Journal article
Drugs used in the treatment of bipolar disorder and their effects on cholesterol biosynthesis ? A possible therapeutic mechanism
The world journal of biological psychiatry, Vol.20(10), pp.766-777
16/10/2019
PMID: 31535581
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Abstract
Objectives: To understand the therapeutic mechanisms of bipolar disorder (BD) drugs at molecular and cellular levels.
Methods: Next generation sequencing was used to determine the transcriptional effects of a combination of four commonly prescribed BD drugs (lithium, valproate, lamotrigine and quetiapine) or vehicle (0.2% DMSO) in NT2-N (human neuronal) cells and rats. Differential expression of genes and pathway analysis were performed using edgeR in R and Gene Set Enrichment Analysis software respectively. Free cholesterol levels and neurite outgrowth were quantified in NT2-N cells following combination and individual BD drug treatments.
Results: Pathway analysis showed up-regulation of many elements of the cholesterol biosynthesis pathway in NT2-N cells and oxidative phosphorylation in rat brains. Intracellular cholesterol transport genes were upregulated (NPC1, NPC2 and APOE), while the cholesterol efflux gene (ABCA1) was downregulated. BD drug combination tended to increase intracellular cholesterol levels and neurite outgrowth, but these effects were not seen for the drugs when used individually.
Conclusions: These data suggest that BD drug combination is increasing cholesterol biosynthesis and the newly synthesised cholesterol is being utilised within the cells, possibly for synthesis of new membranes to facilitate neurite outgrowth. This mechanism possibly underpins clinical efficacy in individuals with BD treated with polypharmacy.
Details
- Title
- Drugs used in the treatment of bipolar disorder and their effects on cholesterol biosynthesis ? A possible therapeutic mechanism
- Creators
- Srisaiyini Kidnapillai - Deakin University (Australia, Geelong)Chiara C. Bortolasci - Deakin University (Australia, Geelong)Bruna Panizzutti - Universidade Federal do Rio Grande do SulBriana Spolding - Deakin University (Australia, Geelong)Timothy Connor - Deakin University (Australia, Geelong)Kamila Bonifacio - Universidade Estadual de LondrinaAndrew Sanigorski - Deakin University (Australia, Geelong)Olivia M. Dean - Florey Institute of Neuroscience and Mental HealthTamsyn Crowley - Deakin University (Australia, Geelong)Stephane Jamain - Université Paris-Est CréteilLaura Gray - Deakin University (Australia, Geelong)Marion Leboyer - Université Paris-Est CréteilMichael Berk - Florey Institute of Neuroscience and Mental HealthKen Walder - Deakin University (Australia, Geelong)
- Publication Details
- The world journal of biological psychiatry, Vol.20(10), pp.766-777
- Publisher
- Taylor & Francis
- Number of pages
- 12
- Identifiers
- 991013328527302368
- Copyright
- © 2019 Informa UK Limited, trading as Taylor & Francis Group.
- Academic Unit
- Office of Senior Deputy Vice Chancellor, Research
- Language
- English
- Resource Type
- Journal article