Excitability changes of dorsal root axons following nerve injury: implications for injury-induced changes in axonal Na(+) channels

Electrophysiological recordings were obtained from rat dorsal roots in a sucrose gap chamber to study changes in Na(+) currents following nerve injury. Application of 4-aminopyridine unmasks a prominent and well-characterized depolarization (delayed depolarization) following the action potential. In our previous studies, this potential, which is only present in cutaneous afferent axons, has been shown to correlate with activation of a slow Na(+) current. The delayed depolarization in the dorsal root was reduced 1 week after sciatic nerve ligation, suggesting a reduction in the kinetically slow Na(+) currents on dorsal root axons [control: 44. 2+/-7.3% (n=5); injury: 7.3+/-4.7% (n=5), P<0.001]. The refractory period of the action potential was reduced following nerve injury, in agreement with biophysical studies indicating faster "repriming" of fast Na(+) currents on cutaneous afferent cell bodies. Dorsal root ligation near the spinal cord also results in a reduction in the delayed depolarization. These results indicate that changes in Na(+) channel organization occur on dorsal root axons following either central or peripheral target disconnection, suggesting trophic support can be derived from either the CNS or the PNS.     

慢性癫痫大鼠脑组织神经生长因子阳性神经元的变化

应用免疫组织化学的方法观察了戊四氮诱导的慢性癫痫大鼠脑组织神经生长因子(NGF)阳性神经元的变化。结果发现慢性癫痫大鼠海马回、齿状回NGF阳性神经元数目明显增多。在所选取的时间点,即末次抽搐发作后24h、72h、7d均较对照组明显升高。结果提示:NGF参与了癫痫的发病过程,可能通过介导突触的重建面具有促痫作用。也可能作为一种保护因子而防止癫痫后脑损害。     

Anti-NGF在躯体疾病疼痛治疗中的潜在价值

神经生长因子(nerve growth factor,NGF)属神经营养因子家族,广泛分布于中枢及外周神经系统,不仅在神经系统的发育存活中起重要作用,而且参与外周伤害性疼痛感受的产生与调节.近年来由于对NGF在急、慢性疼痛及痛觉过敏-中作用的认识不断增强,一种新的抑痛方法--抗-NGF(anti-NGF)治疗悄然兴起.     

神经生长因子联合盐酸多奈哌齐治疗阿尔茨海默病的疗效及对血清炎性因子水平的影响

目的探讨神经生长因子联合盐酸多奈哌齐治疗阿尔茨海默病的临床疗效及对血清炎性因子水平的影响。方法选择2012-10—2014-10我院收治的阿尔茨海默病患者71例,随机分为治疗组36例,对照组35例,对照组给予盐酸多奈哌齐,治疗组在对照组基础上给予注射用鼠神经神经因子,2组均治疗24个周,比较2组患者临床疗效及患者血清IL-6、TNF?α的变化。结果治疗24周后,治疗组总有效率为94.44%,对照组为74.29%,2组总有效率比较差异具有统计学意义(P0.05);治疗前2组MMSE、ADL评分差异均无统计学意义(P0.05),治疗后2组患者MMSE、ADL评分均较治疗前显著改善(P0.05),且治疗组改善情况显著优于对照组(P0.05);治疗前2组患者血清IL-6、TNF?α水平差异无统计意义(P0.05),治疗后2组血清IL-6、TNF?α水平均较治疗前显著降低,且治疗后治疗组血清IL-6、TNF?α水平显著低于对照组(P0.05)。结论神经生长因子联合盐酸多奈哌齐能够有效改善阿尔茨海默病患者的认知功能及日常生活能力,用药安全可靠,其作用可能与显著抑制患者炎性因子的表达有关。     

Regulation of myelinated nociceptor function by nerve growth factor in neonatal and adult rats

The role of nerve growth factor (NGF) as a survival factor for sensory neurons during embryonic life has been well documented. Here we examine the actions of NGF or antisera against NGF (anti-NGF) on physiologically identified sensory neurons with myelinated axons later in life, after the dependence on NGF for survival ends. We find that the effects of NGF and anti-NGF are specific for sensory neurons which are nociceptors. Treatments were found to affect the biophysical properties, the development, or the physiological function of myelinated nociceptors. They also affect the animal's behavioral response to noxious stimulation, depending upon when the treatments were given: neonatally, from 2–5 weeks of age, or chronically, beginning at birth. Thus, we find that the actions of NGF are specific for nociceptors but that the function of this neurotrophic factor changes according to the developmental age of the animal.     

The role of sodium channels in chronic pain

Here we review recent research into the mechanisms of chronic pain that has focused on neuronal sodium channels, a target of classic analgesic agents. We first discuss evidence that specific sodium channel isoforms are essential for the detection and conduction of normal acutely painful stimuli from nociceptors. We then review findings that show changes in sodium channel expression and localization in chronic inflammation and nerve injury in animal and human tissues. We conclude by discussing the role that myelination plays in organizing and maintaining sodium channel clusters at nodes of Ranvier in normal development and how inflammatory processes or nerve injury alter the characteristics of such clusters. Based on these findings, we suggest that chronic pain may in part result from partial demyelination of axons during chronic injury, which creates aberrant sodium channel clusters that serve as sites of ectopic sensitivity or spontaneous activity.     

Substrate-bound nerve growth factor promotes neurite growth in peripheral nerve

Nerve growth factor (NGF), in addition to its well-known effects as a soluble neurite growth-promoting factor, also appears to promote the elongation of neurites when it is adsorbed to tissue culture substrates. Peripheral nerve Schwann cells appear to possess a receptor for NGF on their surfaces which is induced substantially after axotomy. We have found that the adsorption of NGF onto cryostat sections of the distal stump of previously severed sciatic nerve enhances neurite growth over this tissue. This finding, coupled with the two previous observations, suggests that Schwann cell surface NGF receptors serve to bind to NGF-like growth factors so as to provide favorable surfaces for regenerating peripheral nerve axons.     

Cultured rat Schwann cells express low affinity receptors for nerve growth factor

Schwann cell cultures prepared from postnatal Sprague-Dawley rat sciatic nerves were used to demonstrate the presence of specific receptors for the beta-subunit of nerve growth factor (NGF) on rat Schwann cells. Indirect immunofluorescence microscopy with a monoclonal antineuronal NGF receptor (NGFR) antibody indicated that NGFR antigen was expressed on the surface of Schwann cells but not of endoneurial fibroblasts. Studies with 125I-NGF confirmed this distribution of NGFR in the cultures and showed that the Schwann cell NGFR had a single NGF binding affinity (Kd of 1.8 x 10(-9) M). 125I-NGF binding by the cultured Schwann cells increased with time in vitro, reaching a plateau level on the 4th day, but decreased with increasing age, reaching 40% of the neonatal value in Schwann cells isolated from 12-day-old rats. Treatment of the cultures with NGF did not alter Schwann cell phenotype, survival or proliferation.     

A role for nerve growth factor in collateral reinnervation from sensory nerves in the guinea pig

We have investigated whether chronic nerve growth factor (NGF) depletion affects the development of a transmedian collateral reinnervation. The extent of transmedian innervation of the skin supplied by the left inferior alveolar nerve (IAN) was determined either immediately, 2 days or 7-9 weeks after sectioning and preventing regeneration of the contralateral IAN and in another group of animals left to recover for 7-9 weeks but also autoimmunised against NGF. Transmedian innervation was measured by recording the area from which a jaw-opening reflex could be evoked and by recording activity in the left IAN during mechanical and electrical stimulation of the skin. Nerve recording during electrical stimulation revealed extensive transmedian collateral reinnervation 7-9 weeks after denervation but this was prevented by NGF autoimmunisation. No change in transmedian innervation could be detected in any of the groups by nerve recording during mechanical stimulation and reflex responses revealed changes in the anaesthetic area which could not be attributed to collateral reinnervation. These results suggest that NGF plays an important role in collateral reinnervation from high-threshold sensory nerves.     

The role of nerve growth factor in collateral reinnervation by cutaneous C-fibres in the rat

We have investigated whether chronic nerve growth factor (NGF) depletion affects the development of transmedian collateral reinnervation by C-fibres. Using a dye-labelled plasma extravasation technique in rats, the extent of transmedian innervation of the skin by C-fibres in the inferior alveolar nerve (IAN) was determined 8-10 weeks after sectioning and preventing regeneration of the contralateral IAN. Another group of animals were immunised against NGF prior to the nerve section and a third group acted as unoperated controls. A small but significant transmedian collateral reinnervation by C-fibres developed after contralateral denervation alone, but was not found in the animals also immunised against NGF. These results suggest that NGF is essential for the development of collateral reinnervation from cutaneous C-fibres.     

Chronic parasite infection in mice induces brain granulomas and differentially alters brain nerve growth factor levels and thermal responses in paws

Schistosoma mansoni infection, both in humans and in animal models, is known to induce granulomas in the liver and intestine. It has also been reported that in humans the eggs of this parasite can reach the brain, causing psychiatric and neuropathological disorders. Whether this also occurs in rodents is unknown. To answer this question, mice were infected with this parasite and the central nervous system (CNS) examined at various time intervals. The results show that schistosomiasis induced granulomas in several regions of the CNS and increased nerve growth factor (NGF) levels in the cortex, hypothalamus and brain stem, but not in the hippocampus. The infection also caused paw hyperalgesia, as determined by the hot-plate test, and a local increase in NGF, but not in substance P. These findings indicate that the murine model of infection can be used for studying mechanisms leading to human neuroschistosomiasis and suggest that the neuropathological disorders and the sensory deficits observed in human schistosomiasis are associated with impaired levels of NGF in the peripheral and central nervous system. Received: 18 January 1996 / Revised, accepted: 16 April 1996     

注射用鼠神经生长因子治疗慢性多发性周围神经病的初步临床评价

目的了解鼠神经生长因子治疗慢性多发性周围神经病的疗效。方法对60例慢性多发性周围神经病患者进行随机和意愿分组,对照组28例,采用基础治疗,而32例治疗组则增加肌肉注射鼠神经生长因子（苏肽生,30ug,O_D,连续2～4周）,治疗4周后评价运动功能（MMT评分）、日常生活能力（ADL改良）、末梢型感觉障碍范围及疼痛程度（VAs、McGill）等。结果两组病例在治疗4周后MMT、ADL评分、四肢末梢型感觉障碍的范围、疼痛程度均改善,其中治疗组在四肢末梢型感觉障碍的范围及疼痛程度改善较对照组明显。结论在进行基本治疗的基础上加用鼠源性神经生长因子至少2周,能进一步改善感觉功能障碍,包括使感觉障碍的面积缩小、缓解神经痛和提高患者生活质量,然而其对运动功能改善似乎不明显。     

NGF及其受体TrkA在胰腺癌嗜神经侵袭及疼痛发生的作用

目的 分析神经生长因子(NGF)及其受体酪氨酸激酶(TrkA)在胰腺癌嗜神经侵袭及疼痛发生的作用.方法 选择胰腺癌病例28例,根据术前患者的疼痛情况分为疼痛组(A组,14例)和无疼痛组(B组,14例).用Northern blot和免疫组化半定最检测并比较两组胰腺癌组织NGF及TrkA表达强度,并与神经侵袭程度评分和疼痛评分进行相关分析.结果 A组的神经侵犯评分明显高于B组,差异有统计学意义(P＜0.05).胰腺癌伴有外周神经侵犯者比无外周神经侵犯者的NGF和TrkA mRNA表达水平高,差异有统计学意义(P＜0.05),肿瘤伴有疼痛者比不伴有疼痛者的NGF和TrkA mRNA表达水平高,差异有统计学意义(这P＜0.05).免疫组化结果与上相似.外周神经侵犯的程度与NGF mRNA和TrkA mRNA表达水平呈正相关(r=0.622,P＜0.05;r=681.P＜0.05),疼痛程度与NGF mRNA和TrkA mRNA表达水平亦呈正相关(r=0.624,P＜0.05:r=0.632,P＜0.05).外周神经侵犯的程度与NGF和TrkA免疫组化评分呈正相关(r=602,P＜0.05;r=0.551,P＜0.05),疼痛程度与NGF和TrkA免疫组化评分亦呈正相关(r=603,P＜0.05;r=0.612,P＜0.05).结论 NGF及其受体TrkA在胰腺癌患者的疼痛发生和胰腺癌的嗜神经侵犯中起着重要作用.     

真核细胞中人神经生长因子cDNA的表达

目的 构建人神经生长因子cDNA的表达载体pcDNA3．1-NGF,并在哺乳动物细胞中进行一过性表达。为以后人神经生长因子的基因治疗打下基础。方法 在本研究室已克隆人神经生长因子cDNA的基础上。构建表达载体pcDNA3．1-NGF。用DEAE-葡聚糖转染技术将pcDNA3．1-NGF导入COS-7细胞，将人神经生长因子cDNA进行一过性表达。并采用Westernblot方法检测表达情况。以鸡胚背根神经节的生长检测表达蛋白的生物活性。结果 成功构建了表达载体pcDNA3．1-NGF，Western blot方法检测出COS-7细胞表达有目的蛋白，并具有一定的生物活性。结论 用哺乳动物细胞一过性表达了人神经生长因子，并具有一定的生物活性。     

Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome

Nerve growth factor (NGF) has been found to play a crucial role in the neuroplasticity of predominantly cholinergic neurons in brain development, and neuronal survival following brain injury, which reflect in cognitive performance. Wide ranges of neurodevelopmental abnormalities have been reported in schizophrenic patients, who also show poor cognitive performance. We report plasma NGF levels in never-medicated first-episode psychotic (FEP; N=24) and chronic medicated schizophrenic patients (N=24). NGF levels were determined in plasma by Enzyme-Linked ImmunoSorbent Assay (ELISA). Plasma NGF levels were significantly lower in both FEP and medicated chronic patients as compared to normal subjects (P<0.001). However, NGF levels were significantly higher in chronic schizophrenic patients, which were treated with antipsychotics as compared to FEP (P<0.05). Moreover, NGF levels in chronic patients treated with atypical antipsychotics were markedly higher as compared to patients treated with typical antipsychotics (P<0.05). Lower NGF levels in FEP patients at the onset of psychosis may have implications for the neurodevelopmental abnormalities. However, higher NGF levels in chronic patients treated with atypical antipsychotics may have implications for the treatment outcome.     

神经再生素和神经生长液联合应用对成年兔视神经挫伤后修复的影响

目的研究中药神经再生素（NRF）和神经生长液对成年兔视神经挫伤后修复的影响。方法16只成年兔随机分成实验组和对照组．每组8只。建立兔右眼视神经挫伤模型后．分别将载有0．06mL NRF（浓度为2g／L，实验组）或等量磷酸盐缓冲液（PBS）（对照组）的组织工程化神经移植于视神经损伤处；并向右眼玻璃体腔内注入0．02mL NRF（浓度为2g／L，实验组）或等量PBS（对照组）。实验组兔术后每日喂服神经生长液（5mL／kg），共6周。伤后1d、2周、8周进行闪光视觉诱发电位（FVEP）检查。挫伤后8周时作光镜和电镜检查观察视网膜神经节细胞（RGC）、视网膜神经纤维层和视神经的改变，同时用计算机图像处理系统作视神经纤维计数。结果术后8周时实验组致伤眼与未致伤眼FVEP幅值比为0．774±0．184，对照组为0．409±0．119，差异有显著性（P〈0．01）。术后8周时的光镜和电镜检查示：实验组RGC、视神经纤维的退变较对照组轻。两组视神经纤维计数分别为（15045±716．2）根／mm^2（实验组）和（7898±608．8）根／mm^2（对照组），差异有显著性（P〈0．01）。结论NRF和神经生长液联合应用能够增加RGC的存活，促进轴突的再生，因而对视神经挫伤后的修复、视功能的恢复具有一定的促进作用。     

神经生长因子治疗重型颅脑损伤的临床观察

目的 观察神经生长因子(NGF)对重型颅脑损伤患者血浆肌酸激酶同工酶BB(CK-BB)动态变化的影响以及临床疗效.方法 将上海交通大学医学院附属第三人民医院神经外科自2006年8月至2008年8月收治的80例重型颅脑损伤患者(GCS≤8分)分成2组,对照组40例采用常规治疗,试验组40例在常规治疗的基础上加用NGF治疗.观察2组患者血浆CK-BB变化,并于伤后6个月按GOS预后评分评定预后,同时比较2组患者的清醒率及清醒时间.结果 治疗后第1、5、10、20、28天试验组患者血浆CK-BB均明显低于对照组,差异有统计学意义(P<0.05).试验组预后情况明显优于对照组,差异有统计学意义(P<0.05).试验组治疗后1个月清醒32例,对照组18例,差异有统计学意义(P<0.05).试验组清醒时间为(12.43±6.25)d,对照组为(15.96±7.58)d,差异有统计学意义(P<0.05).结论 NGF能有效降低重型颅脑损伤患者血浆CK-BB的水平,促进重型颅脑损伤患者的清醒,改善预后.     

Is nerve growth factor required for the survival of retinal ganglion cells during development?

Staining for nerve growth factor receptor was observed in the ferret's retinal ganglion cell layer, optic nerve and tract, and in the lateral geniculate nucleus and superficial layers of the superior colliculus in the prenatal period, but had disappeared by birth. Thus the incidence of this transient staining does not correspond with the ganglion cell death that is known to occur in the ferret retina during the first postnatal week.     

The use of nerve growth factor as a reverse transforming agent for the treatment of neurogenic tumors: in vivo results

Summary The rationale behind the evaluation of natural differentiating agents, such as nerve growth factor (NGF), for reverse transforming potential is based on the theory that such compounds may represent a nontoxic means of controlling tumor growth. Previous in vitro experiments have shown that NGF is capable of retarding growth and of inducing persistent differentiation of neurogenic tumor cell lines. In vivo, NGF is capable of causing a persistent reduction in the number of ethylnitrosourea-induced neurinomas and of increasing survival time following intracerebral implantation of F98 anaplastic glioma cells. In this study, anaplastic glioma and neurinoma implants were treated with NGF to evaluate the reverse transforming potential of NGF in vivo. Results indicate that NGF is capable of causing a significant decrease in the growth rate of subcutaneous T9 (anaplastic glioma) and clone 16 (anaplastic neurinoma) implants. Significantly, NGF treatment was accompanied by adverse effects that were minimal and transient. Continued tumor growth (although greatly retarded) following NGF treatment is an aspect that requires further investigation. However, the results of this study suggest that NGF may prove useful, alone or in combination with other types of therapy, for the treatment of tumors of neurogenic origin.Supported by NIH grant CA32594, an NIH Post Doctoral Fellowship to M. J. Y., a grant from the Preuss Foundation and a BRSG grant (College of Veterinary Medicine, Michigan State University)