Dataset of histone H3K4me2 modified genes in the liver of female Sprague-Dawleyrats with chronic antipsychotic drugs of olanzapine or clozapine
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE288060 | GEO | 2025/01/29
REPOSITORIES: GEO
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Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways. comparison of olanzapine treated rats vs. control rats for genome-wide DNA methylation changes
2013-11-22 | E-GEOD-52615 | biostudies-arrayexpress
Project description:Dataset of histone H3K4me2 modified genes in the liver of female Sprague-Dawleyrats with chronic antipsychotic drugs of olanzapine or clozapine
| PRJNA1215965 | ENA
Project description:Antipsychotic drugs are commonly used to treat psychosis, mood disorders, and anxiety. While there is indirect evidence that some component of the antipsychotic effect of these drugs may involve modulation of dopamine transmission, their mechanism of action is poorly understood. We hypothesized that antipsychotic drugs mediate their effects via epigenetic modulation. Here we tested the effect of an antipsychotic, olanzapine, on the methylation status of genes following chronic treatment. These effects have been revealed through significantly increased (p<0.01) DNA methylation of genes involved in dopaminergic and non-dopaminergic pathways including the glutamatergic, GABAergic, cholinergic, neuregulin and ErbB signaling pathways. The affected genes included GLS in hippocampus, NR1 in cerebellum and GLUD1 and NR2B in liver. Further, from a set of genes in the 22q11.2 micro-deletions that has been previously implicated in psychosis, 22 genes showed increased methylation following olanzapine treatment. Ingenuity Pathway Analysis (IPA) revealed that chronic olanzapine treatment significantly affected several important pathways such as CREB and CDK5 signaling (p=1.4E-05). Also, DNA replication, recombination and repair, cellular movement and cell cycle have been identified as the top networks affected by olanzapine. The results suggest that these downstream effects, aside from D2 blockade, may play a critical role in the biological actions of antipsychotics. These include altered expressions of relevant genes involved in GABAergic, glutamatergic, cholinergic, neuregulin and ErbB signaling pathways. Epigenetic mechanisms involving changes in DNA methylation could, therefore, explain the delay and individualized non-specificity of biological effects of olanzapine. The results also suggest that DNA methylation may play a role in the process of therapeutic efficacy of olanzapine by altering the transcriptome via tissue-specific methylation of genes involved in schizophrenia signaling pathways.
2013-11-22 | GSE52615 | GEO
Project description:Antipsychotic drugs (APs) are used to treat psychiatric disorders but also have the prominent side effect of weight gain resulting in a higher incidence of metabolic disease in this patient group. While the majority of patients gain significant weight in response to APs some patients are relatively resistant to these effects. APs such as clozapine and olanzapine are deemed to be highly efficacious at treating psychiatric conditions yet they have some of the highest weight gain liabilities. Therefore, there is a need to determine which patients are less susceptible to the metabolic side effects of APs and would be good candidates for drugs such as olanzapine, and conversely, identifying patients that should be prescribed alternative APs with less weight gain liabilities.
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Project description:Atypical antipsychotic Clozapine has a superior antipsychotic and antimanic effects compared to other antisphicotics. Its widespread use was limited by the side effects of agranulocytosis, cardiomyopathy and metabolic anomalies such as weight gain, and diabetes. Very little is known about mechanisms by which Clozapine works. The aim of this experiment is to compare the chronic gene expression profile of the atypical antipsychotic Clozapine to the typical antipsychotic drug Haloperidol using gene expression Microarray in order to understand the intercellular mechanism behind the therapeutic and the toxic effects of Clozapine. Keywords: drug response
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Project description:Atypical antipsychotic Clozapine has a superior antipsychotic and antimanic effects compared to other antisphicotics. Its widespread use was limited by the side effects of agranulocytosis, cardiomyopathy and metabolic anomalies such as weight gain, and diabetes. Very little is known about mechanisms by which Clozapine works. The aim of this experiment is to compare the chronic gene expression profile (i.e four weeks) of the atypical antipsychotic Clozapine to the typical antipsychotic drug Haloperidol using gene expression Microarray in order to understand the intercellular mechanism behind the therapeutic and the toxic effects of Clozapine. Keywords: drug response
2006-12-13 | GSE6511 | GEO
Project description:Atypical antipsychotic Clozapine has a superior antipsychotic and antimanic effects compared to other antisphicotics. Its widespread use was limited by the side effects of agranulocytosis, cardiomyopathy and metabolic anomalies such as weight gain, and diabetes. Very little is known about mechanisms by which Clozapine works. The aim of this experiment is to compare the chronic gene expression profile of the atypical antipsychotic Clozapine to the typical antipsychotic drug Haloperidol using gene expression Microarray in order to understand the intercellular mechanism behind the therapeutic and the toxic effects of Clozapine. Experiment Overall Design: The study was designed to compare the chronic therapeutic and toxic expression profile of Clozapine to Haloperidol in the mouse brain. All experiments were performed in male C57BL mice at four weeks of age (Biological services, University Collage London). Several theoretical and practical considerations influenced the final experimental design. To avoid the effect of injections on genes expression and to simulate the clinical scenario in human, both drugs were applied to the animals drinking water using the maximum human therapeutic dose (i.e. 1.6mg/kg/day for Haloperidol and 12mg/kg/day for Clozapine). Thirty animals were divided equally between three treatment groups and received either Haloperidol (10 animals), Clozapine (10 animals) or no treatment (10 animals) for 12 weeks. After twelve weeks, the total RNA from the right forebrains were extracted and hybridized to the Affymetrix MOE430A array. In all the Microarray experiments we have avoided pooling and each RNA sample was an independent biological replicate. The total numbers of used arrays were 30 Affymetrix MOE430A arrays.
2009-02-07 | E-GEOD-6467 | biostudies-arrayexpress
Project description:Atypical antipsychotic Clozapine has a superior antipsychotic and antimanic effects compared to other antisphicotics. Its widespread use was limited by the side effects of agranulocytosis, cardiomyopathy and metabolic anomalies such as weight gain, and diabetes. Very little is known about mechanisms by which Clozapine works. The aim of this experiment is to compare the chronic gene expression profile (i.e four weeks) of the atypical antipsychotic Clozapine to the typical antipsychotic drug Haloperidol using gene expression Microarray in order to understand the intercellular mechanism behind the therapeutic and the toxic effects of Clozapine. Experiment Overall Design: The study was designed to compare the chronic therapeutic and toxic expression profile of Clozapine to Haloperidol in the mouse brain. All experiments were performed in male C57BL mice at four weeks of age (Biological services, University Collage London). Several theoretical and practical considerations influenced the final experimental design. To avoid the effect of injections on genesâ expression and to simulate the clinical scenario in human, both drugs were applied to the animalsâ drinking water using the maximum human therapeutic dose (i.e.1.6mg/kg/day for Haloperidol and 12mg/kg/day for Clozapine).Thirty animals were divided equally between three treatment groups and received either Haloperidol (10 animals), Clozapine (10 animals) or no treatment (10 animals) for 4 weeks. After four weeks,the plasma drug level for both drugs was assesed by Tandem mass Spectrometry LC- MS/MS. The total RNA from the right forebrains of nine selected animals (three from each treatment group) were extracted and hybridized to the Affymetrix U74Av2. In all the Microarray experiments we have avoided pooling and each RNA sample was an independent biological replicate. The total numbers of used arrays were 9 Affymetrix U74Av2.
2009-04-30 | E-GEOD-6511 | biostudies-arrayexpress
Project description:Analysis of gene expression in the striatum, the liver, the pancreas, and the visceral adipose tissue of mice treated for 28 days with a daily dose of an atypical antipsychotic: risperidone (1 mg/kg) or olanzapine (3.5 mg/kg). Results provide new insights into the molecular mechanisms underlying antipschotic effects, particularly in tissues relevant for antipsychotic-induced metabolic dysregulation. Antipsychotics are associated with weight gain and other metabolic abnormalities such as hyperglycemia, dyslipidemia and metabolic syndrome. We used microarrays to uncover the underlying molecular mechanisms and identify the key genes involved in AP-induced metabolic effects.
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