Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back

Bosia, Marta; Pigoni, Alessandro; Cavallaro, Roberto

doi:10.1517/17460441.2015.976552

Cited by 15 publications

(11 citation statements)

References 112 publications

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“…4 Between 5% and 25% of schizophrenia patients are resistant to the most commonly prescribed antipsychotic medications, 5 and clozapine is a second-generation antipsychotic often prescribed to patients with such treatmentresistant schizophrenia. Although clozapine has been shown to have increased effectiveness compared to other commonly prescribed antipsychotic drugs, 6,7 over 40% of patients treated with clozapine show an inadequate response 8 and its use is associated with severe side-effects. For example, patients prescribed clozapine need to be carefully monitored for the development of serious blood disorders such as agranulocytosis.…”

Section: Introductionmentioning

confidence: 99%

Clozapine-induced transcriptional changes in the zebrafish brain

et al. 2020

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Clozapine is an atypical antipsychotic medication that is used to treat schizophrenia patients who are resistant to other antipsychotic drugs. The molecular mechanisms mediating the effects of clozapine are not well understood and its use is often associated with severe side-effects. In this study, we exposed groups of wild-type zebrafish to two doses of clozapine ('low' (20 µg/L) and 'high' (70 µg/L)) over a 72-h period, observing dose-dependent effects on behaviour. Using RNA sequencing (RNA-seq) we identified multiple genes differentially expressed in the zebrafish brain following exposure to clozapine. Network analysis identified co-expression modules characterised by striking changes in module connectivity in response to clozapine, and these were enriched for regulatory pathways relevant to the etiology of schizophrenia. Our study highlights the utility of zebrafish as a model for assessing the molecular consequences of antipsychotic medications and identifies genomic networks potentially involved in schizophrenia.

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Section: Introductionmentioning

confidence: 99%

Clozapine-induced transcriptional changes in the zebrafish brain

et al. 2020

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“…Epigenetic modifications may affect gene expression without the existence of changes in DNA sequence [ 1 ]. They are known to affect a number of neurological disorders [ 2 , 3 ] including psychosis [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Insights into the origin of DNA methylation differences between monozygotic twins discordant for schizophrenia

et al. 2015

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BackgroundDNA methylation differences between monozygotic twins discordant for schizophrenia have been previously reported. However, the origin of methylation differences between monozygotic twins discordant for schizophrenia is not clear. The findings here argue that all DNA methylation differences may not necessarily represent the cause of the disease; rather some may result from the effect of antipsychotics.MethodsMethylation differences in rat brain regions and also in two pairs of unrelated monozygotic twins discordant for schizophrenia have been studied using genome-wide DNA methylation arrays at Arraystar Inc. (Rockville, Maryland, USA). The identified gene promoters showing significant alterations to DNA methylation were then further characterized using ingenuity pathway analysis (Ingenuity System Inc, CA, USA).ResultsPathway analysis of the most significant gene promoter hyper/hypomethylation revealed a significant enrichment of DNA methylation changes in biological networks and pathways directly relevant to neural development and psychiatric disorders. These included HIPPO signaling (p = 3.93E-03) and MAPK signaling (p = 4.27E-03) pathways involving hypermethylated genes in schizophrenia-affected patients as compared to their unaffected co-twins. Also, a number of significant pathways and networks involving genes with hypomethylated gene promoters have been identified. These included CREB signaling in neurons (p = 1.53E-02), Dopamine-DARPP32 feedback in cAMP signaling (p = 7.43E-03) and Ephrin receptors (p = 1.13E-02). Further, there was significant enrichment for pathways involved in nervous system development and function (p = 1.71E-03-4.28E-02).ConclusionThe findings highlight the significance of antipsychotic drugs on DNA methylation in schizophrenia patients. The unique pathways affected by DNA methylation in the two pairs of monozygotic twins suggest that patient-specific pathways are responsible for the disease; suggesting that patient-specific treatment strategies may be necessary in treating the disorder. The study reflects the need for developing personalized medicine approaches that take into consideration epigenetic variations between patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40303-015-0013-5) contains supplementary material, which is available to authorized users.

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“…Исследования влияния обогащенной среды на когнитивные функции важны для понимания механизмов действия когнитивно-поведенческой терапии и нейрокогнитивных тренингов больных шизофренией. Кроме того, эпигенетические модификации представляют собой обратимые процессы, в связи с чем являются привлекательными мишенями медикаментозного лечения [48,49]. В модельных опытах на животных было установлено, что фармакологическое воздействие ведет к восстановлению активности генома и нормализации поведения, в том числе тех изменений, которые связаны с особенностями метилирования генов дофаминергического пути, вызванных стрессом или мутациями [50,51].…”

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“…Ряд авторов [54,55] указывают, что ингибиторы деацетилаз гистонов могут быть использованы для коррекции когнитивной сферы больных шизофренией. Следует отметить, что в механизмы действия уже существующих антипсихотических препаратов вовлечены эпигенетические процессы [49,56,57]. Галоперидол связан с рядом модификаций, включая ацетилирование, фосфорилирование и фосфоацетилирование гистонов и метилирование ДНК [57].…”

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Results and promises of genetics of cognitive impairment in schizophrenia: epigenetic approaches

Алфимова¹,

Kondratiev²,

Голимбет³

2017

Z. nevrol. psikhiatr. im. S.S. Korsakova

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В клеточном ядре ДНК в комплексе с гистоновыми белками образует трехмерную структуру-хроматин, от которой зависит доступ транскрипционного аппарата клетки к ДНК. Эпигенетика изучает механизмы изменения состояния хроматина, не затрагивающие нуклеотидную последовательность ДНК, но влияющие на экспрессию генов-эпигенетические модификации [1]. В узком смысле ее предметом является метилирование ДНК и посттрансляционные модификации гистонов. Однако часто к сфере изучения эпигенетики относят любые локальные свойства хроматина, могущие влиять на активность генома. Метилирование ДНК представляет собой присоединение метильной группы к основанию цитозина (С) и имеет место в подавляющем большинстве случаев в участках ДНК, где за цитозином следует гуанин (G), т.е. динуклеотидах CpG. Еще в 60-х годах прошлого века было установлено [2], что в геномах многих организмов CpG-динуклеотиды встречаются реже других видов.

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Genomics and epigenomics in novel schizophrenia drug discovery: translating animal models to clinical research and back

Cited by 15 publications

References 112 publications

Clozapine-induced transcriptional changes in the zebrafish brain

Clozapine-induced transcriptional changes in the zebrafish brain

Insights into the origin of DNA methylation differences between monozygotic twins discordant for schizophrenia

Results and promises of genetics of cognitive impairment in schizophrenia: epigenetic approaches

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