quetiapine-fumarate and Neuroblastoma

Epigenetic regulation may be involved in the pathophysiology of mental disorders, such as schizophrenia and bipolar disorder, and in the pharmacological action of drugs. Characterizing the epigenetic effects of drugs is an important step to optimal treatment. We performed comprehensive and gene-specific DNA methylation analyses of quetiapine using human neuroblastoma cells. Human neuroblastoma cells were cultured with quetiapine for 8 days, and DNA methylation analysis was performed using Infinium HumanMethylation27 BeadChip. A total of 1173 genes showed altered DNA methylation. Altered DNA methylation predominantly occurred as hypomethylation within the CpG island compared to DNA isolated from non-treated cells. Gene ontology analysis revealed that these genes were related to the cellular process of intracellular protein binding. There was no common effect of quetiapine with three mood stabilizers (lithium, valproate, and carbamazepine). However, common DNA methylation changes in eight genes, including ADRA1A, which encodes adrenoceptor alpha 1A, were found with quetiapine and lithium treatments. Finally, bisulfite-sequencing analysis revealed that quetiapine decreased the DNA methylation level of the promoter region of SLC6A4, where hypermethylation with bipolar disorder and hypomethylation with mood stabilizers have been reported.

Topics: Antipsychotic Agents; Cell Line, Tumor; Cluster Analysis; Dibenzothiazepines; DNA Methylation; Epigenesis, Genetic; Gene Expression Profiling; Humans; Neuroblastoma; Oligonucleotide Array Sequence Analysis; Quetiapine Fumarate; Receptors, Adrenergic, alpha-1; Serotonin Plasma Membrane Transport Proteins

Delirium occurs frequently in critically ill children, and children with neuroblastoma may be at particular risk. Early diagnosis and treatment may improve short- and long-term outcomes. In this case series, we present four critically ill children with neuroblastoma who were diagnosed with delirium in the post-operative period. In all four patients, the diagnosis of delirium facilitated targeted intervention and improvement. Heightened awareness by pediatric oncologists, surgeons, and intensivists may lead to earlier diagnosis and improvement in clinical outcomes.

Topics: Benzodiazepines; Child, Preschool; Cholinergic Antagonists; Delirium; Dibenzothiazepines; Female; Humans; Infant; Male; Narcotics; Neuroblastoma; Pain, Postoperative; Postoperative Complications; Quetiapine Fumarate; Risk Factors; Soft Tissue Neoplasms; Sotos Syndrome

Antipsychotics are known to alter antioxidant activities in vivo. Therefore, the aim of the present study was to examine in the human neuroblastoma SH-SY5Y cell line the impact of a typical (haloperidol) and an atypical (quetiapine) antipsychotic on the expression of genes encoding the key enzymes of the antioxidant metabolism (Cu, Zn superoxide dismutase; Mn superoxide dismutase; glutathione peroxidase; catalase) and enzymes of the glutathione metabolism (gamma-glutamyl cysteine synthetase, glutathione-S-transferase, gamma-glutamyltranspeptidase, glutathione reductase). The cells were incubated for 24h with 0.3, 3, 30 and 300microM haloperidol and quetiapine, respectively; mRNA levels were measured by polymerase chain reaction. In the present study, we observed mostly significant decreases of mRNA contents. With respect to the key pathways, we detected mainly effects on the mRNA levels of the hydrogen peroxide detoxifying enzymes. Among the enzymes of the glutathione metabolism, glutathione-S-transferase- and gamma-glutamyltranspeptidase-mRNA levels showed the most prominent effects. Taken together, our results demonstrate a significantly reduced expression of genes encoding for antioxidant enzymes after treatment with the antipsychotics, haloperidol and quetiapine.

Topics: Antioxidants; Antipsychotic Agents; Catalase; Cell Line, Tumor; Dibenzothiazepines; Down-Regulation; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutamate-Cysteine Ligase; Glutathione Peroxidase; Glutathione Reductase; Glutathione Transferase; Haloperidol; Humans; Neuroblastoma; Quetiapine Fumarate; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Superoxide Dismutase

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; CHO Cells; Clozapine; Corpus Striatum; COS Cells; Cricetinae; Dibenzothiazepines; Dopamine; Female; Guinea Pigs; Haloperidol; Indoles; Kidney; Male; Microdialysis; Neuroblastoma; Nucleus Accumbens; Olanzapine; Piperazines; Pirenzepine; Prefrontal Cortex; Pyridines; Quetiapine Fumarate; Radioligand Assay; Rats; Rats, Sprague-Dawley; Risperidone; Tritium; Tumor Cells, Cultured