Self-Protective Mechanism Awakened by Glutamate in Retinal Ganglion Cells
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The progression of degeneration in chronic optic neuropathies or in animal models of optic nerve injury is thought to be caused, at least in part, by an increase in glutamate to abnormally high concentrations. We show here that glutamate, when injected in subtoxic amounts into the vitreal body of the rat eye, transduces a self-protecting signal that renders the retinal ganglion cells resistant to further toxicity, whether glutamate-derived or not. This neuroprotective effect is attained within 24 h and lasts at least 4 days. Western blot analysis of rat retinas revealed increased amounts of bcl-2 four days after injection of glutamate in either subtoxic or toxic (120 nmol) amounts, but not after saline injection. The effects of intravitreal glutamate or saline injection on the secretion of neurotrophins by retinal ganglion cells was evaluated in rat aqueous humor 6 h, 1 day, and 4 days after injection. Nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 showed similar kinetic patterns in all of the eyes; that is, they increased to a peak 1 day after the injection and returned to normal by day 4. However, increased amounts the neurotrophin receptor TrkA within the retinal ganglion cell layer and nerve fiber layer were detected 1 day after injection of glutamate in either toxic or subtoxic amounts, but not after saline injection. This finding points to the possible involvement of neurotrophin receptors in regulation of the cellular responses to glutamate challenge. Identification of the intracellular signals that trigger the glutamate-induced self-protective mechanism would shed light on the genetic balance needed for survival, and guide the development of drugs for the up-regulation of desired genes and their products.Keywords:
Ganglion cell layer
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在哺乳动物的大脑，四 neurotrophins 被识别了：神经生长因素(NGF ) ，导出大脑的神经营养的因素(BDNF ) ， neurotrophin-3 (NT-3 ) 和 neurotrophin-4/5 (NT-4/5 ) 。NGF 在中央、外部的神经系统的开发和函数施加一个重要角色。然而，有免疫力的房间的几种类型例如桅杆房间，淋巴细胞， basophils 和嗜曙红血球，生产，存储并且释放 NGF，这最近被记录了。积累现出症状之前的潜、临床的数据显示 NGF 和另外的 neurotrophins 的机能障碍可以贡献损害有免疫力的回答， NGF 的集中经常与疾病严厉相关。因此，这研究的目的是阐明贡献的 cytokineneurotrophins 相互作用的潜在的发信号机制增加了 NGF 层次。我们抄写 factorNF-B 玩的数据表演在调整 B-cell-derived NGF 的一个枢轴的角色表示。
Neurotrophin-3
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The development and survival of sympathetic neurons is critically dependent on the related neurotrophic factors nerve growth factor (NGF) and neurotrophin-3 (NT3), the actions of which must be executed appropriately despite spatial and temporal overlaps in their activities. The tyrosine receptor kinases, trkA and trkC, are the cognate receptors for NGF and NT3, respectively. The p75 neurotrophin receptor has been implicated in neurotrophin binding and signaling for both NGF and NT3. In this study, the authors used mice that overexpressed NGF (NGF-OE) or NT3 (NT3-OE) in skin and mice that lacked p75 (p75−/−) to understand the dynamics of sympathetic neuron response to each neurotrophin and to address the role of p75. NGF and NT3 were measured in sympathetic ganglia and skin (a major target of sympathetic neurons) by using the enzyme-linked immunosorbent assay (ELISA) technique. A three- to four-fold increase in skin NT3 was seen in both NT3-OE and p75−/− mice. Moreover, both mouse lines exhibited a three-fold increase in ganglionic NT3. However, the increase in ganglionic NT3 was accompanied by a decrease in ganglionic NGF in p75−/− mice but not in NT3-OE mice. This indicated that p75 plays an important role in determining the level of NGF within sympathetic neurons. In NGF-OE mice, the overexpression of NGF was correlated with increased ganglionic NGF and increased ganglionic expression of p75 mRNA. In addition, in NGF-OE mice, ganglionic trkC expression was decreased, as was the amount of NT3 present within sympathetic ganglia. These results indicate that the level of p75 is integral in determining the level of sympathetic NGF and that NGF competes with NT3 by increasing the expression of p75 and decreasing the expression of trkC. J. Comp. Neurol. 424:99–110, 2000. © 2000 Wiley-Liss, Inc.
Neurotrophin-3
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Neurotrophin-3
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Neurotrophin-3
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The nerve growth factor (NGF) belongs to a family of proteins named neurotrophins, consisting of NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5 and NT-6. NGF regulates a large number of physiological mechanisms that result in neurotrophic, metabotrophic and/or immunotrophic effects. Neurodegenerative diseases, including Alzheimer disease, psychiatric disorders (e.g. depression and schizophrenia) and brain parasitic infection have in common the effect of changing the brain levels of neurotrophins, in particular NGF. The contribution of both NGF and its receptor TrkA in such events and the recent promising results of NGF based therapies are here presented and discussed.
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Neurotrophin-3
Peripheral Nervous System
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Peripheral nerve injury
Ciliary neurotrophic factor
Nerve Injury
Peripheral Nervous System
Nerve guidance conduit
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We used compartmented cultures to study the regulation of adult sensory neurite growth by neurotrophins. We examined the effects of the neurotrophins nerve growth factor (NGF), neurotrophin-3 (NT3), and BDNF on distal neurite elongation from adult rat dorsal root ganglion (DRG) neurons. Neurons were plated in the center compartments of three-chambered dishes in the absence of neurotrophin, and neurite extension into the distal (side) compartments containing NGF, BDNF, or NT3 was quantitated. Initial proximal neurite growth did not require any of the neurotrophins, while subsequent elongation into distal compartments required NGF. After neurites had extended into NGF-containing distal compartments, removal of NGF by treatment with anti-NGF resulted in the cessation of growth with minimal neurite retraction. In contrast to the effects of NGF, no distal neurite elongation was observed into compartments with BDNF or NT3. To examine possible additive influences, neurite extension into compartments containing BDNF plus NGF or NT3 plus NGF was quantitated. There was no increased neurite extension into NGF plus NT3 compartments, while the combination of BDNF plus NGF resulted in an inhibition of neurite extension compared with NGF alone. We then investigated whether the regrowth of neurites that had originally grown into NGF subsequent to in vitro axotomy still required NGF. The results demonstrated that unlike adult sensory nerve regeneration in vivo, the in vitro regrowth did require NGF, and neither BDNF nor NT3 was able to substitute for NGF. Since the initial growth from neurons after dissociation (which is also a regenerative response) did not require NGF, it would appear that neuritic growth and regrowth of adult DRG neurons in vitro includes both NGF-independent and NGF-dependent components. The compartmented culture system provides a unique model to further study aspects of this differential regulation of neurite growth. © 1997 John Wiley & Sons, Inc. J Neurobiol 33: 395–410, 1997
Neurite
Neurotrophin-3
Axotomy
Dorsal root ganglion
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Neurotrophin-3
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