Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunosuppressant drugs FK506 and cyclosporin A inhibit T-cell proliferation via a common mechanism: calcineurin inhibition following binding to their respective binding proteins, the peptidyl prolyl isomerases FKBP-12 and cyclophilin A. In contrast, FK506, but not cyclosporin A, accelerates nerve regeneration. In the present study, we show that the potent FKBP-12 inhibitor V-10,367, which lacks the structural components of FK506 required for calcineurin inhibition, increases neurite outgrowth in SH-SY5Y neuroblastoma cells and speeds nerve regeneration in the rat sciatic nerve crush model. In SH-SY5Y cells, V-10,367 increased the lengths of neurite processes in a concentration-dependent (between 1 and 10 nM) fashion over time (up to 168 h). Daily subcutaneous injections of V-10,367 accelerated the onset of clinical signs of functional recovery in the hind feet compared to vehicle-treated control animals. Interdigit distances (between the first and fifth digits) measured on foot prints obtained during walking showed an increase in toe spread in V-10,367-treated rats compared to vehicle-treated controls. Electron microscopy demonstrated larger regenerating axons distal to the crush site in the sciatic nerve from V-10,367-treated rats. Quantitation of axonal areas in the soleus nerve revealed a shift to larger axonal calibers in V-10,367-treated rats (400 or 200 mg/kg/day); mean axonal areas were increased by 52 and 59%, respectively, compared to vehicle-treated controls. FKBP-12 ligands lacking calcineurin inhibitory activity represent a new class of potential drugs for the treatment of human peripheral nerve disorders.
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PMID:A nonimmunosuppressant FKBP-12 ligand increases nerve regeneration. 934 52

The amyloid precursor protein may be processed by several different pathways, one of which produces the amyloid beta-peptide betaA4 present in the amyloid plaques characteristic of Alzheimer's disease. A recent report suggested that axonal-amyloid precursor protein is present in a membrane fraction "with caveolae-like properties." In the present study we have isolated detergent-insoluble, caveolae-like membranes from both mouse cerebellum and the human neuroblastoma cell line SH-SY5Y. Detergent-insoluble membranes from mouse cerebellum retained nearly all of the glycosylphosphatidylinositol-anchored proteins--alkaline phosphatase, 5'-nucleotidase, and the F3 protein--while excluding the majority of the plasmalemmal marker protein alkaline phosphodiesterase I. Although the inositol trisphosphate receptor was highly enriched in this detergent-insoluble fraction, neither amyloid precursor protein nor clathrin immunoreactivity could be detected. Similar results were obtained with SH-SY5Y cells, where 5'-nucleotidase activity was enriched at least 30-fold in the detergent-insoluble membranes, but no amyloid precursor protein or clathrin immunoreactivity could be detected. Caveolin could not be detected in microsomal membranes from either mouse cerebellum or SH-SY5Y cells. These observations suggest that amyloid precursor protein is not normally present in detergent-insoluble, caveolae-like membrane microdomains.
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PMID:The amyloid precursor protein is not enriched in caveolae-like, detergent-insoluble membrane microdomains. 934 65

Neurofilament accumulations are characteristic of a number of neurological conditions including amyotrophic lateral sclerosis, giant axonal neuropathies and several chemically-induced neuropathies. Although the mechanism(s) leading to neurofilament accumulation are unknown, it is possible that similar processes occur both in disease and in chemically-induced neuropathies. Understanding the mechanism(s) of chemically-induced neurofilament accumulation, which is more amenable to experimental manipulation, may give insight into the neurological diseases they mimic. We have compared the effects of two chemically-dissimilar neurotoxins, 2,5-hexanedione and acrylamide, on neurofilaments in the human neuroblastoma cell line, SH-SY5Y. Both undifferentiated and differentiated SH-SY5Y cells were exposed to 2,5-hexanedione or acrylamide and changes in cytoskeletal organization examined by immunofluorescence and electron microscopy. Although distinct morphological differences have previously been characterized in the neuropathies induced by 2,5-hexanedione and acrylamide in vivo, we have found that both compounds had similar direct effects on neurofilaments in SH-SY5Y cells, inducing formation of perikaryal inclusion bodies. In addition, differentiated SH-SY5Y cells were more sensitive to both 2,5-hexanedione and acrylamide compared with undifferentiated cells. These similar effects of 2,5-hexanedione and acrylamide lend further support that a common mechanism(s) may lead to neurofilament accumulation in these neuropathies. SH-SY5Y cells provide a useful model to investigate further the biochemical basis of neurofilament accumulation.
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PMID:Acrylamide and 2,5-hexanedione induce collapse of neurofilaments in SH-SY5Y human neuroblastoma cells to form perikaryal inclusion bodies. 936 61

Extracellular recordings were made in the dorsal respiratory group (DRG) and adjacent reticular formation following single-shock stimulation of the anterior ethmoidal nerve (AEN) and during sneeze evoked by repetitive stimulation of the AEN in nembutal-anaesthetized, curarized and ventilated cats. These neurones were characterised according to (i) their activity during the respiratory cycle (as inspiratory augmenting or decrementing (I Aug or I Dec), expiratory augmenting or decrementing (E Aug or E Dec), silent or tonic), and (ii) their axonal projection (bulbospinal or non-bulbospinal-non-vagal (BS or NBS-NV)). Following single-shock stimulation of the AEN, most of the inspiratory neurones were transiently inhibited, whereas E Aug neurones were activated and E Dec neurones were activated and then inhibited. Silent neurones responded with a multispike or a paucispike pattern. Following repetitive stimulation of the AEN and during the resulting sneeze reflex, I Aug neurones increased their activity in parallel with the phrenic activity, I Dec neurones fired at the onset and at the end of the inspiration, E Dec and some silent neurones fired either during the compressive phase or after the expulsive phase, whereas E Aug and some silent neurones fired during the expulsive phase. We conclude that sneeze involves a reconfiguration of the central respiratory drive which uses, at least partly, the respiratory network to trigger a non-ventilatory defensive motor act.
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PMID:Role of respiratory and non-respiratory neurones in the region of the NTS in the elaboration of the sneeze reflex in cat. 936 3

The function of truncated trkB receptors during nervous system plasticity and regeneration is currently unknown. The extensive nonneuronal localization of truncated trkB-T1 receptors, coupled with their up-regulation by CNS glial cells in response to injury, has led to the speculation that these receptors may sequester BDNF and NT-4/5 to reduce their local availability and, thus, limit axonal sprouting. Conversely, trkB-T1 receptors could bind and present neurotrophins to injured axons and facilitate their regeneration in a manor analogous to that proposed for p75(NTR) receptors on Schwann cells. To address this issue, we used an in vitro coculture paradigm in which wild-type 3T3 NIH fibroblasts or two different 3T3 cell clones stably expressing trkB-T1 receptors served as monolayer substrates upon which to evaluate the effect of trkB-T1 receptors on nonneuronal cells to influence neurotrophin (NGF, BDNF, NT-3, and NT-4/5)-induced neurite outgrowth from retinoic acid (RA)-treated SY5Y neuroblastoma cells. In these experiments, BDNF and NT-4/5 produce a strong phosphorylation of trk receptors on the RA-SY5Y cells and induce differentiation of the SY5Y cells (as measured by the development of neurofilament-positive neuritic processes). This ability of the trkB ligands to stimulate neurite outgrowth is dose dependent since increasing concentrations of BDNF (5, 25, and 100 ng/ml) result in an increased percentage of SY5Y cells developing neurites and in progressively longer neurites from SY5Y cells on the control 3T3 monolayers. In these experiments, BDNF and NT-4/5 induce the strongest neurite outgrowth, followed by NT-3 and then NGF. When trkB-T1 receptors are present on the 3T3 cell substratum both BDNF- and NT-4/5-induced neurite extension from the SY5Y cells are strongly inhibited. In contrast, NGF-induced neurite growth is unaffected and NT-3-associated growth is somewhat reduced. These results suggest that the inhibitory effect of the trkB-T1 receptors on the nonneuronal cell substrates is selective for neurite outgrowth that is mediated via the trkB-kinase receptors on the neuroblastoma cells. This ability of trkB-T1 receptors on the nonneuronal substratum to inhibit BDNF-induced neurite outgrowth can be overcome by the addition of high concentrations of BDNF (1 microg/ml). Binding assays using 125I-BDNF suggest that this inhibitory effect could be mediated via binding and internalization of BDNF by the trkB-T1 receptors on the 3T3 cells. These results provide strong support for the hypothesis that the up-regulation of trkB-T1 receptors on astrocytes following CNS lesions enhances the sequestration of the trkB ligands, BDNF and NT- 4/5, at the site of reactive gliosis and, thus, contributes to the inhibition of CNS axonal regeneration from neurons expressing trkB-kinase receptors by removing their ligands from the extracellular environment.
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PMID:Truncated trkB receptors on nonneuronal cells inhibit BDNF-induced neurite outgrowth in vitro. 941 37

1. Prolongation of action potentials by cooling or pharmacological treatment can restore conduction in demyelinated axons. We have assessed the ability of pyrethroids (in vitro) to modify action potential kinetics and to reverse conduction block in lesioned peripheral nerve. 2. Fast Na+ currents were isolated in mammalian neuroblastoma (NIE115). Pyrethroids (4 microM) concurrently slowed inactivation and produced a spectrum of pronounced tail currents: s-bioallethrin (duration 12.2+/-7 ms), permethrin (24.2+/-3 ms) and deltamethrin (2230+/-100 ms). 3. Deltamethrin (5 microM) effected a slowly developing depression of compound action potential (CAP) amplitude in peroneal nerve trunks (P<0.05). Permethrin produced no net effect on CAP amplitude, area or repolarization time. 4. s-Bioallethrin (5 microM) enhanced CAP area, time for 90% repolarization and induced regenerative activity in a subpopulation of axons. 5. Tibial nerve trunks were demyelinated by lysolecithin (2 micro1) injection: 6-14 days later, slowly-conducting axons in the CAP (and peri-axonal microelectrode recordings) were selectively blocked by warming to 37 degrees C. 6. At 37 degrees C, s-bioallethrin (45 min, 5 microM) produced much greater after-potentials in lesioned nerves than in uninjected controls: area (P< 0.05) and relative amplitude ratios (P< 0.0001) were significantly altered. 7. In 3 of 4 cells (single-unit recording), s-bioallethrin restored conduction through axons exhibiting temperature-dependent block by raising blocking temperature (by 1.5 to > 3 degrees C) and reducing refractory period. 8. s-Bioallethrin induced temperature-dependent regenerative activity only in a sub-population of axons even after prolonged superfusion (> 1 h). 9. It was concluded that pyrethroids differentially alter Na+ current kinetics and action potential kinetics. The effects of s-bioallethrin are consistent with reversal of conduction block by demyelinated axons but regenerative/ectopic firing even in normal cells is likely to underpin its acknowledged neurotoxic actions and severely limit the clinical potential of this and related molecules.
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PMID:Effects of pyrethroid molecules on rat nerves in vitro: potential to reverse temperature-sensitive conduction block of demyelinated peripheral axons. 950 90

We examined the form(s) in which NF subunits undergo axonal transport. Pulse-chase radiolabeling analyses with 35S-methioinine revealed that newly synthesized Triton-soluble NF subunits accumulated within axonal neurites elaborated by NB2a/d1 neuroblastoma prior to the accumulation of Triton-insoluble subunits. Gel chromatographic, immunological, ultrastructural, and autoradiographic analyses of Triton-soluble axonal fractions demonstrated that radiolabeled, Triton-soluble subunits were associated with NFs. Triton-soluble, radiolabeled axonal NF subunits were also detected within retinal ganglion cell axons following intravitreal injection of 35S-methioinine. Microinjected biotinylated subunits were prominent within axonal neurites of NB2a/d1 cells and cultured dorsal root ganglion neurons substantially before they were retained following Triton-extraction. Prevention of biotinylated subunit, but not dextran tracer, translocation into neurites by nocodazole confirmed that microinjected subunits did not enter axons merely due to diffusion or injection-based pressure. Immuno-EM confirmed the association of biotin label with axonal NFs. These findings point towards multiple populations of NF subunits within axons and leave open the possibility that axonal NFs may be more dynamic than previously considered.
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PMID:Neurofilament subunits can undergo axonal transport without incorporation into Triton-insoluble structures. 960 71

The pronounced increases in gangliosides belonging to the gangliotetraose family during the neurite outgrowth phase of neuronal differentiation have suggested a functional requirement for these substances related to process extension, arborization, and possibly synaptogenesis. Support for this hypothesis has come from a variety of experimental paradigms utilizing neuroblastoma cell lines, primary neuronal cultures, and observations on the developing nervous system. We have recently observed that differentiation of both primary neurons and neuroblastoma cells by Ca(2+)-elevating stimulants is characterized by upregulation of GM1 in the nuclear membrane. Immunostaining revealed these Ca(2+)-induced neurites to have axonal characteristics. Recent work has indicated that nuclear GM1 facilitates efflux of nuclear Ca2+, thereby contributing to the reduced level of nuclear Ca2+ that characterizes the differentiated neuron. Thus, while GM1 is generally recognized as a pluripotent molecule with several modulatory roles in the plasma membrane of developing and mature neurons, regulation of Ca2+ flux across the nuclear membrane is proposed as another critical function of this ganglioside in neuronal development, with special relevance to axonogenesis.
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PMID:The role of GM1 and other gangliosides in neuronal differentiation. Overview and new finding. 966 50

Tau and other microtubule-associated proteins promote the assembly and stabilization of neuronal microtubules. While each microtubule-associated protein has distinct properties, their in vivo roles remain largely unknown. Tau is important in neurite outgrowth and axonal development. Recently, we showed that the amino-terminal region of tau, which is not involved in microtubule interactions, is important in NGF induced neurite outgrowth in PC12 cells. Here we report that a proline rich sequence in the amino terminus of tau interacts with the SH3 domains of fyn and src non-receptor tyrosine kinases. Tau and fyn were co-immunoprecipitated from human neuroblastoma cells and co-localization of tau and fyn was visualized in co-transfected NIH3T3 cells. Co-transfection of tau and fyn also resulted in an alteration in NIH3T3 cell morphology, consistent with an in vivo interaction. Fyn-dependent tyrosine phosphorylation of tau occurred in transfected cells and tyrosine phosphorylated tau was identified in human neuroblastoma cells as well. Our data suggest that tau is involved in signal transduction pathways. An interaction between tau and fyn may serve as a mechanism by which extracellular signals influence the spatial distribution of microtubules. The tyrosine phosphorylation of tau by fyn may also have a role in neuropathogenesis, as fyn is upregulated in Alzheimer's disease.
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PMID:Tau interacts with src-family non-receptor tyrosine kinases. 976 11

The neuronal microtubule-associated protein tau plays an important role in establishing cell polarity by stabilizing axonal microtubules that serve as tracks for motor-protein-driven transport processes. To investigate the role of tau in intracellular transport, we studied the effects of tau expression in stably transfected CHO cells and differentiated neuroblastoma N2a cells. Tau causes a change in cell shape, retards cell growth, and dramatically alters the distribution of various organelles, known to be transported via microtubule-dependent motor proteins. Mitochondria fail to be transported to peripheral cell compartments and cluster in the vicinity of the microtubule-organizing center. The endoplasmic reticulum becomes less dense and no longer extends to the cell periphery. In differentiated N2a cells, the overexpression of tau leads to the disappearance of mitochondria from the neurites. These effects are caused by tau's binding to microtubules and slowing down intracellular transport by preferential impairment of plus-end-directed transport mediated by kinesin-like motor proteins. Since in Alzheimer's disease tau protein is elevated and mislocalized, these observations point to a possible cause for the gradual degeneration of neurons.
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PMID:Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. 981 97


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