Drugs used in the treatment of bipolar disorder and their effects on cholesterol biosynthesis - A possible therapeutic mechanism.
Srisaiyini KidnapillaiChiara C BortolasciBruna PanizzuttiBriana SpoldingTimothy ConnorKamila BonifacioAndrew SanigorskiOlivia M DeanTamsyn CrowleyStéphane JamainLaura J GrayMarion LeboyerMichael BerkKen R WalderPublished in: The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry (2019)
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.
Keyphrases
- induced apoptosis
- low density lipoprotein
- bipolar disorder
- cell cycle arrest
- genome wide
- copy number
- oxidative stress
- endothelial cells
- type diabetes
- endoplasmic reticulum stress
- genome wide identification
- gene expression
- cell death
- major depressive disorder
- machine learning
- transcription factor
- dna methylation
- cognitive decline
- adipose tissue
- cell proliferation
- electronic health record
- reactive oxygen species
- skeletal muscle
- blood brain barrier
- insulin resistance
- smoking cessation
- replacement therapy