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 study of oxygen radical generation and effects during 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) metabolism was undertaken in an in vitro test system. Three neurochemically discrete neuronal cell lines, B50 (cholinergic) and B65 rat cell lines and SKNSH human neuroblastoma (both catecholaminergic), were exposed to MPTP (0-200 microM). Parallel experiments were performed using reagent H2O2, an intermediate which may be generated during MPTP metabolism, to determine whether MPTP and H2O2 had any selectivity of toxicity and whether the mechanisms of cell death were similar. MPTP toxicity was shown to be reduced by monoamine oxidase B inhibitors, pargyline (P < 0.01) and selegiline (P < 0.05), indicating that toxicity was due to metabolism of MPTP rather than the parent compound. Cytotoxicity was also decreased in the presence of antioxidants, most notably in the presence of superoxide dismutase and catalase together (P < 0.01), suggesting that reactive oxygen species (ROS) play a role in MPTP-induced cell death. Attempts to determine the intracellular target for oxidative attack did not identify significant levels of lipid peroxidation products, but did demonstrate nucleoid expansion, possibly the result of double stranded DNA breaks induced by ROS.
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PMID:An investigation into the role of reactive oxygen species in the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity using neuronal cell lines. 845 68

A series of aliphatic N-methylpropargylamine MAO-B inhibitors have been synthesized and their structural and functional relationships have been investigated. 2-Hexyl-N-methylpropargylamine (2-HxMP), for example, has been found to be a highly potent, irreversible, selective, MAO-B inhibitor both in vitro and in vivo. The R-(-)-enantiomers are much more active than the S-(+)-enantiomers at inhibiting MAO-B activity. Some of these compounds protect mouse nigrostriatal dopamine neurons against the neurotoxin MPTP and the mouse hippocampal noradrenergic system against the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). They rescue hippocampal neurons after damage induced by ischemia and kainic acid treatment, as well as motoneurons in young mice following facial nerve axotomy. Such rescue effects are, interestingly, unrelated to inhibition of MAO-B activity. Some of the aliphatic propargylamines enhance the survival of neuroblastoma cells co-cultured with astrocytes following serum depletion. They stimulate the expression of AADC mRNA and inhibit GFAP mRNA expression. They do not possess amphetamine-like properties and exhibit no effect on noradrenaline or dopamine uptake nor do they increase hypertensive effects in the tyramine pressor test. Unlike R(-)-deprenyl, 2-HxMP does not potentiate dopamine toxicity in vitro. These new MAO-B inhibitors may possess significant chemotherapeutic implications for certain psychiatric and neurodegenerative disorders.
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PMID:Neurochemical, neuroprotective and neurorescue effects of aliphatic N-methylpropargylamines; new MAO-B inhibitors without amphetamine-like properties. 858 47

We have observed that the survival of dopamine neuroblastoma (SH-SY5Y) cells in co-cultures with C-6 glioma in serum-deprived media is slightly but significantly enhanced by R-(-)-deprenyl, a selective monoamine oxidase B inhibitor. This drug, however, does not directly affect the viability of SH-SY5Y cells or glioma cells in serum or serum-deprived media. The results suggest that R-(-)-deprenyl enhances astroglial trophic support in favor of neuronal survival.
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PMID:Increase of survival of dopaminergic neuroblastoma in co-cultures with C-6 glioma by R-(-)-deprenyl. 858 55

The possibility of imaging monoamine oxidase (MAO) containing neurons through the MAO-mediated conversion of the nonfluorescent tetrahydropyridine compound trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetrahydro pyridine (t-THP) to the corresponding fluorescent trans-1-methyl-4-[4-dimethylaminophenylethenyl]pyridinium species (t-P+) was examined with the aid of human neuroblastoma cells (SH-SY5Y). Fluorescence microscopy and fluorescence measurements established the intracellular formation of a fluorescent species with maximal excitation/emission wavelengths of 485/620 and 530/620 nm corresponding to the fluorescence characteristics of synthetic t-P+. An independent assay confirmed the presence of both MAO-A and MAO-B in these cells. As expected, the development of the fluorescence was inhibited by both clorgyline (an MAO-A inhibitor) and deprenyl (an MAO-B inhibitor). Cytotoxic effects, as determined by trypan blue dye exclusion for viability and by the MTT [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide] assay for mitochondrial integrity, were not observed in cells incubated with concentrations of t-THP as high as 10(-3) M for 4 hr. The results from these studies with a neuronal cell line of human origin suggest: (1) that SH-SY5Y cells metabolize and, therefore, can be used for study of tetrahydropyridine compounds in vitro, and (2) that t-THP may be a useful agent to monitor neurodegenerative processes in MAO-rich neurons, including the dopaminergic nigrostriatal neurons that are damaged by the parkinsonian-inducing tetrahydropyrridine MPTP. The potential advantage of using t-THP over related imaging techniques is the possibility of assessing neuronal function by an in vivo processing of the reporter molecule rather than by postmortem immunofluorescent or formaldehyde-based procedures.
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PMID:Biotransformation of the MPTP analog trans-1-methyl-4-[4-dimethylaminophenylethenyl]-1,2,3,6-tetra- hydropyridine to a fluorescent pyridinium metabolite by intact neuroblastoma cells. 866 41

In the present study transcriptional activities has been measured with different fragments of the 5'-flanking sequence of the human monoamine oxidase (MAO) genes linked to human growth hormone which was used as a reporter gene. SH-SY5Y neuroblastoma cells and 1242 MG glioma cells were compared under basal conditions as well as after treatments with different drugs. Under basal conditions, the relative reporter activities of the different promoter fragments were similar for both cell lines. No changes in promoter activities, were observed when cells were treated with L-deprenyl, lithium chloride or raclopride. In contrast, increases (2-3-fold) in both reporter gene expression and enzyme activity were observed after ethanol treatment of cells transfected with MAO-B fragments. Gel retardation analysis showed that ethanol caused changes in transcription factor binding to the MAO-B core promoter in both the SH-SY5Y and 1242 MG cell lines in a cell-type specific fashion.
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PMID:Monoamine oxidase gene transcription in human cell lines: treatment with psychoactive drugs and ethanol. 883 30

Autoxidation of dopamine or L-DOPA (3,4-dihydroxyphenylalanine) generates reactive oxygen species (ROS), i.e., hydrogen peroxide, superoxide, and hydroxyl radical, which are potentially cytotoxic. Increased formation of ROS has been proposed to be involved in the pathogenesis of many human diseases, including Parkinson's disease. Several reports suggest that R(-)-deprenyl (an MAO-B inhibitor and anti-Parkinsonian drug) may directly or indirectly exert antioxidant effects and thus protect neurons. We have assessed the toxic effects of dopamine and L-DOPA toward catecholaminergic neuroblastoma SH-SY5Y cells and whether R(-)-deprenyl and several structurally related compounds possess antioxidant effects in this system. The results show that both dopamine and L-DOPA are quite cytotoxic toward SH-SY5Y cells. R(-)-deprenyl rather than reducing this dopamine-induced toxicity actually enhances it. Structural analogues of R(-)-deprenyl, such as 4-methyldeprenyl, (-)-methylamphetamine, and clorgyline, exhibited similar effects. Some different MAO-B inhibitors, namely, the aliphatic N-methylpropargylamines, e.g., (+/-)-M-2-PP [N-(2-pentyl)-N-methylpropargylamine] and N-[2-hexyl]-N-methylpropargylamine, which can also protect and rescue neurons in several in vivo and in vitro models, did not exacerbate the cytotoxicity of dopamine. Neither R(-)-deprenyl nor (+/-)-M-2-PP affected the L-DOPA-induced cytotoxicity toward SH-SY5Y cells.
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PMID:R(-)-deprenyl potentiates dopamine-induced cytotoxicity toward catecholaminergic neuroblastoma SH-SY5Y cells. 900 48

L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives.
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PMID:Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells. 1079 57

R-(-)-Deprenyl (deprenyl, selegiline), a monoamine oxidase B (MAO-B) inhibitor, delays progression of Parkinson's disease. This action could be mediated by inhibition of MAO-B but there may also be unrelated mechanisms. Direct neuroprotective and antiapoptotic actions of deprenyl have previously been observed in vitro. Here we describe an antineurotoxic action of deprenyl which is independent of direct neuronal effects. We employed a previously described assay in which human neuroblastoma SH-SY5Y cells are exposed to cell-free supernatants of stimulated human monocytic THP-1 cells. Deprenyl reduced the secretion of neurotoxic products by such stimulated cells in a concentration-dependent manner, while the MAO inhibitors iproniazid, isocarboxazid, nialamide, tranylcypromine, phenelzine, and clorgyline were without effect. No antineurotoxic action was observed when deprenyl was added directly to SH-SY5Y cells. Messenger RNAs for MAO-A and MAO-B were not detected in THP-1 cells by reverse transcriptase-polymerase chain reaction analysis of total RNA extracts. Such mRNAs were easily detected in extracts of SH-SY5Y cells under comparable conditions. MAO enzymatic activity was also undetectable in THP-1 cell lysates, while it was readily observed in SH-SY5Y cells. It was concluded that the effect of deprenyl on THP-1 cells was not mediated by MAO and that deprenyl itself was not protecting neurons. These data suggest that deprenyl may have utility in neurodegenerative diseases due to its antineurotoxic actions.
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PMID:R-(-)-Deprenyl inhibits monocytic THP-1 cell neurotoxicity independently of monoamine oxidase inhibition. 1108 11

(-)-Deprenyl, used for the treatment of Parkinson's disease, was reported to possess neurorescuing/antiapoptotic effects independent of its MAO-B inhibiting properties. It is metabolized to (-)-desmethyldeprenyl, which seems to be the active principle, and further to (-)-amphetamine and (-)-methamphetamine, which antagonize its rescuing effects. These complications may explain the limited neurorescuing potential of (-)-deprenyl observed clinically. CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine), structurally related to (-)-deprenyl, exhibits virtually no MAO-B nor MAO-A inhibiting properties and is not metabolized to amphetamines. It was shown to bind to glyceraldehyde-3-phosphate dehydrogenase, a glycolytic enzyme with multiple other functions including an involvement in apoptosis, and shows neurorescuing properties qualitatively similar to, but about 100-fold more potent than those of (-)-deprenyl in several in vitro and in vivo paradigms. In concentrations ranging from 10(-13)-10(-5) M, it rescues partially differentiated PC12 cells from apoptosis induced by trophic withdrawal, cerebellar granule cells from apoptosis induced by cytosine arabinoside, rat embryonic mesencephalic dopaminergic cells from death caused by MPP+, and PAJU human neuroblastoma cells from death caused by rotenone. However, it did not affect apoptosis elicited by a variety of agents in rapidly proliferating cells from thymus or skin or in liver or kidney cells. In vivo, it rescued facial motor neuron cell bodies in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia, and mouse nigral dopaminergic cell bodies from death induced by MPTP, in doses ranging between 0.0003 and 0.1 mg/kg p.o. or s.c., depending on the model. It also partially prevented the loss of tyrosine hydroxylase immunoreactivity in the substantia nigra of 6-OHDA-lesioned rats and improved motor function in these animals. Moreover, it prolonged the life-span of progressive motor neuronopathy (pmn) mice (a model for ALS), preserved their body weight and improved their motor performance. This was accompanied by a decreased loss of motor neurons and motor neuron fibers, and protection of mitochondria. The active concentration- or dose-ranges in the different in vitro and in vivo paradigms were remarkably similar. In several paradigms, bell-shaped dose-response curves were observed, the rescuing effect being lost above about 1 mg/kg, a fact that must be considered in clinical investigations.
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PMID:Neurorescuing effects of the GAPDH ligand CGP 3466B. 1120 40

Rasagiline (N-propargyl-1-(R)-aminoindan) is a selective, irreversible monoamine oxidase B (MAO B) inhibitor which has been developed as an anti-Parkinson drug. In controlled monotherapy and as adjunct to L-dopa it has shown anti-Parkinson activity. In cell culture (PC-12 and neuroblastoma SH-SY5Y cells) it exhibits neuroprotective and anti-apoptotic activity against several neurotoxins (SIN-1, MPTP, 6-hydroxydopamine and N-methyl-(R)-salsolinol) and ischemia. In vivo, it reduces the sequelae of traumatic brain injury in mice and speeds their recovery. The neuroprotective activity of rasagaline does not result from MAO B inhibition, since its S-enantiomer, TVP1022, which has 1000-fold weaker MAO inhibitory activity, exhibits similar neuroprotective properties. Introduction of a carbamate moiety into the rasagiline molecule to confer cholinesterase inhibitory activity for the treatment of Alzheimer's disease, resulted in compounds TV3326 [(N-Propargyl-(3R)Aminoindan-5-YL)-Ethyl Methyl Carbamate] and its S-enantiomer TV3279 [(N-Propargyl-(3S)Aminoindan-5-YL)-Ethyl Methyl Carbamate], which retain the neuroprotective activities of rasagiline and TVP1022. They also antagonize scopolamine-induced impairments in spatial memory. In addition, TV3326 exhibits brain-selective MAO A and B inhibitory activity after chronic administration and has antidepressant-like activity in the forced swim test. This is associated with an increase in brain levels of serotonin. The anti-apoptotic activity of these propargylamine-containing derivatives may be related to their ability to delay the opening of voltage-dependent anion channels (VDAC), which are part of the mitochondrial permeability transition pore. The propargylamine moiety is responsible for the increase in the mitochondrial family of Bcl-2 proteins, prevention in the fall in mitochondrial membrane potential, prevention of the activation of caspase 3, and of translocation of glyceraldehyde-3-phosphate dehydrogenase from the cytoplasm to the nucleus. The latter processes are closely associated with neurotoxin-induced apoptosis. Rasagiline interacts with and prevents the binding of PKI 1195 to the pro-apoptotic peripheral benzodiazepine receptor, which together with Bcl-2, hexokinase, porin, and adenine nucleotide translocator constitutes part of the VDAC. Furthermore, rasagiline, TV3326 and TV3279 are able to influence the processing of amyloid precursor protein by activation of alpha-secretase and increasing the release of soluble alpha APP in rat PC-12 and human neuroblastoma SH-SY5Y cells and in rat and mice cortex and hippocampus. This process has been shown to involve the upregulation of PKC and MAP kinase. It is quite likely that the induction of Bcl-2 and activation of PKC by rasagiline and TV3326 is closely linked to the anti-apoptotic action of these drugs and their ability to process APP by activation of alpha-secretase.
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PMID:Molecular basis of neuroprotective activities of rasagiline and the anti-Alzheimer drug TV3326 [(N-propargyl-(3R)aminoindan-5-YL)-ethyl methyl carbamate]. 1204 33


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