Nerve growth factor and neuroimmune responses: basic and clinical observations

Nerve growth factor (NGF) is a polypeptide that in addition to its effect on survival of peripheral and brain neuron acts also on a variety of cells localized in the immune system. We have recently shown that the constitutive levels of NGF undergo trough significant changes during inflammatory conditions and in neuroimmune pathologies. We have also reported that autoimmune inflammatory disorders are characterized by a disregulation of synthesis and utilization of NGF. Though the mechanisms implicated in these events are not yet known, there emerging evidence indicating this polypeptide can play an important role in healing processes within the nervous and cutaneous tissues and in inflammatory conditions.     

Human cytokines, tumor necrosis factor, and interferons: gene cloning, animal studies, and clinical trials

Presented is a comprehensive program designed to isolate human cytokine genes and investigate their relative induction, and to analyze cytokine activities in cell culture, animal tumor models, and human clinical trials. Human cytokine cDNAs have been isolated from a cDNA library made from normal human peripheral blood leukocytes (PBLs) treated with Sendai virus and the relative induction of tumor necrosis factor (TNF), alpha and gamma interferons (IFN-alpha, IFN-gamma), and interleukin-1 beta IL-1 beta) genes has been analyzed. In the Sendai virus-induced PBL system, IL-1 beta mRNA was shown to be approximately twofold higher than TNF or IFN-alpha mRNA whereas IFN-gamma mRNA was 50-100-fold lower than TNF or IFN-alpha mRNA. The cytotoxic activity of TNF was analyzed on several cell lines and IFN-alpha and IFN-gamma were shown to potentiate TNF cytotoxicity about 2-200-fold depending on cell lines. The LD50 for recombinant TNF in BALB/c mice was determined to be 6 X 10(7) U/kg and the therapeutic dose of recombinant TNF in sarcoma 180 bearing BALB/c mice was 3 X 10(5) U/kg, indicating a wide therapetic index. Phase I clinical trials of recombinant TNF given I.V. indicated a tolerated dose of 150,000 U/kg with biphasic half-life (T-1/2) of 2 and 31 min following TNF injection. Phase II trials of TNF and trials of TNF combined with IFN-alpha are in progress. These studies indicate that cytokines such as TNF and IFN-alpha are subject to similar induction systems, potentiate each other's activities, and can be tolerated at specific doses for potential therapeutic use.     

Probiotics: from myth to reality. Demonstration of functionality in animal models of disease and in human clinical trials

The enteric flora comprise approximately 95% of the total number of cells in the human body and are capable of eliciting immune responses while also protecting against microbial pathogens. However, the resident bacterial flora of the gastrointestinal tract (GIT) may also be implicated in the pathogenesis of several chronic conditions such as inflammatory bowel disease (IBD). The University College Cork-based Probiotic Research Group has successfully isolated and identified lactic acid bacteria (LAB) which exhibit beneficial probiotic traits. These characteristics include the demonstration of bile tolerance; acid resistance; adherence to host epithelial tissue; and in vitro antagonism of potentially-pathogenic micro-organisms or those which have been implicated in promoting inflammation. The primary objective of this report is to describe the strategy adopted for the selection of potentially effective probiotic bacteria. The study further describes the evaluation of two m embers of the resulting panel of micro-organisms (Lactobacillus salivarius subsp. salivarius UCC118 and Bifidobacterium longum infantis 35624) under in vitro conditions and throughout in vivo murine and human feeding trials. Specifically, an initial feeding study completed in Balb/c mice focused upon (i) effective delivery of the probiotic micro-organisms to the GIT and evaluation of the ability of the introduced strains to survive transit through, and possibly colonise, the murine GIT; (ii) accepting the complexity of the hostile GIT and faecal environments, development of a method of enumerating the introduced bacterial strains using conventional microbiological techniques; and (iii) assessment of the effects of administered bacterial strains on the numbers of specific recoverable indigenous bacteria in the murine GIT and faeces. Additional research, exploiting the availability of murine models of inflammatory bowel disease, demonstrated the beneficial effects of administering probi otic combinations of Lactobacillus salivarius UCC118 and Bifidobacterium longum infantis 35624 in prevention of illness-related weight loss. A further ethically-approved feeding trial, successfully conducted in 80 healthy volunteers, demonstrated that yoghurt can be used as a vehicle for delivery of Lactobacillus salivarius strain UCC118 to the human GIT with considerable efficacy in influencing gut flora and colonisation.     

Nerve growth factor levels in mouse serum: Variations due to stress

The presence of nerve growth factor (NGF) in the serum of adult male mice was assayed using the chick embryo dorsal root ganglion (DRG) bioassay technique in a serum free N1 supplemented medium. Wide variations in the serum-induced nerve fiber outgrowth response were observed when serum was obtained from animals maintained four per cage. Of 64 mice tested, sera of 7 animals induced a profound nerve fiber outgrowth response while the sera of 57 mice failed to show a similar response. In animals kept in isolation for 7 days prior to the start of the experiment, aggression provoked a marked increase in serum NGF levels. In contrast to the sera of aggression-unprovoked mice, the sera of all aggression-provoked mice stimulated a dense nerve fiber outgrowth. The sera of both groups of mice stimulated an intense proliferation and migration of nonneuronal cells. The neurite outgrowth responses elicited by sera from aggression-provoked and unprovoked mice were completely inhibited by the rabbit anti-NGF antiserum. In conclusion, both crowded housing and aggression in mice may provoke an elevation in the serum NGF levels that can be confirmed by the ganglion bioassay technique.     

Reaction to injectable collagen: results in animal models and clinical use

Since its commercial release, Zyderm collagen implant has been used to treat more than 200,000 subjects in the United States for soft-tissue contour defects and more than 250,000 patients internationally (including the United States). Approximately 3 percent of subjects' skin tested with Zyderm collagen experience localized hypersensitivity reactions to collagen, whereas approximately 1 percent of treated patients demonstrate symptoms of hypersensitivity at treatment sites. Of the latter treatment responses reported since the conclusion of clinical trials with Zyderm, 56 percent occurred following the first treatment, 28 percent following the second, 10 percent following the third, and 6 percent following subsequent exposures. The data indicate that most patients receive a median of three treatments (mean = 4.4) with Zyderm collagen, but most patients who are likely to develop sensitivity to Zyderm collagen appear to respond immunologically to the test implant or first treatment exposure. Examining these treatment responses, 45 percent of the patients reported an onset of symptoms within 10 days and 22 percent at more than 30 days following the last treatment with Zyderm collagen. Erythema was the sole symptom in 24 percent of cases, whereas erythema plus induration comprised an additional 42 percent. Antibodies against Zyderm collagen were detected in the sera of 88 percent of these subjects using an ELISA, but no reactivity was observed against human collagen. Sera from patients reporting only systemic symptoms were not found to have anticollagen antibodies. These data suggest that the relative risk of a hypersensitivity reaction to Zyderm collagen does not increase with multiple exposures, since patients who are going to develop an immune response to bovine collagen react with greatest frequency to initial injections of collagen. In animal models, Zyderm collagen was shown to be less immunogenic than other medical devices which are composed of bovine collagen. Specifically, comparative studies were conducted in which Zyderm collagen and hemostatic agents were implanted in the guinea pig subcutaneum: sera from animals treated with collagen-derived hemostatic devices possessed significant levels of anti-implant antibodies (titers greater than 640), whereas animals treated with Zyderm collagen mounted minimal responses (titers less than 40). Additional studies were conducted in which implant materials were compared in a guinea pig parietal (bony defect) model and in a rabbit hemostasis model: in both, Zyderm collagen demonstrated lower immunogenicity than commercial bovine collagen hemostatic agents. Histologic results from these studies showed Zyderm     

Nerve growth factor: structure/function relationships.

Nerve growth factor (NGF), which has a tertiary structure based on a cluster of 3 cystine disulfides and 2 very extended, but distorted beta-hairpins, is the prototype of a larger family of neurotrophins. Prior to the availability of cloning techniques, the mouse submandibular gland was the richest source of NGF and provided sufficient material to enable its biochemical characterization. It binds as a dimer to at least 2 cell-surface receptor types expressed in a variety of neuronal and non-neuronal cells. Residues involved in these interactions and in the maintenance of tertiary and quaternary structure have been identified by chemical modification and site-directed mutagenesis, and this information can be related to their location in the 3-dimensional structure. For example, interactions between aromatic residues contribute to the stability of the NGF dimer, and specific surface lysine residues participate in receptor contacts. The conclusion from these studies is that receptor interactions involve broad surface regions, which may be composed of residues from both promoters in the dimer.     

Nerve growth factor: two receptors,multiple functions

Nerve growth factor (NGF) was characterized over 4 decades ago, and like the other neurotrophins subsequently discovered, it is best known for its trophic role, including the prevention of programmed cell death in specific populations of neurones in the peripheral nervous system. This property can be accounted for by the activation of a tyrosine kinase receptor. NGF also regulates neuronal function, as illustrated by its role in pain and inflammation, and in synaptic plasticity. Finally, NGF recently was shown to activate the neurotrophin receptor p75 (p75^NTR), a receptor with no intrinsic catalytic activity and with similarities to members of the tumor necrosis factor receptor family. During normal development, the activation of p75^NTR by NGF actually kills cells in the central nervous system. One remarkable property of NGF is then that it controls cell numbers in opposite ways in the developing nervous system, a result of its unique ability to activate two different receptor types. BioEssays 20:137–145, 1998. © 1998 John Wiley & Sons, Inc.     

The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models

Over the past two decades it has become widely appreciated that a relationship exists between the insulin-like growth factors (IGFs) and cancer. Many cancers have been shown to overexpress the IGF-I receptor and produce the ligands (IGF-I or IGF-II) and some combinations of the six IGF-binding proteins. With the recent demonstration by epidemiological studies that an elevated serum IGF-I level is associated with an increased relative risk of developing a number of epithelial cancers, interest has been sparked in this area of research with the possibility of targeting the IGF-I receptor in cancer treatment protocols. This review highlights many of the most relevant studies in this exciting area of research, focusing in particular on lessons learned from animal models of cancer.     

Nerve growth factor binds to serum alpha-2-macroglobulin.

Nerve growth factor labelled with ¹²⁵I and incubated with mouse serum became associated with a serum protein that eluted in a high molecular weight position on Sepharose 6B. The binding protein for the nerve growth factor was purified to homogeneity and characterized as the murine counterpart of the human α₂-macroglobulin. The nerve growth factor was quantitatively bound to highly purified mouse α₂-macroglobulin after a few hours of incubation. The interaction displayed little species specificity in as much as human and equine α₂-macroglobulin strongly bound murine nerve growth factor.     

Nerve growth factor: a chemotactic factor for polymorphonuclear leukocytes in vivo

Previous studies have shown that mouse submandibular gland nerve growth factor (NGF) stimulates chemotactic migration of human polymorphonuclear leukocytes in vitro. The results of the present study demonstrate that subdermal injection of NGF in mice also stimulates rapid and marked chemotactic recruitment of leukocytes. This property of NGF is manifest in the nanomolar range of concentrations, it requires the known serine class protease activity of the growth factor, and it does not require participation of the fifth component of complement. Another, as yet unrecognized, C5-independent pathway must be involved. Chemotactic stimulation of cells involved in the early inflammatory response to injury may help to explain earlier observations that NGF can accelerate the rate of contraction of experimentally induced wounds in mice.     

神经生长因子与骨折愈合

神经生长因子主要由来源于神经嵴的神经元支配的靶组织产生,其被这些神经元轴突摄取后逆行运输至胞体,通过多种途径调节神经细胞的基因转录而发挥生物效应,维持神经元的存活、刺激轴突的生长.并对外周神经的发育、营养起重要的作用.在骨组织和骨折骨痴中均可见神经生长因子及其受体的表达,神经生长因子主要是通过促进骨折部位神经的再生参与骨折修复.骨折愈合的机制十分复杂,神经生长因子对骨组织的作用也是多方面、多层次和相互交叉的,其机制尚未完全明确.虽然神经生长因子促进骨折修复作用机制的研究已经取得一些进展,但仍处于初级阶段,其作用机制仍不明确.     

Nerve growth factor and pancreatic APUD cells

Pancreatic endocrine cells have been considered APUD cells and been thought to be of neural crest origin. Neonatal rats were passively immunized with nerve growth factor antiserum and the development of neural crest derived superior cervical ganglia was markedly inhibited. The pancreatic content of glucagon, insulin, and somatostatin was unaffected, suggesting that pancreatic A,B, and D cells are under different developmental control than are cells of known neural crest origin.