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1.
Photodynamic therapy (PDT), an inducer of oxidative stress, is used for treatment of cancer, including brain tumors. To study the mechanisms of photodynamic injury of neurons and glial cells (GC), we used a simple model object — isolated crayfish mechanoreceptor consisting of a single sensory neuron surrounded by a multilayered glial envelope. PDT caused inhibition and elimination of neuronal activity, impairment of intracellular organelles involved in the biosynthetic, bioenergetic, and transport processes and neuroglial interactions, necrosis of neurons and glial cells, and in glial apoptosis. PDT-induced death of a neuron and GC was mediated by intercellular molecular messengers and intracellular signaling cascades. PDT-induced inhibition and elimination of neuronal activity was associated with opening of mitochondrial permeability transition pores, Ca2+ release into cytosol, protein kinase C and NO synthase activities. Necrosis of neurons was mediated by protein kinases B/Akt, GSK-3β and mTOR, opening of mitochondrial permeability transition pores and Ca2+/calmodulin/CaMKII pathway. NO and GDNF reduced neuronal necrosis. Multiple signal pathways, such as phospholipase C/Ca2+, Ca2+/calmodulin/CaMKII, Ca2+/PKC, Akt/mTOR, MEK/p38, and protein kinase G mediated PDT-induced necrosis both in glial cells and in neurons. NOS/NO and neurotrophic factors NGF and GDNF protected glial cells and demonstrated antinecrotic activity. Glial apoptosis was reduced by neurotrophic factors NGF and GDNF, protein kinase C, and MAP kinase JNK. In contrast, mitochondrial permeability transition pores and phospholipase C, which mobilize intracellular Ca2+, NOS/NO/protein kinase G, proteins GSK-3β and mTOR, stimulated apoptosis of glial cells. The schemes of involvement of various inter- and intracellular signaling processes in the responses of neurons and GC to PDT are developed.  相似文献   

2.
3.
The effects of physiological concentrations of K+ on Mn2+ accumulation were compared in rat glial cells and neurons in culture. Increasing the K+ concentration in growth medium increased significantly the Mn2+ level of the cultivated cells, with glial cells more affected than neurons. Ethanol markedly increased the Mn2+ accumulation within glia but not within neurons while ouabaïn caused inhibition of Mn2+ uptake with neurons and glial cells. A modulation of the total protein synthesis by Mn2+ and ethanol level in the growth medium was observed with glial cells. These data suggest that the mechanisms involved in Mn2+ accumulation in glial cells are different from those present in neurons. Moreover, the results are consistent with the hypothesis that Mn2+ plays a regulatory role in glial cell metabolism.  相似文献   

4.
A new paradigm has recently emerged in brain science whereby communications between glial cells and neuron-glia interactions should be considered together with neurons and their networks to understand higher brain functions. In particular, astrocytes, the main type of glial cells in the cortex, have been shown to communicate with neurons and with each other. They are thought to form a gap-junction-coupled syncytium supporting cell-cell communication via propagating Ca2+ waves. An identified mode of propagation is based on cytoplasm-to-cytoplasm transport of inositol trisphosphate (IP3) through gap junctions that locally trigger Ca2+ pulses via IP3-dependent Ca2+-induced Ca2+ release. It is, however, currently unknown whether this intracellular route is able to support the propagation of long-distance regenerative Ca2+ waves or is restricted to short-distance signaling. Furthermore, the influence of the intracellular signaling dynamics on intercellular propagation remains to be understood. In this work, we propose a model of the gap-junctional route for intercellular Ca2+ wave propagation in astrocytes. Our model yields two major predictions. First, we show that long-distance regenerative signaling requires nonlinear coupling in the gap junctions. Second, we show that even with nonlinear gap junctions, long-distance regenerative signaling is favored when the internal Ca2+ dynamics implements frequency modulation-encoding oscillations with pulsating dynamics, while amplitude modulation-encoding dynamics tends to restrict the propagation range. As a result, spatially heterogeneous molecular properties and/or weak couplings are shown to give rise to rich spatiotemporal dynamics that support complex propagation behaviors. These results shed new light on the mechanisms implicated in the propagation of Ca2+ waves across astrocytes and the precise conditions under which glial cells may participate in information processing in the brain.  相似文献   

5.
Han SI  Kim YS  Kim TH 《BMB reports》2008,41(1):1-10
Apoptosis is considered to be a programmed and controlled mode of cell death, whereas necrosis has long been described as uncontrolled and accidental cell death resulting from extremely harsh conditions. In the following review, we will discuss the features and physiological meanings as well as recent advances in the elucidation of the signaling pathways of both apoptotic cell death and programmed necrotic cell death.  相似文献   

6.
Enhancements to memory are associated with enhanced neural structures that support those capabilities. A great deal of work has examined this relationship in the context of natural variation in spatial memory capability and hippocampal (Hp) structure. Most studies have focused on volumetric and neuron measures, but have seldom examined the role of glial cells. Once considered involved only in supportive functions associated with neurons, the importance of glial cells in cognitive processes, including memory, is gaining more attention. Building upon our previous study on the relationship between the brain, memory, and environmental severity in food‐caching birds, we compared the total number of Hp glial cells in wild‐sampled and in lab‐reared (common garden) black‐capped chickadees (Poecile atricapillus) originating from two different environmental extremes. We found that birds from more harsh climate tended to have significantly more Hp glial cells than those from more mild climate and that lab‐reared chickadees had significantly fewer Hp glial cells compared to the wild‐sampled birds. These results suggest that population differences in glial numbers may be controlled, at least in part, by heritable mechanisms, but glial numbers appear to be additionally regulated by an individual's environment. The pattern of Hp glial cell abundance among our treatment groups closely followed that of the Hp volume, suggesting that Hp glial cell number may be associated with the Hp volume. Unlike Hp neurons, however, the number of Hp glial cells may be, at least in part, affected by an individual's experiences and environment. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 480–485, 2013  相似文献   

7.
Recent studies show that specification of some neural crest lineages occurs prior to or at the time of migration from the neural tube. We investigated what signaling events establish the melanocyte lineage, which has been shown to migrate from the trunk neural tube after the neuronal and glial lineages. Using in situ hybridization, we find that, although Wnts are expressed in the dorsal neural tube throughout the time when neural crest cells are migrating, the Wnt inhibitor cfrzb-1 is expressed in the neuronal and glial precursors and not in melanoblasts. This expression pattern suggests that Wnt signaling may be involved in specifying the melanocyte lineage. We further report that Wnt-3a-conditioned medium dramatically increases the number of pigment cells in quail neural crest cultures while decreasing the number of neurons and glial cells, without affecting proliferation. Conversely, BMP-4 is expressed in the dorsal neural tube throughout the time when neural crest cells are migrating, but is decreased coincident with the timing of melanoblast migration. This expression pattern suggests that BMP signaling may be involved in neural and glial cell differentiation or repression of melanogenesis. Purified BMP-4 reduces the number of pigment cells in culture while increasing the number of neurons and glial cells, also without affecting proliferation. Our data suggest that Wnt signaling specifies melanocytes at the expense of the neuronal and glial lineages, and further, that Wnt and BMP signaling have antagonistic functions in the specification of the trunk neural crest.  相似文献   

8.
The chemokine IL-8 is known to be synthesized by glial cells in the brain. It has traditionally been shown to have an important role in neuroinflammation but recent evidence indicates that it may also be involved in rapid signaling in neurons. We investigated how IL-8 participates in rapid neuronal signaling by using a combination of whole-cell recording and single-cell RT-PCR on dissociated rat septal neurons. We show that IL-8 can acutely reduce Ca(2+) currents in septal neurons, an effect that was concentration-dependent, involved the closure of L- and N-type Ca(2+) channels, and the activation of G(ialpha1) and/or G(ialpha2) subtype(s) of G-proteins. Analysis of the mRNAs from the recorded neurons revealed that the latter were all cholinergic in nature. Moreover, we found that all cholinergic neurons that responded to IL-8, expressed mRNAs for either one or both IL-8 receptors CXCR1 and CXCR2. This is the first report of a chemokine that modulates ion channels in neurons via G-proteins, and the first demonstration that mRNAs for CXCR1 are expressed in the brain. Our results suggest that IL-8 release by glial cells in vivo may activate CXCR1 and CXCR2 receptors on cholinergic septal neurons and acutely modulate their excitability by closing calcium channels.  相似文献   

9.
Antibodies against the chondroitin sulfate proteoglycan NG2 label a subpopulation of glial cells within the CNS, which have a small cell body and thin radiating processes. Physiological recordings from these small cells in acute brain slices have revealed that they possess unique properties, suggesting that they may comprise a class of glial cells distinct from astrocytes, oligodendrocytes, or microglia. NG2-expressing glial cells (abbreviated as “NG2 cells” here) have a moderate input resistance and are not dye- or tracer-coupled to adjacent cells. They express voltage-gated Na+, K+and Ca2+conductances, though they do not exhibit regenerative Na+or Ca2+action potentials due to the much larger K+conductances present. In addition to voltage-gated conductances, they express receptors for various neurotransmitters. In the hippocampus, AMPA and GABAAreceptors on these cells are activated by release of transmitter from neurons at defined synaptic junctions that are formed with CA3 pyramidal neurons and GABAergic interneurons. These rapid forms of neuron-glial communication may regulate the proliferation rate of NG2 cells or their development into mature oligodendrocytes. These depolarizing inputs may also trigger the release of neuroactive substances from NG2 cells, providing feedback regulation of signaling at neuronal synapses. Although the presence of Ca2+permeable AMPA receptors provides a pathway to link neuronal activity to Ca2+dependent processes within the NG2 cells, these receptors also put these cells at risk for glutamate-associated excitotoxicity. This vulnerability to the sustained elevation of glutamate may underlie ischemic induced damage to white matter tracts and contribute to cerebral palsy in premature infants.  相似文献   

10.
The presence of an efficient uptake system for l-pyroglutamate was demonstrated in cultured glial cells originating from newborn rats. This compound is also transported by a high affinity uptake mechanism in neurons cultured from rat embryos cerebral hemispheres, but the Vmax is 6 times lower than for glial cells. It is shown that l-pyroglutamate like l-glutamate is preferentially transported by glial cells, but with a Vmax 40 to 60 times lower than for glutamate. The metabolism of l-pyroglutamate was also studied in cultured rat neuronal and glial cells, using l-[3H]pyroglutamate. Pyroglutamate, its metabolites and the various amino acids were separated by thin-layer electrophoresis. [3H]Pyroglutamate is more actively metabolised in glial cells than in neurons and glutamate is the main metabolite. Glutamate maximal specific activity is 4 times higher in glial than in neuronal cultures. It should also be noted that some [3H]pyroglutamate is transformed in [3H]GABA after longer incubation periods, but only in neurons. These results show the importance of glial cells for pyroglutamate uptake and metabolism in nervous tissue. They also suggest that pyroglutamate may interfere with glutamate neurotransmission in vivo.  相似文献   

11.
Anomalies in glutamate homeostasis may contribute to the pathological processes involved in Alzheimer’s disease (AD). Glutamate released from neurons or glial cells is normally rapidly cleared by glutamate transporters, most of which are expressed at the protein level by glial cells. However, in some patho-physiological situations, expression of glutamate transporters that are normally considered to be glial types, appears to be evoked in populations of distressed neurons. This study analysed the expression of exon-skipping forms of the three predominant excitatory amino acid (glutamate) transporters (EAATs1-3) in brains afflicted with AD. We demonstrate by immunocytochemistry in temporal cortex, the expression of these proteins particularly in limited subsets of neurons, some of which appeared to be dys-morphic. Whilst the neuronal expression of the “glial” glutamate transporters EAAT1 and EAAT2 is frequently considered to represent the abnormal and ectopic expression of such transporters, we suggest this may be a misinterpretation, since neurons such as cortical pyramidal cells normally express abundant mRNA for these EAATs (but little if any EAAT protein expression). We hypothesize instead that distressed neurons in the AD brain can turn on the translation of pre-existent mRNA pools, or suppress the degradation of alternately spliced glutamate transporter protein, leading to the “unmasking” of, rather than evoked expression of “glial” glutamate transporters in stressed neurons. Special issue article in honor of Dr. Graham Johnston.  相似文献   

12.
Effects of glial cells on electrical isolation and shaping of synaptic transmission between neurons have been extensively studied. Here we present evidence that the release of proteins from astrocytes as well as microglia may regulate voltage-activated Na+ currents in neurons, thereby increasing excitability and speed of transmission in neurons kept at distance from each other by specialized glial cells. As a first example, we show that basic fibroblast growth factor and neurotrophin-3, which are released from astrocytes by exposure to thyroid hormone, influence each other to enhance Na+ current density in cultured hippocampal neurons. As a second example, we show that the presence of microglia in hippocampal cultures can upregulate Na+ current density. The effect can be boosted by lipopolysaccharides, bacterial membrane-derived stimulators of microglial activation. Comparable effects are induced by the exposure of neuron-enriched hippocampal cultures to tumour necrosis factor-α, which is released from stimulated microglia. Taken together, our findings suggest that release of proteins from various types of glial cells can alter neuronal excitability over a time course of several days. This explains changes in neuronal excitability occurring in states of thyroid hormone imbalance and possibly also in seizures triggered by infectious diseases.  相似文献   

13.
Summary 1. The blood–brain barrier (BBB) is formed by brain capillary endothelial cells (ECs). There are various cell types, in particular astrocytes, but also pericytes and neurons, located in close vicinity to the capillary ECs which may influence formation and function of the BBB. Based on this consideration, this paper discusses various aspects of the influence of the surrounding cells on brain capillary ECs with special focus on the role of astrocytes.2. Based on the morphology of the BBB, important aspects of brain EC functions are summarized, such as transport functions and maintenance of low paracellular permeability. Moreover, various facets are discussed with respect to the influence of astrocytes, pericytes, microglia, and neurons on the BBB. Data on the role of glial cells in the ontogenesis of the BBB are presented subsequently. The knowledge on this subject is far from being complete, however, these data imply that the neural/neuronal environment rather than glial cells may be of importance in the maturation of the barrier.3. The role of glial cells in the induction and maintenance of the BBB is discussed under physiological as well as pathological conditions. Although the literature presents manifold evidence for a great variety of effects induced by astroglia, there are also many controversies, which may result from different cellular models and experimental conditions used in the respective studies. Numerous factors secreted by astrocytes have been shown to induce a BBB phenotype. On the molecular level, increased expression of barrier-relevant proteins (e.g., tight junction proteins) is documented in the presence of astrocyte-derived factors, and many studies demonstrate the improvement of physiological parameters, such as increased transendothelial resistance and decreased paracellular permeability, in different in vitro models of the BBB. Moreover, one has to take into account that the interaction of brain ECs and astrocytes is bi-directional, and that the other cell types surrounding the brain microvasculature also contribute to BBB function or dysfunction, respectively.4. In conclusion, it is expected that the present and future research focused on molecular mechanisms and signaling pathways will produce new and exciting insights into the complex network of BBB regulation: the cornerstone is laid.This revised article was published online in May 2005 with a February 2005 cover date.  相似文献   

14.
The view of how astrocytes, a type of glial cells, contribute to the functioning of the central nervous system (CNS) has changed greatly in the last decade. Although glial cells outnumber neurons in the mammalian brain, it was considered for over a century that they played a subservient role to neurons. This view changed. Functions thought to be exclusively present in neurons, i.e. excitability mediated release of chemical messengers, has also been demonstrated in astrocytes. In this process, following an increase in cytosolic calcium activity, membrane bound vesicles, storing chemical messengers (gliotransmitters), fuse with the plasma membrane, a process known as exocytosis, permitting the exit of vesicle cargo into the extracellular space. Vesicles are delivered to and are removed from the site of exocytosis by an amazingly complex set of processes that we have only started to learn about recently. In this paper we review vesicle traffic, which is subject to physiological regulation and may be changed under pathological conditions.  相似文献   

15.
S1P is involved in the regulation of multiple biological processes (cell survival, growth, migration and differentiation) both in neurons and glial cells. The study was aimed at investigating the possible effects of S1P on calcium signaling in cerebellar astrocytes and differentiated granule cells. In cerebellar astrocytes S1P is able to mediate calcium signaling mainly through Gi protein coupled receptors, whereas in differentiated neurons it failed to evoke any calcium signaling, despite acting both extracellularly and intracellularly. The data indicate strict cell specificity in S1P-evoked calcium response, which could be relevant to communication between neurons and glial cells in the cerebellum.  相似文献   

16.
The nervous system consists of neurons and glial cells. Neurons generate and propagate electrical and chemical signals, whereas glia function mainly to modulate neuron function and signaling. Just as there are many different kinds of neurons with different roles, there are also many types of glia that perform diverse functions. For example, glia make myelin; modulate synapse formation, function, and elimination; regulate blood flow and metabolism; and maintain ionic and water homeostasis to name only a few. Although proteomic approaches have been used extensively to understand neurons, the same cannot be said for glia. Importantly, like neurons, glial cells have unique protein compositions that reflect their diverse functions, and these compositions can change depending on activity or disease. Here, I discuss the major classes and functions of glial cells in the central and peripheral nervous systems. I describe proteomic approaches that have been used to investigate glial cell function and composition and the experimental limitations faced by investigators working with glia.The nervous system is composed of neurons and glial cells that function together to create complex behaviors. Traditionally, glia have been considered to be merely passive contributors to brain function, resulting in a pronounced neurocentric bias among neuroscientists. Some of this bias reflects a paucity of knowledge and tools available to study glia. However, this view is rapidly changing as new tools, model systems (culture and genetic), and technologies have permitted investigators to show that glia actively sculpt and modulate neuronal properties and functions in many ways. Glia have been thought to outnumber neurons by 10:1, although more recent studies suggest the ratio in the human brain is closer to 1:1 with region-specific differences (1). There are many different types of glia, some of which are specific to the central nervous system (CNS),1 whereas others are found only in the peripheral nervous system (PNS). The main types of CNS glia include astrocytes, oligodendrocytes, ependymal cells, radial glia, and microglia. In the PNS, the main glial cells are Schwann cells, satellite cells, and enteric glia. These cells differ and are classified according to their morphologies, distinct anatomical locations in the nervous system, functions, developmental origins, and unique molecular compositions. Among the different classes of glia there are additional subclasses that reflect further degrees of specialization. In this review, I will discuss the characteristics and functions of the major glial cell types including astrocytes, microglia, and the myelin-forming oligodendrocytes (CNS) and Schwann cells (PNS). Because of space limitations, it is impossible to give a complete accounting of all glia and what is known about each of these cell types. Therefore, I encourage the interested reader to refer to some of the many excellent reviews referenced below that focus on individual glial cell types. Finally, I will discuss proteomic studies of glial cell function and some of the unique challenges investigators face when working with these cells.  相似文献   

17.
18.
Although it is considered to be the most complex organ in the body, the brain can be broadly classified into two major types of cells, neuronal cells and glial cells. Glia is a general term that encompasses multiple types of non-neuronal cells that function to maintain homeostasis, form myelin, and provide support and protection for neurons. Astrocytes, a major class of glial cell, have historically been viewed as passive support cells, but recently it has been discovered that astrocytes participate in signalling activities both with the vasculature and with neurons at the synapse. These cells have been shown to release d-serine, TNF-α, glutamate, atrial natriuretic peptide (ANP) and ATP among other signalling molecules. ATP and its metabolites are well established as important signalling molecules, and astrocytes represent a major source of ATP release in the nervous system. Novel molecular and genetic tools have recently shown that astrocytic release of ATP and other signalling molecules has a major impact on synaptic transmission. Via actions at the synapse, astrocytes have now been shown to regulate complex network signalling in the whole organism with impacts on respiration and the sleep–wake cycle. In addition, new roles for astrocytes are being uncovered in psychiatric disorders, and astrocyte signalling mechanisms represents an attractive target for novel therapeutic agents.  相似文献   

19.

In the past, glial cells were considered to be ‘glue’ cells whose primary role was thought to be merely filling gaps in neural circuits. However, a growing number of reports have indicated the role of glial cells in higher brain function through their interaction with neurons. Myelin was originally thought to be just a sheath structure surrounding neuronal axons, but recently it has been shown that myelin exerts effects on the conduction velocity of neuronal axons even after myelin formation. Therefore, the investigation of glial cell properties and the neuron-glial interactions is important for understanding higher brain function. Moreover, since there are many neurological disorders caused by glial abnormalities, further understanding of glial cell-related diseases and the development of effective therapeutic strategies are warranted. In this review, we focused on oligodendrocyte-neuron interactions, with particular attention on (1) axonal signals underlying oligodendrocyte differentiation and myelination, (2) neuronal activity-dependent myelination and (3) the effects of myelination on higher brain function.

  相似文献   

20.
Necrosis: a specific form of programmed cell death?   总被引:17,自引:0,他引:17  
For a long time necrosis was considered as an alternative to programmed cell death, apoptosis. Indeed, necrosis has distinct morphological features and it is accompanied by rapid permeabilization of plasma membrane. However, recent data indicate that, in contrast to necrosis caused by very extreme conditions, there are many examples when this form of cell death may be a normal physiological and regulated (programmed) event. Various stimuli (e.g., cytokines, ischemia, heat, irradiation, pathogens) can cause both apoptosis and necrosis in the same cell population. Furthermore, signaling pathways, such as death receptors, kinase cascades, and mitochondria, participate in both processes, and by modulating these pathways, it is possible to switch between apoptosis and necrosis. Moreover, antiapoptotic mechanisms (e.g., Bcl-2/Bcl-x proteins, heat shock proteins) are equally effective in protection against apoptosis and necrosis. Therefore, necrosis, along with apoptosis, appears to be a specific form of execution phase of programmed cell death, and there are several examples of necrosis during embryogenesis, a normal tissue renewal, and immune response. However, the consequences of necrotic and apoptotic cell death for a whole organism are quite different. In the case of necrosis, cytosolic constituents that spill into extracellular space through damaged plasma membrane may provoke inflammatory response; during apoptosis these products are safely isolated by membranes and then are consumed by macrophages. The inflammatory response caused by necrosis, however, may have obvious adaptive significance (i.e., emergence of a strong immune response) under some pathological conditions (such as cancer and infection). On the other hand, disturbance of a fine balance between necrosis and apoptosis may be a key element in development of some diseases.  相似文献   

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