Nerve growth factor regulates neuroectodermal tumor cell responses to mitogenic growth factors

Previous studies showed that nerve growth factor (NGF) decreases the proliferation of neuroectodermal tumor (NET) cells (C-1300 and Neuro2A murine neuroblastoma, PC12 rat pheochromocytoma) within 5-7 days in a dose-dependent manner. This effect is regulated by the concentration of serum in the culture medium. Therefore, we hypothesized that NGF exerts its antimitogenic activities by interfering with the proliferative action of other growth factors. We studied the effects of short-term vs. long-term as well as endogenous vs. exogenous NGF on NET cell proliferation in response to various mitogenic growth factors. Retrovirus-mediated transfer of the beta-NGF gene into NET cells activated TrkA and consistently decreased their proliferative responses to insulin-like growth factor (IGF)-I, IGF-II, fibroblast growth factor-2, and epidermal growth factor (EGF), down-regulating EGF and IGF-I binding sites. It also decreased tyrosine phosphorylation of ERK-1, STAT3, and EGF or IGF receptors after treatment with IGF-I or EGF. Long-term incubation of NET cells with NGF mimicked the responses induced by beta-NGF gene transfer, albeit in a reversible manner. Short-term NGF treatment augmented the proliferative responses to IGF-I or EGF by enhancing cell survival. It also increased tyrosine phosphorylation of signal transducing proteins after exposure to IGF or EGF, an effect opposite to that of long-term NGF treatments. Hence, long-term NGF exposure in vitro might better reproduce the effects of NGF in vivo than short-term treatments. Only long-term exposure to NGF decreased the responses of NET cells to mitogenic growth factors by down-regulating their receptors and attenuating signal transduction events required for cell proliferation. These results suggest that NGF could exert similar actions on cellular responses to growth factors in vivo.     

Nerve growth factor and Alzheimer's disease

Alzheimer's disease is associated with a pronounced loss of the cholinergic neurons that form the ascending cholinergic projections of the basal forebrain. Even though the disease is also characterized by changes in other neuronal systems and by a high frequency of neuronal plaques and tangles, the cholinergic deficit seems to be a principal element responsible for the memory loss typical of Alzheimer's disease. This review summarizes findings in experimental animals which indicate that nerve growth factor (NGF), a well-characterized protein, acts as a neurotrophic factor for cholinergic neurons of the basal forebrain. NGF is present in the target areas of these cholinergic neurons and affects their survival, fiber growth, and expression of transmitter-specific enzymes. Furthermore, NGF is able to prevent the degeneration of cholinergic neurons in adult rats with experimental lesions mimicking the cholinergic deficit in Alzheimer's disease. These findings suggest that increasing the availability of NGF to human cholinergic cells might promote their survival in certain disease processes. Additional steps are discussed for establishing the possible involvement of NGF in the pathogenesis of Alzheimer's disease and the development of an effective therapy.     

Nerve growth factor and neural oncology

The precise role of the nerve growth factor protein (NGF) during the growth and development of the human nervous system is not determined. Although it appears to influence a number of neural functions, its mechanism of action is poorly understood. A number of researchers have proposed that NGF may be involved in several pathological conditions including cancer. It has been shown that NGF is secreted by certain sarcoma (23), neuroblastoma (113), and glioma (7,102,136) cell lines and can bind to neuroblastoma and metastatic melanoma cell lines (42). Neuroblastoma (136,181) and pheochromocytoma (165) cells in vitro can be induced by NGF to differentiate toward a morphologically "more benign" state and appropriate NGF treatment of rats can reduce the number of chemically induced gliomas and neurinomas (174,178). NGF can also reduce the growth of intracerebrally inoculated anaplastic glioma cells (172). Anti-NGF treatment of rats (178) and mice (179) can alter the tumor distribution observed following ethylnitrosourea or benzo(a)pyrene treatment (10). In humans, it has been reported that serum levels of NGF are usually elevated in persons "at risk" for neurofibromatosis (156). The precise nature of the NGF role is not known in these instances. Further understanding of the action of NGF could be of clinical importance.     

Nerve growth factor and the neostriatum

1. The present review summarizes evidence describing the expression, immunoreactivity, binding, transport, development, aging, and functions of NGF in the mammalian neostriatum. 2. Neostriatal NGF binding sites and intrinsic cholinergic neurons are co-localized, increase at a similar rate during ontogeny, and are lost to an equal extent following age- or injury-induced loss of neostriatal neurons. 3. Exogenously administered NGF augments ChAT activity in the intact caudate-putamen, nucleus accumbens, and following mechanical or excitotoxin-induced cholinergic injury. NGF antibodies lower ChAT in the intact caudate-putamen. 4. Neostriatal cholinergic interneurons are lost in the aged rat but also in Alzheimer's disease, Parkinson's disease, supranuclear palsy, and Huntington's chorea. Future studies need to address the extent to which these losses result from an abbreviation of NGF production, binding, or transport and whether rhNGF administration may retard or reverse these cholinergic losses.     

Nerve growth factor treatment in dementia

Millions of people are affected by Alzheimer disease. As longevity increases, so will the number of patients with dementia. This has led to an intense search for successful treatment strategies. One area of interest is neurotrophic factors. Brain development and neuronal maintenance, as well as protective efforts, are mediated by a large number of different neurotrophic factors acting on specific receptors. In neurodegenerative disorders, there may be a possibility of rescuing degenerating neurons and stimulating terminal outgrowth with use of neurotrophic factors. The first neurotrophic factor discovered was nerve growth factor (NGF). A wealth of animal studies have shown that cholinergic neurons are NGF sensitive and NGF dependent, which is especially interesting in cognitive disorders, in which central cholinergic projections are important for cognitive function. In Alzheimer disease, cholinergic neurons have been shown to degenerate. This suggests that NGF may be used to pharmacologically counteract cholinergic degeneration and/or induce terminal sprouting in Alzheimer disease. Data from animal studies, as well as from the author's recent clinical trial, in which NGF was infused to the lateral ventricle in patients with Alzheimer disease, will be presented. Effects of NGF on cognition, as well as issues regarding dosage, side effects, and alternative ways of administering NGF, will be discussed.     

Nerve factors and retinal ganglial cell regeneration

Totally three articles focusing on erythropoietin,granulocyte colony-stimulating factor and basic fibroblast growth factor promoting retinal ganglion cell regeneration are published in three issues.We hope that our readers find these papers useful to their research.     

Nerve growth factor promotes olfactory axonal elongation

An explant culture system was used to test the effect of nerve growth factor (NGF) on olfactory axonal elongation. Statistical analysis showed that exogenously applied NGF (50 ng/ml) significantly enhanced olfactory neurite elongation from E14 rat olfactory epithelial explants (p = 0.025). Immunostaining showed that the neurites expressed active TrkA receptors and that S-100-positive ensheathing cells were also present. In a separate experiment, immunoassay confirmed that following a growth period of 72 h, E14 presumptive olfactory bulb expressed and secreted NGF into the culture medium. The results indicate that during ontogeny, the olfactory bulb secretes NGF which binds to olfactory axons and facilitates their elongation.     

Nerve growth activities in rat peripheral nerve

Nerve growth activities in rat sciatic nerves were assayed by recording the neuritic outgrowth from chick embryonic ganglia cultured in collagen gels beside nerve fragments for two days. Living nerve explants released activity that resembled nerve growth factor (NGF) in its effect on sympathetic ganglia and that was almost totally blocked by an antiserum to 2.5 S mouse NGF. Frozen and thawed specimens from normal nerves elicited responses from sympathetic ganglia that were only partially suppressed by anti-NGF and also induced neuritic outgrowth from ciliary ganglia. Thus, from observations on normal nerves, at least two agents promoting axonal extension in vitro were deduced to exist; one substance similar to NGF plus another, non-NGF factor. The level of NGF-like activity was low in killed segments of normal nerves but higher in autologous nerve grafts and degenerating nerves two days after grafting or cutting. However, one or two weeks after nerve transection, distal nerve segments contained little nerve growth activity of either kind. Furthermore, when endoneurial fragments from chronically denervated stumps were cultured, they appeared to have lost some of their capacity to produce NGF-like activity in vitro although the production of activity had, if anything, increased in the perineurial region. In summary, rat peripheral nervous tissue releases two or more soluble substances that stimulate neuritic outgrowth. The level of one or both activities in the endoneurium can be altered by manipulation of nerves in vivo.     

Nerve growth factor supports growth of rat skeletal myotubes in culture

Effects of nerve growth factor (NGF) were examined on the growth of rat skeletal myotubes in culture and the expression of Na-K pump activity in this preparation. We found NGF to cause an immediate increase in electrogenic Na-K pump activity as determined by electrogenic component of membrane potential (Em) and ouabain-sensitive 86Rb uptake. When given chronically, NGF was able to replace serum as an essential supplement for development of cultured myotubes. Thus, when maintained in a serum-free, basal nutrient medium (DMEM), myotubes progressively deteriorated as indicated by morphological appearance, Em and the number of [3H]ouabain binding sites compared with myotubes grown in normal, serum-supplemented growth medium (GM). In contrast, the presence of NGF in DMEM completely prevented the deterioration of these properties, their values actually exceeding those in GM. These findings demonstrate a trophic effect of NGF on bioelectric properties of neonatal mammalian muscle cells.     

Nerve regeneration model and trophic factors in vivo

The proximal stump of a transected rat sciatic nerve has been observed to regenerate through a cylindrical silicone chamber across a 10 mm gap to the distal stump. The fluid filling such in vivo chambers contains trophic factors that ensure in vitro survival and growth of at least sensory neurons from rodent dorsal root ganglia — as already demonstrated for fluid generated in vitro from Schwann and other cell cultures.     

Nerve growth factor catches copper in neuronal inning

正The physiological effect of neurotrophic factors and their role in Alzheimer's disease(AD):Neurotrophins(NTs)are a family of homologues proteins that play an essential role in neuronal cells growth,survival and differentiation.These proteins include the nerve growth     

Nerve growth factor, birth outcome and pre-eclampsia

The present study compares nerve growth factor (NGF) levels between preeclamptic (PE) (n = 86) and normotensive (NT) women (n = 105) and their associations with blood pressure and infant size. Maternal plasma NGF levels were reduced (p < 0.05) in the PE group as compared to the NT group. Furthermore, NGF levels were reduced in PE mothers delivering low birth weight babies (LBW) as compared to NT mothers delivering LBW babies. Maternal NGF levels were negatively (p = 0.029) associated with blood pressure in preeclamptic mothers. Cord NGF levels were negatively associated (p = 0.026) with birth weight in the normotensive group.NGF levels are differently regulated in preeclamptic and normotensive mothers delivering LBW babies. Future studies need to investigate mechanisms underlying this pathophysiology and follow-up of these babies to better understand the role of NGF in brain development in later life.     

Nerve growth factor and injured peripheral nerve regeneration

Nerve growth factor （NGF） exhibits many biological activities, such as supply of nutrients, neuroprotection, and the generation and rehabilitation of injured nerves. The neuroprotective and neurotrophic qualities of NGF are generally recognized. NGF may enhance axonal regeneration and myelination of peripheral nerves, as well as cooperatively promote functional recovery of injured nerves and limbs. The clinical efficacy of NGF and its therapeutic potentials are reviewed here. This paper also reviews the latest NGF research developments for repairing injured peripheral nerve, thereby providing scientific evidence for the appropriate clinical application of NGF.     

Nerve growth factor expression in human dystrophic muscles

Nerve growth factor (NGF) is a neurotrophin that is expressed during muscle development and is also capable of favoring muscle regeneration in experimental studies. The presence of NGF in muscular dystrophies, such as Duchenne and Becker muscular dystrophies, has never been fully explored. By means of immunohistochemistry, we show that regenerating muscle fibers from such patients consistently express NGF, as do myofibroblasts and mast cells. By contrast, rest fibers from dystrophic patients, as well as muscle fibers from healthy, control patients and even regenerative muscle fibers in polymyositis do not show NGF immunoreactivity. The paracrine effect of NGF on muscle regeneration, as well as its chemoattractant capacities for mast cells, may contribute to explaining why regenerating fibers most frequently occur in clusters and why mast cells are more numerous in dystrophic muscles. Moreover, being a mediator of wound healing and tissue fibrosis, NGF may contribute to long-term muscle regeneration impairment by tissue fibrosis in the muscular dystrophies.     

Nerve growth factor enhances regeneration through silicone chambers

The effect of exogenous NGF on axonal growth across a gap between sectioned ends of a sciatic nerve within silicone chambers was examined in Sprague-Dawley rats. After nerve section and surgical implantation, silicone chambers were filled with either a 1 mg/ml nerve growth factor (NGF)/saline solution (experimental) or a normal saline solution (control). Four weeks after surgery, the regenerated nerves from within the silicone chambers were dissected and fixed for histological studies at both light microscopic and ultrastructural levels. Morphological analysis of the nerves showed no difference between the NGF-treated and control groups in the size of the regenerated nerves within the chambers or in the diameters of myelinated axons. Total myelinated axonal counts were determined from within the distal chamber. NGF significantly increased the number of myelinated axons that grew into the distal end of the chamber (2126 +/- 437 NGF/saline; 1064 +/- 268 saline; P less than 0.05 Student's t test). Counts of the unmyelinated axons from the distal nerve segment from the two groups were not different. Myelin sheath thickness was 58% greater in the NGF-treated group compared with that in the saline group. There was no difference between the two groups in the size-frequency spectra of the diameters of the myelinated axons in the distal segment. The NGF/saline group showed a more mature-appearing regenerated nerve based on the percentage of myelinated axons, thickness of the myelin sheaths, and development of internal organization (e.g., amount of endoneurial collagen fibers, ensheathment of unmyelinated axons by Schwann cells, and interfascicular patterns).(ABSTRACT TRUNCATED AT 250 WORDS)     

Nerve growth factor and the neurotrophic factor hypothesis

The discovery of nerve growth factor (NGF) over 40 years ago led to the formulation of the “Neurotrophic Factor Hypothesis”. This hypothesis states that developing neurons compete with each other for a limited supply of a neurotrophic factor (NTF) provided by the target tissue. Successful competitors survive; unsuccessful ones die. Subsequent research on NTFs has shown that NTF expression and actions are considerably more complex and diverse than initially predicted. Even for NGF, different regulatory patterns are seen for different neuronal populations. As would be predicted by the “Neurotrophic Factor Hypothesis”, NGF levels critically regulate basal forebrain cholinergic neuron size and neurochemical differentiation. In contrast, the level of trkA, the NGF receptor, regulates these properties in caudate-putamen cholinergic neurons. Understanding NTF regulation and actions on neurons has led to their use in clinical trials of human neurological diseases. NTFs may emerge as important therapies to prevent neuronal dysfunction and death.     

Nerve growth factor gene therapy in Alzheimer disease

Nervous system growth factors potently stimulate cell function and prevent neuronal death. These broad effects on survival and function arise from direct downstream activation of antiapoptotic pathways, inhibition of proapoptotic pathways, and stimulation of functionally important cellular mechanisms including ERK/MAP kinase and CREB. Thus, as a class, growth factors offer the potential to treat neurodegenerative disorders for the first time by preventing neuronal degeneration rather than compensating for cell loss after it has occurred. Different growth factors affect distinct and specific populations of neurons: the first nervous system growth factor identified, nerve growth factor, potentially stimulates the survival and function of basal forebrain cholinergic neurons, suggesting that nerve growth factor could be a means for reducing the cholinergic component of cell degeneration in Alzheimer disease. This review will discuss the transition of growth factors from preclinical studies to human clinical trials in Alzheimer disease. The implementation of clinical testing of growth factor therapy for neurologic disease has been constrained by the dual need to achieve adequate concentrations of these proteins in specific brain regions containing degenerating neurons, and preventing growth factor spread to nontargeted regions to avoid adverse effects. Gene therapy is one of a limited number of potential methods for achieving these requirements.