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)

Our recent studies aimed to elucidate the molecular and biochemical mechanism of actions of the novel anti-Parkinson's drug, rasagiline, an irreversible and selective monoamine oxidase (MAO)-B inhibitor and its propargyl moiety, propargylamine. In cell death models induced by serum withdrawal in rat PC12 cells and human SH-SY5Y neuroblastoma cells, both rasagiline and propargylamine exerted neuroprotective and neurorescue activities via multiple survival pathways, including: stimulation of protein kinase C (PKC) phosphorylation; up-regulation of protein and gene levels of PKCalpha, PKCepsilon and the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w; and up-regulation of the neurotrophic factors, BDNF and GDNF mRNAs. Rasagiline and propargylamine inhibited the cleavage and subsequent activation of pro-caspase-3 and poly ADP-ribose polymerase. Additionally, these compounds significantly down-regulated PKCgamma mRNA and decreased the level of the pro-apoptotic proteins, Bax, Bad, Bim and H2A.X. Rasagiline and propargylamine both regulated amyloid precursor protein (APP) processing towards the non-amyloidogenic pathway. These structure-activity studies have provided evidence that propargylamine promoted neuronal survival via neuroprotective/neurorescue pathways similar to that of rasagiline. In addition, recent study demonstrated that chronic low doses of rasagiline administered to mice subsequently to 1 methyl-4 phenyl 1,2,3,6 tetrahydropyridine (MPTP), rescued dopaminergic neurons in the substantia nigra pars compacta via activation of the Ras-PI3K-Akt survival pathway, suggesting that rasagiline may possess a disease modifying activity.
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PMID:Involvement of multiple survival signal transduction pathways in the neuroprotective, neurorescue and APP processing activity of rasagiline and its propargyl moiety. 1701 68

Positive allosteric modulation of AMPA receptor function has therapeutic potential in a number of psychiatric disorders and neurodegenerative diseases. AMPA receptor potentiators can induce neurite sprouting in vivo. Using a strategy of combined morphological and biochemical analyses, we investigated the effect of the AMPA receptor potentiator LY404187 on neurite growth in the SH-SY5Y human neuroblastoma cell line. LY404187 (0.1-10 microM) increased average neurite length and neurofilament expression when co-administered with s-AMPA. Co-incubation with s-AMPA and LY404187 also increased Trk receptor expression. All actions of LY404187 were sensitive to AMPA receptor blockade by the selective antagonist CNQX (10 microM). Antibody sequestration of BDNF attenuated neurite growth following AMPA receptor potentiator administration, suggesting that LY404187 increases neurite length in vitro by a BDNF mediated mechanism. AMPA receptor potentiation activates multiple intracellular neurochemical cascades and the present report identifies BDNF as one key mediator of the neurotrophic effects of AMPA receptor potentiation.
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PMID:Molecular mechanisms of neurite growth with AMPA receptor potentiation. 1710 Nov 56

Previous studies showed that cocaine exposure decreased brain-derived neurotrophic factor (BDNF) function and resulted in neuronal cell death. To investigate a role of BDNF in cocaine's cytotoxicity, an RNA interference (RNAi) approach was used. Transfection of neuroblastoma SK-N-AS cells or primary rat hippocampal neurons with the small double-stranded interfering RNA (siRNA) targeting BDNF mRNA, but not the scrambled siRNA, resulted in reductions in levels of BDNF mRNA and proteins by more than 70% in the transfected cells as compared with the control group, suggesting an RNAi-mediated, sequence-specific gene silencing. The results also showed that cocaine-induced cytotoxicity, assessed by the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazodium bromide) assay, was more pronounced in the cells transfected with the siRNA than in the cells transfected with the scrambled siRNA or in the cells treated with Lipofectamine 2000 alone (the control group), suggesting that inhibition of BDNF expression enhances cocaine's cytotoxicity. Together with previous studies showing that cocaine suppresses BDNF expression, the present data suggest that the drug-induced reduction of BDNF productions may make neurons more vulnerable to cocaine's toxic effects and precipitate cocaine-induced central nervous system damages.
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PMID:RNA interference-mediated inhibition of brain-derived neurotrophic factor expression increases cocaine's cytotoxicity in cultured cells. 1719 38

Neuroblastomas are pediatric tumors originating from immature neuroblasts in the developing peripheral nervous system. Differentiation therapies could help lowering the high mortality due to rapid tumor progression to advanced stages. Oleic acid has been demonstrated to promote neuronal differentiation in neuronal cultures. Herein we report on the effects of oleic acid and of a specific synthetic PPARbeta agonist on cell growth, expression of differentiation markers and on parameters responsible for the malignancy such as adhesion, migration, invasiveness, BDNF, and TrkB expression of SH-SY5Y neuroblastoma cells. The results obtained demonstrate that many, but not all, oleic acid effects are mediated by PPARbeta and support a role for PPARbeta in neuronal differentiation strongly pointing towards PPAR ligands as new therapeutic strategies against progression and recurrences of neuroblastoma.
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PMID:PPARbeta agonists trigger neuronal differentiation in the human neuroblastoma cell line SH-SY5Y. 1739 Feb 99

Exposure to OP compounds that inhibit neurotoxic esterase (NTE) induces a delayed neuropathy (OPIDN) characterized by Wallerian-like degeneration of long axons in certain animals, including humans. Pope et al. (Toxicol. Lett. 75:111-117, 1995) found that neurite outgrowth occurred following the addition of spinal cord extracts from chickens with active OPIDN to neuroblastoma cells, suggesting growth factor expression during the neuropathy. We hypothesized that, shortly after exposure to a neuropathic OP compound, the central nervous system (CNS) attempts to recover from the toxic insult through upregulation of the neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) in susceptible regions of the nervous system. We hypothesized that such upregulation is transient and cannot be sustained. To test this hypothesis, we exposed 10-week-old chickens to a neuropathic OP compound (PSP, 2.5 mg/kg), a non-neuropathic OP compound (paraoxon, 0.10 mg/kg), and vehicle (DMSO, 0.5 ml/kg) intramuscularly. By day 8, all PSP-treated birds demonstrated clinical signs of OPIDN. We sacrificed chickens by pentobarbital overdose at 4, 8, 24, and 48 hours, and 5 and 10 days post-exposure and confirmed NTE inhibition in birds treated with PSP 4 and 24 hours earlier. Enzyme-linked immunosorbant assays indicated that NGF, BDNF, and NT-3 are found in chicken lumbar spinal cord after exposure to a neuropathic OP compound. However, exposure to the neuropathic OP compound, PSP, did not preferentially elevate levels of NGF, BDNF, and NTE compared to the non-neuropathic OP compound, paraoxon. This suggests that these neurotrophins alone do not contribute to a sustained regenerative effort in the CNS.
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PMID:Early effects of neuropathy-inducing organophosphates on in vivo concentrations of three neurotrophins. 1744 51

Cyclic AMP response element-binding protein (CREB) plays important roles in neuronal plasticity and amyloid beta-peptide (Abeta)-induced cognitive impairment in Alzheimer's disease (AD). Here we demonstrated that Ginkgo biloba extract, EGb 761, displayed the neuron protective effect by activating the CREB signaling pathway. Wild-type neuroblastoma cells cultured in a conditioned medium containing cell-secreted Alphabeta exhibited reduced levels of phosphorylated CREB (pCREB). Addition of EGb 761 (100 microg/mL) or an anti-oligomer-specific antibody (A-11) to the conditioned medium could restore pCREB level. In a neuroblastoma cell line expressing Alphabeta, treatment with EGb 761 increased levels of pCREB and brain-derived neurotrophic factor. Furthermore, CREB phosphorylation induced by EGb 761 was blocked by inhibitors of several upstream signaling pathways of CREB, including protein kinase C, ERK, ribosomal S6 kinase(RSK)90 and nitric oxide pathway. Moreover, these inhibitors differentially blocked the effects of individual components of EGb 761, ginkgolide C, quercetin and bilobalide, which suggest diverse effects of the EGb 761 individual components. Actions of individual EGb 761 components provide further insights into direct mechanisms underlying the effect of EGb 761 on enhancing the cognitive performance of patients with AD.
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PMID:Restoration of impaired phosphorylation of cyclic AMP response element-binding protein (CREB) by EGb 761 and its constituents in Abeta-expressing neuroblastoma cells. 1800 Dec 88

Neuroblastoma (NB) is a neural crest precursor cell-derived extracranial solid tumor in children. Patients with a poor prognosis are often resistant to chemotherapy and have tumors that express the neuronal growth/survival factor brain-derived neurotrophic factor and its tyrosine kinase receptor, TrkB. In this article, the authors discuss a growth/survival factor-stimulated mechanism leading to chemoresistance in NB that is mediated by the PI3K/Akt signaling pathway. Besides brain-derived neurotrophic factor/TrkB, other growth/survival factors and their receptors also activate the PI3K/Akt pathway and have the potential to mediate chemoresistance in NB. These findings raise the possibility of a new therapeutic approach in NB that would target Akt, the common downstream mediator of multiple growth/survival factor signaling pathways, to enhance the efficacy of chemotherapeutics. Several classes of Akt inhibitors, including phosphatidylinositol ether lipid analogs, alkylphospholipid analogs, allosteric Akt kinase inhibitors, HSP90 inhibitor and HIV protease inhibitors are discussed.
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PMID:Targeting Akt to increase the sensitivity of neuroblastoma to chemotherapy: lessons learned from the brain-derived neurotrophic factor/TrkB signal transduction pathway. 1802 Sep 81

Elucidating signaling pathways that mediate cell survival or apoptosis will facilitate the development of targeted therapies in cancer. In neuroblastoma tumors, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with poor prognosis. Our previous studies have shown that BDNF activation of TrkB induces resistance to chemotherapy via activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. To study targets of PI3K/Akt that mediate protection from chemotherapy, we focused on glycogen synthase kinase-3beta (GSK-3beta), which is a known modulator of apoptosis. We used pharmacologic and genetic methods to study the role of GSK-3beta in the BDNF/TrkB/PI3K/Akt protection of neuroblastoma from chemotherapy. BDNF activation of TrkB induced the Akt-dependent phosphorylation of GSK-3beta, resulting in its inactivation. Treatment of neuroblastoma cells with inhibitors of GSK-3beta, LiCl, GSK-3beta inhibitor VII, kenpaullone, or a GSK-3beta-targeted small interfering RNA (siRNA) resulted in a 15% to 40% increase in neuroblastoma cell survival after cytotoxic treatment. Transfection of neuroblastoma cells with a constitutively active GSK-3beta S9A9 caused a 10% to 15% decrease in cell survival. Using real-time, dynamic measurements of cell survival, we found that 6 to 8 h after etoposide treatment was the period during which critical events regulating the induction of cell death or BDNF/TrkB-induced protection occurred. During this period, etoposide treatment was associated with the dephosphorylation and activation of GSK-3beta in the mitochondria that was blocked by BDNF activation of TrkB. These data indicate that the inactivation of GSK-3beta contributes to the BDNF/TrkB/PI3K/Akt protection of neuroblastoma cells from chemotherapy.
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PMID:Inactivation of glycogen synthase kinase-3beta contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells. 1808 6

The transcription factor Pitx3 is crucial for the development and differentiation of dopamine (DA) neurons. Our previous work has shown the Pitx3 can up-regulate the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma cell line SH-SY5Y. Primary astrocytes are the major nonneuronal cells and can be easily modified genetically to deliver therapeutic molecules into the brain, so we investigated whether Pitx3 can increase the expression and secretion of BDNF and GDNF in primary astrocytes. We first transfected Pitx3 plasmid in purified rat astrocytes and collected the conditioned medium (CM) from the Pitx3-transfected cultures, and then we measured the BDNF and GDNF levels from the CM and tested the protective effect of the CM against rotenone-induced DA neuron injury in ventral mesencephalon (VM) cultures. We found that the BDNF and GDNF levels were 1.4-fold and 1.5-fold higher in the CM from Pitx3-transfected astrocytes than empty vectors-transfected controls. Incubation with the CM from Pitx3-transfected astrocytes significantly attenuated the rotenone-induced DA neuron injury, and such protection can be significantly blocked by preincubation with antibodies against either BDNF or GDNF, whereas preincubation with purified BDNF or GDNF replicated the neuroprotection against rotenone-induced injury in VM cultures. These results demonstrate that Pitx3-transfection in astrocytes can up-regulate BDNF and GDNF expression and produce protective benefit to DA neurons, which might be a potential therapeutic alternative for Parkinson's disease.
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PMID:Pitx3-transfected astrocytes secrete brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and protect dopamine neurons in mesencephalon cultures. 1864 5

Polysialic acid (polySia) is the homopolymer of sialic acid and negatively regulates neuronal cell-cell and cell-extracellular matrix interactions through steric and repulsive hindrance due to its bulky polyanionic structure. Whether polySia also functions as a positive regulator in the nervous system through binding to specific ligands is not known. In the present study, we demonstrated that a brain-derived neurotrophic factor (BDNF) dimer binds directly to polySia to form a large complex with an M(r) greater than 2000 kDa under physiologic conditions. Although somewhat affected by the linkage and type of sialic acid components in the polySia, the complex formation is highly dependent on the polySia chain length. The minimum degree of polymerization required for the complex formation is 12. This is the first study to demonstrate the biologic significance of the degree of polySia polymerization in eukaryotes. Similar large polySia complexes form with other neurotrophic factors such as nerve growth factor, neurotrophin-3, and neurotrophin-4. Furthermore, the BDNF, after making a complex with polySia, can bind to the BDNF receptors, TrkB and p75NTR. The complex formation of BDNF with polySia upregulates growth or/and survival of neuroblastoma cells. These findings suggest that polySia functions as a reservoir of BDNF and other neurotrophic factors and may serve to regulate their local concentrations on the cell surface.
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PMID:Direct binding of polysialic acid to a brain-derived neurotrophic factor depends on the degree of polymerization. 1879 48


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