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)

Sodium 4-phenylbutyrate (4-PBA) is a low molecular weight fatty acid that has been used for treatment of urea cycle disorders in children, sickle cell disease, and thalassemia. It has been demonstrated recently that 4-PBA can act as a chemical chaperone by reducing the load of mutant or mislocated proteins retained in the endoplasmic reticulum (ER) under conditions associated with cystic fibrosis and liver injury. In the present study, we evaluated the neuroprotective effect of 4-PBA on cerebral ischemic injury. Pre- or post-treatment with 4-PBA at therapeutic doses attenuated infarction volume, hemispheric swelling, and apoptosis and improved neurological status in a mouse model of hypoxia-ischemia. Moreover, 4-PBA suppressed ER-mediated apoptosis by inhibiting eukaryotic initiation factor 2alpha phosphorylation, CCAAT/enhancer-binding protein homologous protein induction, and caspase-12 activation. In neuroblastoma neuro2a cells, 4-PBA reduced caspase-12 activation, DNA fragmentation, and cell death induced by hypoxia/reoxygenation. It protected against ER stress-induced but not mitochondria-mediated cell death. Additionally, 4-PBA inhibited the expression of inducible nitric-oxide synthase and tumor necrosis factor-alpha in primary cultured glial cells under hypoxia/reoxygenation. These results indicate that 4-PBA could protect against cerebral ischemia through inhibition of ER stress-mediated apoptosis and inflammation. Therefore, the multiple actions of 4-PBA may provide a strong effect in treatment of cerebral ischemia, and its use as a chemical chaperone would provide a novel approach for the treatment of stroke.
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PMID:Sodium 4-phenylbutyrate protects against cerebral ischemic injury. 1522 15

The opening of the adenosine triphosphate (ATP)-sensitive potassium (KATP) channel has been proposed as a therapeutic approach for ischemia. Here we examined the opening effect of KR-31378 on the KATP channel using patch clamp recording in neuroblastoma 2a (N2a) cells and investigated the neuroprotective effect of KR-31378 in organotypic hippocampal slice cultures exposed to oxygen/glucose deprivation. The treatment with KR-31378 (10 microM) to N2a cells seemed to induce KATP channel opening in a dose dependent manner. The opening effect of KR-31378 was more significant than that of other known KATP channel openers. Pretreatment with KR-31378 (10 microM) showed a neuroprotective effect in both CA1 and CA3 regions and its effect was attenuated by glibenclamide in a dose dependent manner in both areas. This remarkable neuroprotective effect of KR-31378 seemed to be mediated by the opening of the KATP channel. These results suggest that KR-31378 could be a possible neuroprotective agent against cerebral ischemia.
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PMID:Neuroprotective effect of KR-31378 via KATP channel opening against ischemic insult. 1530 38

Prion diseases are induced by pathologically misfolded prion protein (PrPSc), which recruit normal sialoglycoprotein PrPC by a template-directed process. In this study, we investigated the expression of PrPC in a rat model of cerebral ischemia to more fully understand its physiological role. Immunohistochemical analysis demonstrated that PrPC-immunoreactive cells increased significantly in the penumbra of ischemic rat brain compared with the untreated brain. Western blot analysis showed that PrPC protein expression increased in ischemic brain tissue in a time-dependent manner. In addition, PrPC protein expression was seen to colocalize with neuron, glial, and vascular endothelial cells in the penumbric region of the ischemic brain. Overexpression of PrPC by injection of rAd (replication-defective recombinant adenoviral)-PGK (phosphoglycerate kinase)-PrPC-Flag into ischemic rat brain improved neurological behavior and reduced the volume of cerebral infarction, which is supportive of a role for PrPC in the neuroprotective adaptive cellular response to ischemic lesions. Concomitant upregulation of PrPC and activated extracellular signal-regulated kinase (ERK1/2) under hypoxia-reoxygenation in primary cortical cultures was shown to be dependent on ERK1/2 phosphorylation. During hypoxia-reoxygenation, mouse neuroblastoma cell line N18 cells transfected with luciferase rat PrPC promoter reporter constructs, containing the heat shock element (HSE), expressed higher luciferase activities (3- to 10-fold) than those cells transfected with constructs not containing HSE. We propose that HSTF-1 (hypoxia-activated transcription factor), phosphorylated by ERK1/2, may in turn interact with HSE in the promoter of PrPC resulting in gene expression of the prion gene. In summary, we conclude that upregulation of PrPC expression after cerebral ischemia and hypoxia exerts a neuroprotective effect on injured neural tissue. This study suggests that PrPC has physiological relevance to cerebral ischemic injury and could be useful as a therapeutic target for the treatment of cerebral ischemia.
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PMID:Overexpression of PrPC by adenovirus-mediated gene targeting reduces ischemic injury in a stroke rat model. 1619 87

Granulocyte colony-stimulating factor (G-CSF) protects neurons against experimental focal cerebral ischemia. However, its neuroprotective effect on human brain is unknown. We sought to determine whether G-CSF can protect the human cerebral neurons in vitro. Human cerebral-neuroblastoma hybrid cell line (A1) was exposed to oxygen and glucose deprivation with or without G-CSF. G-CSF promoted cell survival and decreased cytotoxicity effectively at 25 ng/ml. G-CSF reduced early apoptotic (annexin V+/PI-), and late apoptotic or necrotic (annexin V+/PI+) cells, and decreased active caspase-3 immunoreactivity. G-CSF could protect human cerebral neurons following in vitro ischemia.
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PMID:G-CSF protects human cerebral hybrid neurons against in vitro ischemia. 1629 88

Calpains represent a superfamily of Ca2+-activated cysteine-proteases, which are important mediators of apoptosis and necrosis. In the brain, m-calpain and micro-calpain, the two ubiquitous calpain-isoforms, are strongly activated in neurones after an excitotoxic Ca2+ influx occurring, for example, during cerebral ischemia. Because oestrogen and its receptors (ERalpha/ERbeta) can exert neuroprotective activity, we investigated their influence on expression of calpains and their endogenous inhibitor, calpastatin. We found that ectopic expression of ERalpha in human neuroblastoma SK-N-MC cells led to a ligand-independent constitutive down-regulation of m-calpain accompanied by an up-regulation of micro-calpain expression. Up-regulation of micro-calpain was reversed in the presence of oestrogen, which, in turn, could be blocked by co-treatment with the oestrogen-receptor antagonist ICI 182,780. Expression of calpastatin was not altered, either in the absence or in the presence of oestrogen. Additional studies revealed that ERalpha-expressing cells exhibited decreased calpain enzymatic activity and increased survival when cells were exposed to the Ca2+ ionophore, ionomycin. Since all investigated effects could be observed exclusively in the presence of ERalpha, but not ERbeta, and since the effects are reduced when ERalpha and ERbeta are co-expressed, our data suggest a novel ER subtype-specific neuroprotective action by repressing calpain expression and calpain activity under conditions of a massive Ca2+ influx.
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PMID:Oestrogen receptor subtype-specific repression of calpain expression and calpain enzymatic activity in neuronal cells--implications for neuroprotection against Ca-mediated excitotoxicity. 1652 85

FK506 and FK506-derived inhibitors of the FK506-binding protein (FKBP)-type peptidylprolyl cis/trans-isomerases (PPIase) display potent neuroprotective and neuroregenerative properties in various neurodegeneration models, showing the importance of neuroimmunophilins as targets for the treatment of acute and chronic neurodegenerative diseases. However, the PPIase activity targeted by active site-directed ligands remains unknown so far. Here we show that neurotrophic FKBP ligands, such as GPI1046 and N-[methyl(ethoxycarbonyl)]cycloheximide, inhibit the calmodulin/Ca(2+) (CaM/Ca(2+))-regulated FKBP38 with up to 80-fold higher affinity than FKBP12. In contrast, the non-neurotrophic rapamycin inhibits FKBP38.CaM/Ca(2+) 500-fold less affine than other neuroimmunophillins. In the context of the high expression of FKBP38 in neuroblastoma cells, these data suggest that FKBP38.CaM/Ca(2+) inhibition can mediate neurotrophic properties of FKBP ligands. The FKBP38-specific cycloheximide derivative, N-(N',N'-dimethylcarboxamidomethyl)cycloheximide (DM-CHX) was synthesized and used in a rat model of transient focal cerebral ischemia. Accordingly, DM-CHX caused neuronal protection as well as neural stem cell proliferation and neuronal differentiation at a dosage of 27.2 mug/kg. These effects were still dominant, if DM-CHX was applied 2-6 h post-insult. In parallel, sustained motor behavior deficits of diseased animals were improved by drug administration, revealing a potential therapeutic relevance. Thus, our results demonstrate that FKBP38 inhibition by DM-CHX regulates neuronal cell death and proliferation, providing a promising strategy for the treatment of acute and/or chronic neurodegenerative diseases.
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PMID:The specific FKBP38 inhibitor N-(N',N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. 1654 4

The nature of the association between ischemic stroke and Alzheimer's disease (AD) at the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insults on the regulation of amyloid precursor protein (APP) processing. We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation) to evaluate the effect of ischemic neuronal insults on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line and primary cultured cells of transgenic mice which expressed human APP (Tg2576). Ischemic neuronal insults increased the production of Abeta in Tg2576 primary culture cells compared to controls. A disintegrin and metalloprotease 10 (ADAM 10) was markedly increased in early stage of ischemic insults, which was followed by decreased level of ADAM 10 expression in later stage. The protein and mRNA expression of beta-site cleavage enzyme (BACE) and BACE activity was not significantly different between the group of ischemic insults and control. By contrast, the activity of gamma-secretase was significantly increased after 4 h of ischemic insults, as compared to controls. The present study showed that the ischemic neuronal insults increased the production of Abeta by influencing APP metabolism, which may link the role of ischemic insults to the pathogenesis of AD.
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PMID:Effect of ischemic neuronal insults on amyloid precursor protein processing. 1679 58

Recent reports have shown that ER stress is involved in the pathology of some neurodegenerative diseases. In a screen for compounds that induce the ER-mediated chaperone BiP/GRP 78 (BiP), we identified BiP inducer X (BIX). BIX induced BiP only, in a dose-dependent manner, without induction of other molecules involved in the ER stress response. Pretreatment of neuroblastoma cells with BIX reduced cell death induced by ER stress. Intracerebroventricular pretreatment with BIX reduced the area of infarction due to focal cerebral ischemia in mice. In the penumbra of BIX-treated mice, ER stress-induced apoptosis was suppressed, leading to a reduction in the number of apoptotic cells. Taken together, BIX induces BiP to prevent neuronal death by ER stress, suggesting that it may be a potential therapeutic agent for cerebral diseases caused by ER stress.
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PMID:[A molecular chaperone inducer as potential therapeutic agent for neurodegenerative disease]. 1751 12

The induction of GRIM-19 has been shown to be essential for interferon-beta (IFN-beta)-induced and retinoic acid (RA)-induced tumor cell death. We have studied the localization and levels of GRIM-19 in IFN/RA-induced cell death in neural cells and in focal cerebral ischemia. Exposure to IFN/RA caused a approximately 15-fold increase in GRIM-19 protein levels and induced >50% cell death in human neuroblastoma SH-SY5Y cells. In rats subjected to permanent focal cerebral ischemia, increased oxidative stress, as well as increased GRIM mRNA levels (32-fold) and increased GRIM-19 (>50%) protein levels were noted in the ipsilateral (affected) hemisphere compared with the contralateral (unaffected) hemisphere. These results suggest that GRIM-19 may play a role in ischemia-induced neuronal cell death.
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PMID:The IFN-beta and retinoic acid-induced cell death regulator GRIM-19 is upregulated during focal cerebral ischemia. 1752 70

Apoptosis contributes to cell death after cerebral ischaemia. A quantitative proteomics approach has been employed to define alterations in protein levels in apoptosis induced with staurosporine (STS). Human neuroblastoma derived SH-SY5Y cells were treated with STS (500 nM for 6 h) to induce apoptosis. Quantitative 2-DE was used to determine the changing protein levels with MALDI-TOF MS identification of proteins. Of the 154 proteins analysed, 13 proteins were significantly altered as a result of the apoptotic stimulus; ten of the proteins showed an increase in level with STS and were identified as heat shock cognate 71 (Hsc71), two isoforms of heat shock protein 70 (Hsp70), glucose regulated protein 78 (GRP78), F-actin capping protein, stress-induced phosphoprotein 1, chromatin assembly factor 1 (CAF-1), protein disulphide isomerase A3 (PDI A3) precursor, transitional ER ATPase and actin interacting protein 1 (AIP 1). Three proteins which displayed significant decrease in levels with STS were identified as tubulin, vimentin and glucose regulated protein 94 (GRP94). The functional roles and subcellular locations of these proteins collectively indicate that STS-induced apoptosis provokes induces an unfolded protein response involving molecular chaperones, cochaperones and structural proteins indicative of ER stress.
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PMID:Apoptosis induced by staurosporine alters chaperone and endoplasmic reticulum proteins: Identification by quantitative proteomics. 1767 60


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