Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The observed response to 131I-metaiodobenzylguanidine (MIBG) therapy in advanced neuroblastoma after conventional therapy, the non-invasiveness of the procedure, and the high metabolic activity which is frequently observed in untreated tumours led to the concept of substituting 131I-MIBG therapy for combination chemotherapy at diagnosis prior to surgery in patients with advanced disease/high-risk neuroblastoma. The objective of introducing 131I-MIBG therapy as the first therapy in the treatment schedule is to reduce the tumour volume, enabling adequate (> 95%) surgical resection of the tumour and to avoid toxicity and the induction of early drug resistance. The advantages of this approach are that the child's general condition is unaffected or improved before it undergoes surgical resection and that chemotherapy is reserved to treat minimal residual disease postoperatively. Thirty-one children who presented with inoperable neuroblastoma (10 Evans stage III, 21 stage IV) were treated according to this protocol. The objective response to the 131I-MIBG therapy at diagnosis with respect to the volume of the primary tumour, the metastases and catecholamine excretion in urine varied from 72 to 81%, which is better than after conventional treatment. Nineteen of 27 evaluable patients (70%) had complete or > 95% resection of the primary tumour or did not require surgery at all. Only 11 of 31 patients developed isolated thrombocytopenia and, despite the fact that the bone marrow was invaded in 16 patients, moderate bone marrow depression occurred in only two cases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:131I-MIBG as a first-line treatment in high-risk neuroblastoma patients. 781 84

1. The ability of lifarizine (RS-87476) to block human voltage-sensitive Na+ channel currents was studied by use of whole cell patch clamp recording from differentiated neuroblastoma cells (SH-SY5Y). 2. The Na+ conductance in differentiated SH-SY5Y cells (24.0 +/- 2.4 nS, n = 11) was half-maximally activated by 10 ms depolarizations to -37 +/- 2 mV and was half-maximally inactivated by predepolarizing pulses of 200 ms duration to -86 +/- 3 mV (n = 11). 3. At low stimulus frequencies (0.1 to 0.33 Hz) voltage-dependent sodium currents were completely blocked, in a concentration-dependent manner, by extracellular application of either tetrodotoxin (EC50 = 4 +/- 1 nM, n = 12) or by lifarizine (EC50 = 783 +/- 67 nM, n = 9). The onset of block by lifarizine (tau = 91 +/- 14 s at 10 microM) was considerably slower than that of tetrodotoxin (tau = 16 +/- 3 s at 100 nM). 4. Lifarizine (1 microM) reduced the peak sodium conductance in each cell (from 26.4 +/- 2.0 nS to 15.1 +/- 2.7 nS, n = 4) without changing the macroscopic kinetics of sodium current activation or inactivation (V1/2 = -35 1 mV and -87 +/- 4 mV respectively, n = 4). Similarly, lifarizine (1 microM) did not affect the reversal potential of the macroscopic sodium current (+14 +/- 5 mV in control and +16 +/- 2 mV in 1 microM lifarizine; n = 4) or reactivation time-constant (tau = 14.0 +/- 4.4 ms). 5. Block of the sodium channel open state by tetrodotoxin (30 nM) did not prevent the inhibition caused by a subsequent application of lifarizine (3 micro M). In contrast the depression caused by lifarizinewas readily reversible after pretreatment of cells with the local anaesthetic, lignocaine (1O mM).6. These data demonstrate that lifarizine is a use- and voltage-dependent antagonist of human voltage sensitive sodium currents. The slow kinetics and pharmacology of the block by lifarizine indicate that access of this drug to the channel is more restricted than that of tetrodotoxin and may involve an allosteric site or state of the channel that is also regulated by local anaesthetics.
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PMID:Block of human voltage-sensitive Na+ currents in differentiated SH-SY5Y cells by lifarizine. 783 13

This study describes the depression of calcium currents caused by activation of human D3 dopamine receptors which have been stably expressed in the neuroblastoma x glioma NG108-15 cell line. Transfected cells, which had been differentiated with prostaglandin E1 and isobutylmethylxanthine, exclusively expressed D3 receptor mRNA, which was demonstrated by reverse transcription polymerase chain reaction techniques. Transfected cells had high affinity binding sites for iodosulpiride, with a Kd of 0.8 nM and receptor density of 240 fmol mg-1 protein. Calcium currents were recorded using nystatin-perforated patch clamp techniques. In contrast to untransfected cells that had been differentiated, high-threshold calcium currents in differentiated hD3-NG108-15 cells were depressed by application of dopamine and quinpirole. These responses were abolished by the dopamine receptor antagonist S-(-)-sulpiride (1 microM), demonstrating that they were caused by the activation of the transfected dopamine receptors. Coupling of human D3 receptors to calcium currents was sensitive to the action of pertussis toxin, suggesting the involvement of G-proteins of the Gi and/or G(o) subtype. These results demonstrate that human D3 receptors represent a functional class of dopamine receptor.
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PMID:Functional expression of human D3 dopamine receptors in differentiated neuroblastoma x glioma NG108-15 cells. 791 12

1. This study examined the regulation of calcium currents in differentiated NG108-15 cells that had been stably transfected with cDNA encoding the short isoform of the human D2 dopamine receptor. Whole cell calcium currents were recorded by nystatin-perforated patch clamp recording. 2. Transient low-threshold calcium currents elicited by depolarizations from -100 mV to -20 mV were reversibly depressed by NiCl2 (84 +/- 8% at 30 microM; n = 3) and by omega-agatoxin IVA (15 +/- 5%; 100 nM, n = 7). These currents were unaffected by hD2 receptor activation. 3. High-threshold calcium currents elicited by depolarizations from -80 mV to 0 mV were partly blocked by omega-conotoxin GVIA (67 +/- 6% at 100 nM, n = 4) and by the subsequent addition of the dihydropyridine, nisoldipine (94 +/- 3% at 1 microM). Consistent with the presence of at least two distinct types of high-threshold calcium channels, nisoldipine alone (38 +/- 15% at 1 microM, n = 6) did not preclude the inhibition caused by omega-conotoxin GVIA (69 +/- 13% at 100 nM, n = 4). The residual current was completely blocked by 100 microM CdCl2 (98.8 +/- 0.4%, n = 7). 4. In hD2-transfected cells, but not untransfected cells, high-threshold currents were depressed by quinpirole (30 +/- 4% at 100 nM; n = 15) with a pEC50 of 8.61 +/- 0.22 (n = 5), as well as by (-)-noradrenaline (28 +/- 5% at 1 microM, n = 9). Responses to both agonists were selectively antagonized by S-(-)sulpiride (100 nM) but not by the alpha-adrenoceptor antagonist, phentolamine (1O microM). The depression caused by (-)-noradrenaline was positively correlated with that of quinpirole for each cell(r2 = 0.91, slope = 0.99).5. hD2-receptor-mediated inhibition of high-threshold calcium currents was abolished by pretreatment of cells with omega-conotoxin GVIA (100 nM; n = 4). However, a component of the high-threshold current was reversibly depressed by omega-conotoxin GVIA (67% to 45% depression after 10 min wash). This current was also depressed by hD2 receptor activation (59 +/- 9% depression in 100 nM quinpirole, n = 3),and was completely blocked by nisoldipine (95 +/- 2% at 1 MicroM).6. These data demonstrate that activation of hD2(short) dopamine receptors can regulate both wconotoxinGVIA, and dihydropyridine-sensitive high-threshold calcium currents in neuroblastoma cells.Morever, the ability of human D2 dopamine receptors to regulate more than one type of calcium current supports the notion that these receptors have a diverse functional role in the central nervous system.
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PMID:Depression of high-threshold calcium currents by activation of human D2 (short) dopamine receptors expressed in differentiated NG108-15 cells. 803 91

The human neuroblastoma line SH-SY5Y expresses three muscarinic receptor genes (m1, m2, and m3). In this study, we have investigated the effect of agonist exposure on the steady state levels of each muscarinic receptor transcript, using a comparative polymerase chain reaction (PCR) assay that allows changes in levels of very rare transcripts to be monitored. Northern blot analysis of cellular RNA revealed the presence of m3 mRNA, whereas PCR amplification of SH-SY5Y cDNA additionally revealed the presence of m1 and m2 transcripts. Cell surface muscarinic receptor number, as assessed by N-[3H]methylscopolamine binding to whole cells, rapidly decreased to 42% of control levels within 1 hr of exposure to 100 microM carbachol; this was followed by a slower decline to 6% of control levels after 48 hr. Total receptor number, measured by binding of [3H]quinuclidinyl benzilate, showed a much slower decline to 21% of control levels after 48 hr of treatment. Comparative PCR analysis showed that each muscarinic transcript was differentially regulated. The level of transcript encoding the major receptor population, the m3 mRNA, was rapidly elevated within 1 hr of agonist challenge and subsequently decreased to about 30% of prestimulation levels within 9 hr; this decrease was sustained for the time course of the experiment. m2 mRNA levels showed a transient increase followed by a decrease to 30% of prestimulation levels after 6 hr but, in contrast to the m3 transcripts, this depression was followed by a transient rise to 270% of prestimulation levels after 24 hr before declining to normal levels by 72 hr after stimulation. Exposure of cells to agonist clearly instigates a complex pattern of changes in levels of receptor and receptor mRNA; comparison of the relative time courses of these changes indicates that the decline in m3 transcripts precedes the loss of muscarinic receptor binding sites.
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PMID:Differential regulation of muscarinic receptor mRNA levels in neuroblastoma cells by chronic agonist exposure: a comparative polymerase chain reaction study. 850 26

While the ability of increased pressure to reverse anaesthesia has been well documented, the cellular or molecular mechanism(s) responsible for their mutual antagonism have remained elusive. Previous work in our laboratory, using diverse cell types, has indicated several processes requiring Ca2+ are affected in opposite directions by hydrostatic pressure [as represented by helium (He)], narcotic gases, and some anesthetics. Here we report on the effects of elevated pressures of He, and of 1 atm abs of the anesthetic gas nitrous oxide (N2O), when present alone and in combination, on calcium mobilization in the human neuroblastoma cell line SK-N-SH. Cytosolic-free Ca2+ ([Ca2+]i) was monitored by fluorescence spectrophotometry in cell suspensions loaded with the intracellular Ca2+ indicator fura-2. N2O reversibly depressed the carbachol-stimulated increase in [Ca2+]i (P < 0.01). The application of both 18 and 35 atm abs He attenuated this N2O-induced depression of carbachol-stimulated increase in [Ca2+]i. These findings support the hypothesis that pressure/anesthetic antagonism may be due in part to effects on neuronal [Ca2+]i and its regulation.
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PMID:Pressure antagonism of nitrous oxide depression of intracellular calcium in a neuroblastoma cell line. 865 62

Three types of ionic current essentially determine the firing pattern of nerve cells: the persistent Na+ current, the M current and the low-voltage-activated Ca(2)+ current. The present article summarizes recent experiments concerned with the basic properties of these currents. Keynes and Meves (Proc R Soc Lond B (1993) 253, 61-68) studied the persistent or steady-state Na+ current on dialysed squid axons and measured the probability of channel opening both for the peak and the steady-state Na+ current (PF(peak) and PF(ss)) as a function of voltage. Whereas PF(peak) starts to rise at -50 mV and reaches a maximum at +40 to +50 mV, PF(ss) only begins to rise appreciably at around 0 mV and is still increasing at +100 mV. This differs from observations on vertebrate excitable tissues where the persistent Na+ current tums on in the threshold region and saturates at around 0 mV. Schmitt and Meves (Pflugers Arch (1993) 425, 134-139) recorded M current, a non-inactivating K+ current, from NGI08-15 neuroblastoma x glioma hybrid cells, voltage-clamped in the whole-cell mode, and studied the effects of phorbol 12,13-dibutyrate (PDB), an activator of protein kinase C (PKC), and arachidonic acid (AA). PDB and AA both decreased I(M), the effective concentrations being 0.1-1 mu M and 5-25 mu M, respectively; while the PDB effect was regularly observed, the M current depression by AA was highly variable from cell to cell. The PKC 19-31 peptide, an effective inhibitor of PKC, in a concentration of 1 muM almost totally prevented the effects of PDB and AA on M current, suggesting that both are mediated by PKC. Schmitt and Meves (Pflugers Arch (1994a) 426, Suppl R 59) measured low-voltage-activated (l-v-a) and high-voltage-activated (h-v-a) Ca2+ currents on NG108-15 cells and investigated the effect of AA and PDB on both types of current. At pulse potentials > -20 mV, AA (25-100 mu M) decreased 1-v-a and h-v-a I(Ca). The decrease was accompanied by a small negative shift and a slight flattening of the activation and inactivation curves of the l-v-a I(Ca). The AA effect was not prevented by 50 mu M eicosa-5,8,11,14-tetraynoic acid (ETYA), an inhibitor of AA metabolism, or PKC 19-31 peptide and not mimicked by 0.1-1 mu M PDB. Probably, AA acts directly on the channel protein or its lipid environment. The physiological relevance of these three sets of observations is briefly discussed.
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PMID:Model experiments on squid axons and NG108-15 mouse neuroblastoma x rat glioma hybrid cells. 886 17

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

Interleukins are potent intercellular messenger peptides, initially found in cells of the immune system and best known for producing chronic, genomic effects in target cells. Here, interleukin-1beta (IL-1beta) was tested for acute effects on neurotransmitter release. The human neuroblastoma-derived cell-line SH-SY5Y is a model for mature post-ganglionic sympathetic neurones and release of tritiated noradrenaline from these cells was measured, in response to stimulation with either elevated extracellular K+ concentration (100 K+) orveratridine. Pre-incubation for 15-25 min with 60 pM (but not 0.06 pM) IL-1beta significantly reduced 100 K+-evoked release (by approximately 75%). The interleukin was without effect on basal or veratridine-evoked noradrenaline release. The present data suggest two distinct stimulatory pathways: one that is activated by 100 K+ and veratridine and is unaffected by IL-1beta and another that is activated by 100 K+ but not veratridine and is inhibited by IL-1beta. The acute depression of 100 K+-evoked transmitter release may be involved in immune system-nervous system interactions.
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PMID:Acute effects of interleukin-1 beta on noradrenaline release from the human neuroblastoma cell line SH-SY5Y. 971 81

Hemopoiesis is disturbed in bone marrow-involving cancers like leukemia and neuroblastoma. Shedding of gangliosides by tumor cells may contribute to this tumor-induced bone marrow suppression. We studied in vitro the inhibitory effects of murine neuroblastoma cells (Neuro-2a and C1300) and their gangliosides on hemopoiesis using normal murine hemopoietic progenitor colony-forming assays. Transwell cultured neuroblastoma cells showed a dose-dependent inhibition on hemopoiesis, indicating that a soluble factor was responsible for this effect. Furthermore, the supernatant of Neuro-2a cultured cells inhibited hemopoietic proliferation and differentiation. To determine whether the inhibitory effect was indeed due to shed gangliosides and not, for instance, caused by cytokines, the effect of DL-threo-1 -phenyl-2-decanoylamino-3-morpholino-1-propanol (DL-PDMP) on Neuro-2a cells was studied. DL-PDMP is a potent inhibitor of glucosylceramide synthase, resulting in inhibition of the synthesis and shedding of gangliosides. The initially observed inhibitory effect of supernatant of Neuro-2a cells was abrogated by culturing these cells for 3 days in the presence of 10 microM DL-PDMP. Moreover, gangliosides isolated from Neuro-2a cell membranes inhibited hemopoietic growth. To determine whether the described phenomena in vitro are a reflection of bone marrow suppression occurring in vivo, gangliosides isolated from plasma of neuroblastoma patients were tested for their effects on human hemopoietic progenitor colony-forming assays. These human neuroblastoma-derived gangliosides inhibited normal erythropoiesis (colony-forming unit-erythroid/burst-forming unit-erythroid) and myelopoiesis (colony-forming unit-granulocyte/macrophage) to a higher extent compared with gangliosides isolated from control plasma. Altogether these results suggest that gangliosides shed by neuroblastoma cells inhibit hemopoiesis and may contribute to the observed bone marrow depression in neuroblastoma patients.
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PMID:Inhibition of hemopoiesis in vitro by neuroblastoma-derived gangliosides. 980 88


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