Srisaiyini Kidnapillai1, Chiara C Bortolasci1, Bruna Panizzutti2, Briana Spolding1, Timothy Connor1, Kamila Bonifacio3, Andrew Sanigorski1, Olivia M Dean4,5, Tamsyn Crowley1,6, Stéphane Jamain7, Laura Gray1,4, Marion Leboyer7, Michael Berk4,5,8,9, Ken Walder1. 1. Centre for Molecular and Medical Research, School of Medicine, Deakin University, Geelong, Australia. 2. Laboratory of Molecular Psychiatry, Hospital de Clínicas de Porto Alegre (HCPA) and Programa de Pós-graduação em Psiquiatria e Ciências do Comportamento, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. 3. Laboratory of Graduation Research, State University of Londrina, Londrina, Brazil. 4. The Florey Institute of Neuroscience and Mental Health, Parkville, Australia. 5. IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. 6. Bioinformatics Core Research Facility (BCRF), Deakin University, Geelong, Australia. 7. INSERM U955, Psychiatrie Translationnelle, Université Paris Est, Créteil, France. 8. Orygen, The National Centre of Excellence in Youth Mental Health, Australia Parkville. 9. Department of Psychiatry, The University of Melbourne, Parkville, Australia.
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.
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.