Protective effect of nerve growth factor against glutamate-induced neurotoxicity in cultured cortical neurons

The effect of recombinant human nerve growth factor (hNGF) and mouse NGF on cultured rat cortical neurons was examined. The DNA fragment coding the human NGF gene was isolated and inserted downstream from the SV40 promoter in a plasmid containing the dihydrofolate reductase cDNA, and this plasmid was introduced into Chinese hamster ovary (CHO) cells to establish cells producing recombinant hNGF. The recombinant hNGF protein secreted by CHO cells was confirmed to be biologically active in an assay using PC12 cells. Brief exposure of cortical cells to glutamate followed by incubation with glutamate-free medium reduced cell viability by 60–70% when compared with the control culture. Simultaneous addition of recombinant hNGF or mouse NGF to rat cortical cultures with glutamate did not affect this reduction of cell viability. However, 24 h pretreatment of rat cortical cultures with recombinant hNGF or mouse NGF resulted in a significant reduction of glutamate-induced neuronal damage. Mouse NGF also protected cortical neurons against N-methyl-d-aspartate (NMDA)- and kainate-induced neuronal damage. These findings suggest that NGF can protect cortical neurons against glutamate-induced neurotoxicity.     

Adenoviral gene transfer of hepatocyte growth factor prevents death of injured adult motoneurons after peripheral nerve avulsion

Hepatocyte growth factor (HGF) exhibits strong neurotrophic activities on motoneurons both in vitro and in vivo. We examined survival-promoting effects of an adenoviral vector encoding human HGF (AxCAhHGF) on injured adult rat motoneurons after peripheral nerve avulsion. The production of HGF in COS1 cells infected with AxCAhHGF and its bioactivity were confirmed by ELISA, Western blot and Madin-Darby canine kidney (MDCK) cell scatter assay. The facial nerve or the seventh cervical segment (C7) ventral and dorsal roots of 3-month-old Fischer 344 male rats were then avulsed and removed from the stylomastoid or vertebral foramen, respectively, and AxCAhHGF, AxCALacZ (adenovirus encoding beta-galactosidase gene) or phosphate-buffered saline (PBS) was inoculated in the lesioned foramen. Treatment with AxCAhHGF after avulsion significantly prevented the loss of injured facial and C7 ventral motoneurons as compared to AxCALacZ or PBS treatment and ameliorated choline acetyltransferase immunoreactivity in these neurons. These results indicate that HGF may prevent the degeneration of motoneurons in adult humans with motoneuron injury and motor neuron diseases.     

Decrease in the number of lower affinity (type II) nerve growth factor receptors on embryonic sensory neurons does not affect fiber outgrowth

Nerve growth factor binds to two different specific receptors on responsive cells. The relationship of these two receptors is not fully understood at this time. We have studied the binding of labeled NGF to a different strain of white leghorn chicken embryo dorsal root ganglionic cells. The equilibrium dissociation constants for the two sites (K = 4.1 ± 1.8 × 10^?11M, K = 1.0 ± 0.8 × 10^?9M) are identical to those obtained previously. Also, the number of type I sites per cell (3.8 ± 1.3 × 10³) is the same as that previously determined. However, the number of type II sites per cell (1.9 ± 1.3 × 10⁴) is significantly different than that previously determined. This 2.5-fold decrease in the number of type II sites does not affect the concentration of NGF needed to obtain maximal fiber outgrowth from explanted sensory ganglia. The rate of association (1.2 ± 0.2 × 10⁷ M^?1 sec^?1 at 22°C) of labeled NGF with receptors on sensory neurons from this different strain of chickens is identical to that previously obtained. The rate of association of NGF with its receptors on sensory neurons was also determined at 4°C. This rate constant (2.1 ± 1.1 × 10⁶ M^?1 sec^?1) along with the rate constants obtained at 22° and 37°C were used to determine an activation energy for the binding of NGF to its receptors. The activation energy obtained (16.2 kcal/mole) suggests that binding is not a diffusion-controlled process.     

Modulation of low-affinity nerve growth factor receptor in injured adult rat spinal cord motoneurons

Spinal and brainstem motoneurons of the adult rat reexpress low-affinity nerve growth factor receptor (LNGFR) and its mRNA after axotomy. We have previously reported the time courses of this reexpression after cut (no regeneration) or crush (followed by regeneration) of the sciatic nerve. We have shown that the length of the different phases of this reexpression (appearance, maintenance and disappearance) can vary according to the type of axotomy. With the present study we expand our previous data and describe and analyze the modulation the LNGFR expression in adult spinal cord motoneurons following different lesion paradigms. In one approach we have imposed three traumatic injuries that still allow regeneration of the sciatic nerve but with a different time course with respect to the crush injury (application of a silicone regeneration chamber, multiple crushes and delayed repair of ligated nerves). In a second approach, we have determined the capability of three toxic or metabolic injuries to induce LNGFR expression without any direct trauma of the nerve (experimental diabetogenesis, botulinum and alpha-bungarotoxin intoxication and 2,5-hexanedione intoxication). In a third approach, we have investigated the effect of the block of the axoplasmic transport on the LNGFR expression following different topical applications of vincristine combined with a nerve crush. The results we present are consistent with the idea that: (1) LNGFR immunoreactivity in adult motoneurons is expressed by motoneurons that are attending to an axonal outgrowth and not a generic signal of cellular damage or impairment of the motor function; (2) LNGFR expression in these motoneurons is related to and parallels the outgrowth process time frame, and (3) the signal/s that trigger and sustain this reexpression may be retrogradely transported from the periphery. © 1993 Wiley-Liss, Inc.     

In utero gene transfer reveals survival effects of nerve growth factor on rat brain cholinergic neurones during development

Nerve growth factor (NGF) is a maintenance factor for cholinergic neurones in the brain, but its properties as a developmental survival factor are largely unknown. The low accessibility of the developing mammalian brain to experimental manipulation makes it difficult to increase NGF levels during the early phases of brain development. In the present study we have used an in utero, ex-vivo gene transfer approach to explore NGF actions during development of the cholinergic system in the rat brain. Significantly increased numbers of cholinergic neurones were found only in the mesopontine complex in animals receiving NGF-secreting transplants, whereas the cholinergic neurones in the basal forebrain and striatum were not clearly affected. The present results suggest that overexpression of NGF during development may promote the survival of distinct populations of central cholinergic neurones into adulthood.     

Effects of nerve growth factor on TTX- and capsaicin-sensitivity in adult rat sensory neurons

We have investigated the effects of nerve growth factor (NGF, 2.5 ng/ml for 1–2 weeks) on enriched adult rat dorsal root ganglion (DRG) neurons maintained in cell culture in defined media. Whole-cell recordings in cells cultured in the absence and presence of NGF revealed no significant difference in resting membrane potential and input resistance. However, the threshold for spike generation was significantly lower in untreated cells than in treated cells; −25 ± 1.1mV vs−19 ± 2.2mV, respectively. The sensitivity of the Na⁺ spike to tetrodotoxin (TTX, 1 μM) was different in cells cultured in the absence or presence of NGF. For example, spikes were abolished by TTX in 100% of untreated cells, while in NGF-treated cells the spike was abolished in only 41% of the neurons. Chemosensitivity of DRG neurons was also different in the absence and presence of NGF. For example, the percent of neurons in which a current activated by 8-methyl-N-vanillyl-6-nonenamide (capsaicin, 500 nM) was detected, increased from 18% in untreated cells to 55% in NGF-treated cells. NGF did not influence the number of cells surviving. The results indicate that NGF can regulate TTX and capsaicin sensitivity in these adult rat sensory neurons. Our experimental protocol indicates that this effect is not mediated by a factor in the serum or released from non-neuronal cells.     

Immunohistochemical phenotype of sensory neurons associated with sympathetic plexuses in the trigeminal ganglia of adult nerve growth factor transgenic mice

Following peripheral nerve injury, postganglionic sympathetic axons sprout into the affected sensory ganglia and form perineuronal sympathetic plexuses with somata of sensory neurons. This sympathosensory coupling contributes to the onset and persistence of injury-induced chronic pain. We have documented the presence of similar sympathetic plexuses in the trigeminal ganglia of adult mice that ectopically overexpress nerve growth factor (NGF), in the absence of nerve injury. In this study, we sought to further define the phenotype(s) of these trigeminal sensory neurons having sympathetic plexuses in our transgenic mice. Using quantitative immunofluorescence staining analyses, we show that the invading sympathetic axons specifically target sensory somata immunopositive for several biomarkers: NGF high-affinity receptor tyrosine kinase A (trkA), calcitonin gene-related peptide (CGRP), neurofilament heavy chain (NFH), and P2X purinoceptor 3 (P2X3). Based on these phenotypic characteristics, the majority of the sensory somata surrounded by sympathetic plexuses are likely to be NGF-responsive nociceptors (i.e., trkA expressing) that are peptidergic (i.e., CGRP expressing), myelinated (i.e., NFH expressing), and ATP sensitive (i.e., P2X3 expressing). Our data also show that very few sympathetic plexuses surround sensory somata expressing other nociceptive (pain) biomarkers, including substance P and acid-sensing ion channel 3. No sympathetic plexuses are associated with sensory somata that display isolectin B4 binding. Though the cellular mechanisms that trigger the formation of sympathetic plexus (with and without nerve injury) remain unknown, our new observations yield an unexpected specificity with which invading sympathetic axons appear to target a precise subtype of nociceptors. This selectivity likely contributes to pain development and maintenance associated with sympathosensory coupling.     

人神经生长因子对大鼠中枢胆碱能神经元损伤后作用的实验研究

目的　研究人神经生长因子（ Ｈ Ｎ Ｇ Ｆ） 对大鼠中枢胆碱能神经元轴突切断后的保护作用。方法　向双侧海马伞切断所致的痴呆大鼠脑室内注入 Ｈ Ｎ Ｇ Ｆ, 采用穿梭箱训练, 检测大鼠学习记忆功能恢复状况, 对脑内隔斜带复合体（ Ｓ Ｄ Ｂ） 中隔区（ Ｍ Ｓ） 胆碱能神经元采用胆碱乙酰基转移酶（ Ｃ Ｈ Ａ Ｔ） 免疫组化法观察其存活状态。结果　 Ｈ Ｎ Ｇ Ｆ 组大鼠术后两周内穿梭箱回避次数高于对照组（ Ｐ＜ ００１） , 回避潜伏期短于对照组（ Ｐ＜ ００１） 。免疫组化及图像分析显示, 其胆碱能神经元存活状态优于对照组。结论　 Ｈ Ｎ Ｇ Ｆ 对大鼠中枢胆碱能神经元损伤具有短期保护作用; 减缓轴突切断引起的退行性变, 对痴呆大鼠学习记忆功能恢复有促进作用。     

神经生长因子对培养的大鼠背根神经节神经元P物质释放的调节作用

目的观察神经生长因子（nerve growth factor, NGF）对原代培养的背根神经节（dorsal root ganglion, DRG）神经元中P物质（substance P, SP）的基础释放量和辣椒素诱发释放量的调节效应。方法将15 天胚龄的Wistar大鼠DRG神经元培养于含有不同浓度NGF的DMEM/F12培养液中,不含NGF的培养液培养的神经元作为对照。72小时后,用RT-PCR检测神经元中SP mRNA和辣椒素受体（vanilloid receptor 1, VR1）mRNA的表达,用放射免疫分析（radioimmunoassay,RIA）法检测SP的基础释放量和辣椒素（100 nmol/L）刺激10 min后的诱发释放量。结果SPmRNA和VR1 mRNA在NGF孵育的标本中表达增加,并与孵育液中NGF的浓度呈剂量依赖关系。SP的基础释放量和辣椒素诱发释放量在NGF孵育的标本中均增加,而且诱发释放量与NGF的浓度呈剂量依赖关系。结论NGF使DRG神经元SP的基础释放量和诱发释放量增加,表明NGF能增加初级传入神经元感受伤害刺激的敏感性,该效应可能与SP和VR1的mRNA表达增加有关。     

神经生长因子对培养的大鼠背根神经节神经元P物质释放的调节作用(英文)

目的观察神经生长因子(nerve growth factor, NGF)对原代培养的背根神经节(dorsal root ganglion, DRG)神经元中P物质(substance P, SP)的基础释放量和辣椒素诱发释放量的调节效应。方法将15 天胚龄的Wistar大鼠DRG神经元培养于含有不同浓度NGF的DMEM/F12培养液中,不含NGF的培养液培养的神经元作为对照。72小时后,用RT-PCR检测神经元中SP mRNA和辣椒素受体(vanilloid receptor 1, VR1)mRNA的表达,用放射免疫分析(radioimmunoassay,RIA)法检测SP的基础释放量和辣椒素(100 nmol/L)刺激10 min后的诱发释放量。结果SPmRNA和VR1 mRNA在NGF孵育的标本中表达增加,并与孵育液中NGF的浓度呈剂量依赖关系。SP的基础释放量和辣椒素诱发释放量在NGF孵育的标本中均增加,而且诱发释放量与NGF的浓度呈剂量依赖关系。结论NGF使DRG神经元SP的基础释放量和诱发释放量增加,表明NGF能增加初级传入神经元感受伤害刺激的敏感性,该效应可能与SP和VR1的mRNA表达增加有关。     

Time and dose dependencies of effects of nerve growth factor on sympathetic and sensory neurons in neonatal rats

Nerve growth factor (NGF) plays a role in the development of several components of the sympathetic and sensory nervous systems. The objectives of this study were to examine the time and dose dependencies of some of the well known effects of NGF on sympathetic ganglia and to examine qualitatively and quantitatively the recently described effects on sensory ganglia of neonatal rats. Single doses of NGF as low as 0.1 mg/kg produce increases in tyrosine hydroxylase (TOH) activity in superior cervical ganglia (SCG), and doses of 3 mg/kg produce maximal effects. Larger doses and longer treatments are required to see increases in protein content of the SCG. Larger doses are also required to affect TOH activity in the adrenal gland. Increases in TOH activity in SCG can be observed within 18 h of injection. Chronic NGF treatment for three weeks produces no change in blood pressure or heart rate in neonatal rats. Chronic administration of NGF (1 or 3 mg/kg/day) results in dose-related increases in the protein content of dorsal root ganglia (DRG). The increase in protein content of the DRG was associated with an increase in the diameter of smaller neurons (those<30 μm in diameter), but NGF caused no change in the number of neurons.     

神经生长因子对糖皮质激素诱导大鼠海马神经元凋亡的保护作用

目的探讨神经生长因子对糖皮质激素诱导的大鼠海马神经元凋亡的保护作用。方法体外分离原代培养18只新生Wister大鼠海马神经元,噻唑蓝法测定地塞米松诱导海马神经元凋亡的最低敏感剂量,观察不同质量浓度神经生长因子对地塞米松(0.10×10~(-6)mol/L)诱导海马神经元凋亡的保护作用。结果与阴性对照组相比,地塞米松Ⅰ组(10×10~(-6)mol/L)、Ⅱ组(1×10~(-6)mol/L)和Ⅲ组(0.10×10~(-6)mol/L)大鼠海马神经元活性均降低(P=0.000,0.000,0.000)。予不同质量浓度神经生长因子后,神经生长因子0.18 ng/ml组大鼠海马神经元活性低于阴性对照组(P=0.000)和阳性对照组(P=0.010),神经生长因子18 ng/ml组大鼠海马神经元活性高于阳性对照组(P=0.000)和神经生长因子0.18 ng/ml组(P=0.000)。结论糖皮质激素可以诱导体外培养的大鼠海马神经元凋亡,地塞米松0.10×10~(-6)mol/L是诱导海马神经元凋亡的最低敏感剂量,神经生长因子可以拮抗地塞米松诱导的大鼠海马神经元凋亡。     

Reduction of nerve growth factor receptor immunoreactivity in ischaemic gerbil hippocampal CA1 neurons after treatment with L-threo-3,4-dihydroxyphenylserine (DOPS)

Abstract

Nerve growth factor (NGF) synthesis in cultured mouse L-M fibroblast and astroglial cells can be increased after the treatment with L-threo-3,4-dihydroxyphenylserine (DOPS). Since the increase of NGF is not blocked by the treatment with decarboxylase inhibitor, DOPS may have direct effect to increase the NGF content. NGF and its receptor (NGFR) are suggested to play an important role in the neuronal survival and regeneration under pathologic conditions. In this study, we studied a possible protective effect of DOPS against the hippocampal CA1 cell death after transient forebrain ischaemia in gerbils in relation to the change of NGFR immunoreactivity. We found that treatment with DOPS (300 mg kg^–1) in combination with a decarboxylase inhibitor (benserazide, 10 mg kg^–1) protected ischaemic hippocampal CA1 cell against delayed neuronal death (neuronal density = 125 ± 24 mm^–1) as compared to the treatment with vehicle (49 ± 11 mm^–1) (p < 0.01). The immunoreactivity for NGFR was scarcely present in the sham-control CA1 area but was induced from 1 h and markedly expressed at 7 days after recirculation in the vehicle group. However; it was slightly and transiently induced from 8 h to 2 days in the DOPS plus benserazide treated group. These data suggest that the protective role of DOPS on the ischaemic hippocampal CA1 cells may act through the NGF and its receptor system. [Neurol Res 1994; 16: 201–204]     

Differential effects of lentiviral vector-mediated overexpression of nerve growth factor and glial cell line-derived neurotrophic factor on regenerating sensory and motor axons in the transected peripheral nerve

Even after reconstructive surgery, major functional impairments remain in the majority of patients with peripheral nerve injuries. The application of novel emerging therapeutic strategies, such as lentiviral (LV) vectors, may help to stimulate peripheral nerve regeneration at a molecular level. In the experiments described here, we examined the effect of LV vector-mediated overexpression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on regeneration of the rat peripheral nerve in a transection/repair model in vivo. We showed that LV vectors can be used to locally elevate levels of NGF and GDNF in the injured rat peripheral nerve and this has profound and differential effects on regenerating sensory and motor neurons. For sensory neurons, increased levels of NGF and GDNF do not affect the number of regenerated neurons 1 cm distal to a lesion at 4 weeks post-lesion but do cause changes in the expression of markers for different populations of nociceptive neurons. These changes are accompanied by significant alterations in the recovery of nociceptive function. For motoneurons, overexpression of GDNF causes trapping of regenerating axons, impairing both long-distance axonal outgrowth and reinnervation of target muscles, whereas NGF has no effect on these parameters. These observations show the feasibility of combining surgical repair of the transected nerve with the application of viral vectors. Furthermore, they show a difference between the regenerative responses of motor and sensory neurons to locally increased levels of NGF and GDNF.     

Transneuronal transfer of herpes simplex virus type 1 (HSV 1) from mixed limb nerves to the CNS. I. Sequence of transfer from sensory, motor, and sympathetic nerve fibres to the spinal cord.

The time course of transneuronal transfer of Herpes simplex virus type 1 (HSV 1) from sensory, motor, and sympathetic nerve fibres to connected spinal neurones was examined. After injection of a constant number of infectious units into distal forelimb or hindlimb nerves of inbred rats of the same age, the extent of viral transfer was strictly dependent on the survival time postinoculation (p.i.). Retrograde transport to somatic motoneurones occurred at 28-29 hours p.i. (stage 1), in synchrony with anterograde transneuronal transfer via small cutaneous afferents (to laminae I-II). At 36-43 hours p.i. (stage 2), retrograde transneuronal transfer from sympathetic nerve fibres first labelled sympathetic preganglionic neurones. At 48-51 hours p.i. (stage 3), transfer via sensory and sympathetic axons became more extensive, labelling laminae III-IV and other preganglionic neurones. Transneuronal transfer from large muscle afferents and motoneurones (to Clarke's columns and the spinal intermediate zone) occurred only at 66-78 hours p.i. (stage 4). Further increases in distribution (stages 5-6) obtained between 78 and 97 hours p.i. may reflect both specific labelling of second and third order neurones and a gradual local loss of specificity. These results indicate that transfer of HSV 1 occurs through all main classes of peripheral axons, but that both anterograde and retrograde transneuronal transfer from small (unmyelinated and fine myelinated) cutaneous and sympathetic axons precedes transfer from large (myelinated) cutaneous and muscle afferents and motor axons. Analysis of viral transfer at sequential intervals is required to distinguish serially connected neurones, determine the route of labelling, and ensure its specificity.     

Effect of nerve growth factor on the elongation of neurites from axotomized rat embryonic septal-basal forebrain neurons: an in vitro analysis

The administration of nerve growth factor (NGF) into the brain of a fornix-fimbria lesioned rat can rescue many cholinergic, septal-basal forebrain (SBF) neurons from imminent cell death. Unfortunately, it is unclear if NGF can stimulate regenerative growth from axotomized, SBF neurons. In the present study, we used an in vitro model system to determine if NGF could affect neurite outgrowth from nonaxotomized and/or axotomized, embryonic SBF neurons. Axotomized neurons were obtained by severing the neuritic fields surrounding embryonic day (E) 15 SBF explants maintained in primary culture. Acetylcholinesterase (AChE) histochemistry was used to assess the effects of NGF on cholinergic neurites. We report that 1) neurite outgrowth on type I collagen from E15 SBF neurons in primary culture (nonaxotomized neurons) was not affected by NGF. 2) NGF enhanced the outgrowth (regeneration) of axotomized, SBF neurons on a collagen substratum; however, neurons had to be treated with NGF both before and after axotomy to stimulate regeneration effectively. Application of NGF either before or after axotomy did not enhance regenerative neurite outgrowth. 3) SBF neurons had to be axotomized for NGF to facilitate neurite outgrowth. This is supported by the observation that SBF explants, initially maintained in NGF-supplemented medium in suspension culture, did not demonstrate enhanced neurite outgrowth in the presence of NGF when plated onto a substratum. 4) The regenerative growth of AChE-negative, as well as AChE-positive, neurites was facilitated by NGF treatment. In addition to data concerning neurite outgrowth, we also found that the NGF receptor, as recognized by the antibody 192-IgG, expands its distribution as time in culture progresses; i.e., staining, originally confined to cell bodies and proximal processes within the explant, later included neurites that emanated from the explant. Thus, our results demonstrate that NGF can stimulate regenerative growth from axotomized, but not nonaxotomized, embryonic SBF neurons. We hypothesize that, given the appropriate substratum for axon elongation in vivo, NGF can stimulate the regeneration of SBF neurons in the injured adult brain.     

Expression and regulation of tyrosine hydroxylase in adult sensory neurons in culture: Effects of elevated potassium and nerve growth factor

To determine whether similar molecular mechanisms regulate the same proteins in diverse neuronal populations, the present study compared regulation of tyrosine hydroxylase (TOH) in placodal sensory and neural crest-derived sympathetic neurons in tissue culture. Long-term explant cultures of adult nodose and petrosal sensory ganglia (NPG) contained abundant TOH-immunoreactive neurons and exhibited TOH catalytic activity, as in vivo. After an initial decline during the first week of culture, enzyme activity was maintained at a stable plateau of 60% of zero time values for at least 3 weeks. However, exposure of 2-week-old cultures to depolarizing concentrations of potassium (K+; 40 mM) increased TOH activity approximately two-fold; total protein was unchanged, suggesting that the rise was due to increased TOH specific activity. Therefore, membrane depolarization in vitro appears to regulate this specific catecholaminergic (CA) trait in sensory, as in sympathetic CA cells. In sympathetic neurons, NGF regulates TOH activity throughout life. In marked contrast, TOH activity in adult NPG cultures was unchanged in the presence of 0, 10 or 100 units NGF/ml or in the presence of high concentrations of antiserum against the beta-subunit of NGF. Adult sympathetic neurons, however, grown under identical conditions, exhibited a 5- to 10-fold rise in TOH activity in the presence of NGF. Thus, unlike sympathetics, CA metabolism in adult NPG neurons is not regulated by NGF in vitro; NGF is therefore unlikely to mediate target effects on CA metabolism in placodal sensory neurons in vivo. Our findings indicate that certain mechanisms of CA regulation are shared by placodal sensory and neural crest-derived sympathetic neurons, whereas others are not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic intraventricular injections of nerve growth factor elevate hippocampal choline acetyltransferase activity in adult rats with partial septo-hippocampal lesions

Nerve growth factor (NGF) was injected intraventricularly during 4 weeks into adult rats with unilateral partial lesions of the cholinergic septo-hippocampal pathway. On the lesioned side, NGF treatment elevated choline acetyltransferase (ChAT) activity up to 60% above the activity measured on the lesioned side of cytochrome c-treated controls. On the unlesioned side, NGF treatment increased ChAT activity only to an insignificant degree. ChAT activity in the septum of NGF-treated animals was increased by 60% as compared to controls. The NGF-induced increases on the lesioned side and in the septum were not accompanied by elevations in acetylcholinesterase (AChE) activity. Furthermore, histochemical analysis revealed no difference in AChE staining pattern or intensity between NGF-treated and control animals. The lack of effect on AChE strongly suggests that the increases in ChAT activity in hippocampus and septum are due to an elevation of ChAT activity within cholinergic neurons surviving the lesion rather than to a promotion of sprouting of cholinergic fibers.     

Activation of epidermal growth factor receptors in astrocytes: from development to neural injury

The epidermal growth factor receptor (EGFR) pathway controls the phenotypic characteristics of astrocytes. In the developing central nervous system (CNS), activation of the EGFR pathway induces astrocyte differentiation, forming the cribriform structure that surrounds axons and providing a supportive environment for neurons. In the adult CNS, the EGFR pathway is absent from astrocytes but is highly up-regulated and activated following neuronal injury. Activation of the EGFR pathway triggers quiescent astrocytes to become reactive astrocytes. Although astrocytes regulated by the EGFR pathway play constructive roles in the developing CNS, astrocytes that become reactive in response to activation of the EGFR pathway appear to be destructive to neurons in the adult CNS. The reappearance and activation of EGFRs in astrocytes under pathological conditions may activate a developmental process in an adult tissue. Regulation of EGFR function in astrocytes may be a new therapeutic strategy for the treatment of neural disorders.