Srisaiyini Kidnapillai1, Chiara C Bortolasci1, Madhara Udawela2, Bruna Panizzutti3, Briana Spolding1, Timothy Connor1, Andrew Sanigorski1, Olivia M Dean2,4,5, Tamsyn Crowley1,6, Stéphane Jamain7, Laura Gray1,2, Elizabeth Scarr2,8, Marion Leboyer7, Brian Dean2,9, Michael Berk2,4,5,10, Ken Walder1. 1. Centre for Molecular and Medical Research, School of Medicine, Deakin University, Geelong, Australia. 2. The Florey Institute of Neuroscience and Mental Health, Parkville, Australia. 3. 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. 4. IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Deakin University, Geelong, Australia. 5. Department of Psychiatry, the University of Melbourne, Parkville, Australia. 6. Bioinformatics Core Research Facility (BCRF), Deakin University, Geelong, Australia. 7. INSERM U955, Psychiatrie Translationnelle, Université Paris Est, Créteil, France. 8. Faculty of Veterinary and Agricultural Sciences, Melbourne Veterinary School, The University of Melbourne, Victoria, Australia. 9. Faculty of Health Arts and Design, Centre for Mental Health, Swinburne University, Victoria, Australia. 10. Orygen, the National, Centre of Excellence in Youth Mental Health, Parkville, Australia.
Abstract
OBJECTIVES: To create a gene expression signature (GES) to represent the biological effects of a combination of known drugs for bipolar disorder (BD) on cultured human neuronal cells (NT2-N) and rat brains, which also has evidence of differential expression in individuals with BD. To use the GES to identify new drugs for BD using Connectivity Map (CMap). Methods: NT2-N (n = 20) cells and rats (n = 8) were treated with a BD drug combination (lithium, valproate, quetiapine and lamotrigine) or vehicle for 24 and 6 h, respectively. Following next-generation sequencing, the differential expression of genes was assessed using edgeR in R. The derived GES was compared to differentially expressed genes in post-mortem brains of individuals with BD. The GES was then used in CMap analysis to identify similarly acting drugs. Results: A total of 88 genes showed evidence of differential expression in response to the drug combination in both models, and therefore comprised the GES. Six of these genes showed evidence of differential expression in post-mortem brains of individuals with BD. CMap analysis identified 10 compounds (camptothecin, chlorambucil, flupenthixol, valdecoxib, rescinnamine, GW-8510, cinnarizine, lomustine, mifepristone and nimesulide) acting similarly to the BD drug combination.Conclusions: This study shows that GES and CMap can be used as tools to repurpose drugs for BD.
OBJECTIVES: To create a gene expression signature (GES) to represent the biological effects of a combination of known drugs for bipolar disorder (BD) on cultured human neuronal cells (NT2-N) and rat brains, which also has evidence of differential expression in individuals with BD. To use the GES to identify new drugs for BD using Connectivity Map (CMap). Methods: NT2-N (n = 20) cells and rats (n = 8) were treated with a BD drug combination (lithium, valproate, quetiapine and lamotrigine) or vehicle for 24 and 6 h, respectively. Following next-generation sequencing, the differential expression of genes was assessed using edgeR in R. The derived GES was compared to differentially expressed genes in post-mortem brains of individuals with BD. The GES was then used in CMap analysis to identify similarly acting drugs. Results: A total of 88 genes showed evidence of differential expression in response to the drug combination in both models, and therefore comprised the GES. Six of these genes showed evidence of differential expression in post-mortem brains of individuals with BD. CMap analysis identified 10 compounds (camptothecin, chlorambucil, flupenthixol, valdecoxib, rescinnamine, GW-8510, cinnarizine, lomustine, mifepristone and nimesulide) acting similarly to the BD drug combination.Conclusions: This study shows that GES and CMap can be used as tools to repurpose drugs for BD.
Entities:
Keywords:
Bipolar disorder; CMap; drug discovery; drug repurposing; gene expression signature
Authors: Bruna Panizzutti; Chiara C Bortolasci; Briana Spolding; Srisaiyini Kidnapillai; Timothy Connor; Mark F Richardson; Trang T T Truong; Zoe S J Liu; Gerwyn Morris; Laura Gray; Jee Hyun Kim; Olivia M Dean; Michael Berk; Ken Walder Journal: Int J Mol Sci Date: 2021-07-02 Impact factor: 5.923
Authors: Rammohan Shukla; Nicholas D Henkel; Khaled Alganem; Abdul-Rizaq Hamoud; James Reigle; Rawan S Alnafisah; Hunter M Eby; Ali S Imami; Justin F Creeden; Scott A Miruzzi; Jaroslaw Meller; Robert E Mccullumsmith Journal: Neuropsychopharmacology Date: 2020-06-30 Impact factor: 8.294