神经生长因子在脑挫裂伤救治中的应用

目的 探讨神经生长因子(NGF)在脑挫裂伤中的治疗作用. 方法 将南京医科大学附属南京第一医院神经外科自2008年1月至2009年7月收治的80例急性重型脑挫裂伤患者按照随机数字表法分为治疗组与对照组,每组各40例,对照组给予常规治疗,治疗组在常规完成手术前,在血肿腔或脑挫裂伤表面(打开脑挫裂伤表面的蛛网膜)直接用含有NGF 20 μg的明胶海绵敷布填塞或覆盖,术后用NGF20 μg肌肉注射,每日一次,15 d为一个疗程.连续1～2个疗程.两组患者在治疗结束后行GOS评分,进行统计学分析.结果 治疗组的疗效明显优于对照组,差异有统计学意义(P<0.05).治疗组术后恢复的时间也较对照组明显缩短,差异有统计学意义(P(0.05).结论 NGF可以促进脑功能的恢复,提高临床疗效,改善患者的生活质量.     

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 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 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 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.     

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 treatment alters Ca2+ pump levels in PC12 cells

Nerve growth factor (NGF) treatment converts rapidly dividing PC12 cells into a neuronal phenotype. To understand the Ca2+ sequestration mechanisms accompanying this differentiation, we examined the endoplasmic reticulum Ca2+ (SERCA) pump levels using two different assays: ATP-dependent azide insensitive oxalate stimulated 45Ca2+ uptake by PC12 cells permeabilized with saponin, and Western blots using a monoclonal antibody which reacts with all the SERCA isoforms. We also examined the reaction to an antibody against the plasma membrane Ca2+ (PMCA) pump. NGF treatment decreased the SERCA pump expression but it increased the PMCA pump level. These results are consistent with a greater role of PMCA pumps in neuronal cells than in most other cells and with an increased role of SERCA pumps during cell proliferation.     

Nerve growth factor and brain-derived neurotrophic factor in human paediatric hemimegalencephaly

Paediatric hemimegalencephaly (HME) is a congenital central nervous system (CNS) disorder, characterized by monolateral cerebral hemisphere enlargement, intractable seizures starting in the post-neonatal period, and mental retardation associated with neuropathological anomalies (mainly cortical thickness and lack of lamination). Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are two neurotrophic factors produced in the mammalian CNS that are involved in the survival, development, and function of a variety of brain cells. In the present study, we found increased cerebral tissue levels of NGF and BDNF in 4 infants with HME; these changes appear to be also associated with abnormal NGF-receptor expression in subcortical blood vessels. Moreover, the marked reduction of cortical choline acetyltransferase immunoreactivity is strongly suggestive of a dysregulation in the NGF differentiative activity in this site that could lead to the pathogenesis of HME.     

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 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 growth factor prevents toxic neuropathy in mice.

Taxol is a promising new antitumor drug with therapeutic use that is limited by a toxic sensory neuropathy. Taxol is also cytotoxic to dorsal root ganglion neurons in vitro, but this effect is prevented by cotreatment with the trophic protein, nerve growth factor. We sought to develop an animal model and then to determine whether nerve growth factor can prevent taxol neuropathy in vivo. Administration of taxol to mice resulted in a profound sensory neuropathy characterized by decreases in dorsal root ganglion content of the peptide neurotransmitter, substance P, elevated threshold to thermally induced pain, and diminished amplitude of the compound action potential in the caudal nerve. Coadministration of nerve growth factor prevented all of these signs of neurotoxicity. These findings suggest that administration of nerve growth factor may prevent certain toxic sensory neuropathies.     

Nerve growth factor and gastric hyperalgesia in the rat

We recently demonstrated an association between the development of hyperalgesia and an increase in nerve growth factor (NGF) during gastric inflammation. We hypothesized that block of NGF signalling will blunt injury-induced hyperalgesia. Male Sprague-Dawley rats (300-400 g) were anaesthetized, the stomach was exposed and placed in a circular clamp. Acetic acid (60%) or saline (control) was injected into this area and aspirated 45 s later, resulting in kissing ulcers. A balloon was surgically placed into the stomach and electromyographic responses to gastric distension (GD) were recorded from the acromiotrapezius muscle. Animals received a daily injection of neutralizing NGF antibody or control serum for 5 days. NGF in the stomach wall was measured with an ELISA. The severity of gastric injury was assessed macroscopically and by determination of myeloperoxidase (MPO) activity. Gastric injury enhanced the visceromotor response to GD and increased NGF content. Anti-NGF significantly blunted the development of hyperalgesia and led to a decrease in gastric wall thickness and MPO activity. Increases in NGF contribute to the development of hyperalgesia after gastric injury. This may be partly mediated by direct effects on afferent nerves and indirectly by modulatory effects on the inflammatory response.     

Nerve growth factor receptors in the central nervous system

Nerve growth factor (NGF) is well known to be involved in the development, survival, and maintenance of sympathetic and neural crest-derived sensory neurons in the peripheral nervous system. Over the last 10-15 years, however, the role of NGF as a necessary trophic substrate for magnocellular cholinergic neurons in the central nervous system (CNS) has emerged. Because the trophic effects of NGF are initiated by its interaction with membrane-bound receptors, the characterization, localization, and function of these specific NGF receptors are essential to understanding the many actions of NGF. The first part of this review will summarize briefly the presence and possible role of NGF in the CNS, with the remainder of the review focusing on what is known about the receptor to NGF.     

Nerve growth factor and chronic ethanol treatment alter calcium homeostasis in developing rat septal neurons

Chronic ethanol treatment (CET) during development produces cellular adaptations resulting in tolerance to the acute effects of ethanol (EtOH). The objectives of this study were to determine whether CET during the prenatal period (PCET) followed by a period of in vitro CET (PCET-CET) altered intracellular calcium [Ca(2+)](i) and produced tolerance to acute EtOH treatment (AET), and whether nerve growth factor (NGF) modulated the effects of PCET-CET in cultured developing rat septal neurons. Fetuses were obtained from EtOH-fed and sucrose-fed (diet-control) female rats. Neurons from PCET fetuses were cultured in the presence of NGF (+NGF) and 200 mg/dl (mg %) EtOH and diet-control cultures received NGF and no EtOH. PCET and diet-control cultures were then divided into two groups, +NGF and -NGF (withdrawn from NGF), and exposed acutely to one of five doses of EtOH during stimulation with potassium (K(+)) chloride. [Ca(2+)](i) was measured using fura-2. PCET-CET did not affect resting [Ca(2+)](i). PCET-CET decreased and acute EtOH withdrawal increased overall K(+)-stimulated changes in [Ca(2+)](i), but only in +NGF PCET neurons. Reducing the level of EtOH from 200 to 100 mg % decreased overall K(+)-stimulated [Ca(2+)](i) in -NGF PCET neurons. The effects of PCET-CET or PCET-CET combined with NGF on overall K(+)-stimulated changes in [Ca(2+)](i) occurred mostly in the early and middle phases of the K(+)-response. NGF reduced overall K(+)-stimulated changes in [Ca(2+)](i) in PCET neurons during EtOH withdrawal and during AET with 200 mg % EtOH and increased overall K(+)-stimulated changes in [Ca(2+)](i) during AET with 400 and 800 mg % EtOH. There was no effect of NGF on overall K(+)-stimulated changes in [Ca(2+)](i) in diet-control neurons with the exception that NGF-treatment decreased overall K(+)-stimulated changes in [Ca(2+)](i) during AET with 400 mg % EtOH. The effects of AET on overall K(+)-stimulated changes in [Ca(2+)](i) mostly occurred in +NGF PCET neurons. In conclusion, CET during development of the brain could adversely affect Ca(2+)-dependent functions such as neuronal migration, neurite outgrowth, and synaptogenesis in neurons even in the presence of neurotrophin support.