Clozapine-induced transcriptional changes in the zebrafish brain

Viana, Joana; Wildman, Nick; Hannon, Eilís; Farbos, Audrey; Neill, Paul O'; Moore, Karen; Aerle, Ronny van; Paull, Gregory C.; Santos, Eduarda M.; Mill, Jonathan

doi:10.1038/s41537-019-0092-x

Cited by 15 publications

(6 citation statements)

References 74 publications

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“…At a broader level however, it is worth noting that associations between antipsychotics and side-effects, and enrichment of relevant biological pathways were observed across all compounds, despite their differing MoAs. Further comparison in different biological models, including those where ageing and frailty can be incorporated, and epidemiological studies is now warranted [33]. The overall trend towards downregulation of genes in this experiment is also worth comment.…”

Section: Discussionmentioning

confidence: 85%

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

Malekizadeh

Williams

Kelson

et al. 2020

Preprint

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BACKGROUND Stroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events. METHODS Whole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone and volinanserin using RNA-sequencing. Bioinformatic analysis was performed which scored the association between antipsychotic signatures and expression data from 415,252 samples in the NCBI GEO repository. RESULTS Atherosclerosis, venous thromboembolism and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (e.g. BDNF, PDGFR-beta, TNF, TGF-beta, selenoamino acid metabolism and influenza infection). CONCLUSIONS These findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.

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Section: Discussionmentioning

confidence: 85%

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

Malekizadeh

Williams

Kelson

et al. 2020

Preprint

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“…Moreover, aberrant epigenetic regulation of TGFB2 and alteration in TGFβ signaling might contribute to loss or reversal of brain laterality in SCZ cases. A previous study revealed that clozapine exposure is correlated with down-regulation of ANGPTl4 ( 89 ). Clozapine, an uncommon antipsychotic treatment, is used for SCZ patients with other antipsychotic drug resistance ( 90 ).…”

Section: Discussionmentioning

confidence: 97%

Identification of key long non-coding RNA-associated competing endogenous RNA axes in Brodmann Area 10 brain region of schizophrenia patients

et al. 2022

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Schizophrenia (SCZ) is a serious mental condition with an unknown cause. According to the reports, Brodmann Area 10 (BA10) is linked to the pathology and cortical dysfunction of SCZ, which demonstrates a number of replicated findings related to research on SCZ and the dysfunction in tasks requiring cognitive control in particular. Genetics' role in the pathophysiology of SCZ is still unclear. Therefore, it may be helpful to understand the effects of these changes on the onset and progression of SCZ to find novel mechanisms involved in the regulation of gene transcription. In order to determine the molecular regulatory mechanisms affecting the SCZ, the long non-coding RNA (lncRNA)-associated competing endogenous RNAs (ceRNAs) axes in the BA10 area were determined using a bioinformatics approach in the present work. A microarray dataset (GSE17612) consisted of brain post-mortem tissues of the BA10 area from SCZ patients and matched healthy subjects was downloaded from the Gene Expression Omnibus (GEO) database. This dataset included probes for both lncRNAs and mRNAs. Using the R software's limma package, the differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) were found. The RNA interactions were also discovered using the DIANA-LncBase and miRTarBase databases. In the ceRNA network, positive correlations between DEmRNAs and DElncRNAs were evaluated using the Pearson correlation coefficient. Finally, lncRNA-associated ceRNA axes were built by using the co-expression and DElncRNA-miRNA-DEmRNA connections. We identified the DElncRNA-miRNA-DEmRNA axes, which included two key lncRNAs (PEG3-AS1, MIR570HG), seven key miRNAs (hsa-miR-124-3p, hsa-miR-17-5p, hsa-miR-181a-5p, hsa-miR-191-5p, hsa-miR-26a-5p, hsa-miR-29a-3p, hsa-miR-29b-3p), and eight key mRNAs (EGR1, ETV1, DUSP6, PLOD2, CD93, SERPINB9, ANGPTL4, TGFB2). Furthermore, DEmRNAs were found to be enriched in the “AGE-RAGE signaling pathway in diabetic complications”, “Amoebiasis”, “Transcriptional misregulation in cancer”, “Human T-cell leukemia virus 1 infection”, and “MAPK signaling pathway”. This study offers research targets for examining significant molecular pathways connected to the pathogenesis of SCZ, even though the function of these ceRNA axes still needs to be investigated.

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“…We therefore investigated the expression of proteins involved in mitochondrial function. The expression of PKMb is closely associated with the function of ETC (Prado‐Lima & Val, 2016), and CKma is known to regulate mitochondrial morphology and function including mitochondrial permeability transition pore (MPTP) and ΔΨ in zebrafish (Ding et al, 2017; Rickmann et al, 2007; Viana et al, 2020). HSP90 and HSC70 regulate mitochondrial protein turnover (Margineantu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Molecular processes underlying the ROS ‐induced changes in muscle hardness in grass carp: Insights from a dietary pro‐oxidant and oxidant approach

Chen

Wang

et al. 2022

Aquaculture Research

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Reactive oxygen species (ROS) is known to increase muscle hardness, which has been of particular interest in food animals, but the detailed mechanism for the ROS‐induced changes remains unclear. To explore the responsible molecular pathway, we conducted a detailed gene/protein expression analysis on the crisp grass carp model using four groups fed with different diets: control commercial feed (C group), a natural pro‐oxidant faba bean (FB group) only, FB + antioxidants vitamins C and E (FB + AO group), and commercial feed + a pro‐oxidant vitamin K3 (O group). Real‐time PCR and parallel reaction monitoring, an emerging high‐resolution mass spectrometry analysis, were employed. Our expression analysis highlighted two main effects of dietary pro‐oxidants: endogenous ROS production and enhancement of muscle regeneration. The CGC and O groups generally increased the expression of genes/proteins related to ROS generation (e.g. mitochondrial proteins), caspase 3 (a candidate mediator of muscle regeneration) and muscle structural proteins such as tropomyosin and collagen. Most changes were not observed in the FB + AO group, indicating the causal role of ROS in the observed changes. These results explain part of molecular processes of ROS‐induced improvement in muscle hardness in grass carp and would be useful for further application of dietary pro‐oxidants to other species.

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Clozapine-induced transcriptional changes in the zebrafish brain

Cited by 15 publications

References 74 publications

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

Whole transcriptome in-silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side-effects

Identification of key long non-coding RNA-associated competing endogenous RNA axes in Brodmann Area 10 brain region of schizophrenia patients

Molecular processes underlying the ROS ‐induced changes in muscle hardness in grass carp: Insights from a dietary pro‐oxidant and oxidant approach

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