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Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.
Bortolasci, Chiara C; Kidnapillai, Srisaiyini; Spolding, Briana; Truong, Trang T T; Connor, Timothy; Swinton, Courtney; Panizzutti, Bruna; Liu, Zoe S J; Sanigorski, Andrew; Dean, Olivia M; Crowley, Tamsyn; Richardson, Mark; Bozaoglu, Kiymet; Vlahos, Katerina; Cowdery, Stephanie; Watmuff, Brad; Steyn, Stephan F; Wolmarans, De Wet; Engelbrecht, Barend J; Perry, Christina; Drummond, Katherine; Pang, Terence; Jamain, Stéphane; Gray, Laura; McGee, Sean L; Harvey, Brian H; Kim, Jee Hyun; Leboyer, Marion; Berk, Michael; Walder, Ken.
Afiliación
  • Bortolasci CC; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Kidnapillai S; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Spolding B; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Truong TTT; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Connor T; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Swinton C; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Panizzutti B; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Liu ZSJ; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Sanigorski A; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Dean OM; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Crowley T; The Florey Institute of Neuroscience and Mental Health, Parkville, Australia.
  • Richardson M; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Bozaoglu K; Bioinformatics Core Research Facility (BCRF), Deakin University, Geelong, Australia.
  • Vlahos K; Bioinformatics Core Research Facility (BCRF), Deakin University, Geelong, Australia.
  • Cowdery S; Murdoch Children's Research Institute, Parkville, Victoria, Australia.
  • Watmuff B; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
  • Steyn SF; Murdoch Children's Research Institute, Parkville, Victoria, Australia.
  • Wolmarans W; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Engelbrecht BJ; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Perry C; Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa.
  • Drummond K; Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa.
  • Pang T; Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa.
  • Jamain S; The Florey Institute of Neuroscience and Mental Health, Parkville, Australia.
  • Gray L; The Florey Institute of Neuroscience and Mental Health, Parkville, Australia.
  • McGee SL; The Florey Institute of Neuroscience and Mental Health, Parkville, Australia.
  • Harvey BH; Univ Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, AP-HP, DMU IMPACT, FHU ADAPT, Fondation FondaMental, Créteil, France.
  • Kim JH; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Leboyer M; The Florey Institute of Neuroscience and Mental Health, Parkville, Australia.
  • Berk M; IMPACT, The Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin University, Geelong, Australia.
  • Walder K; Centre of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa.
Bipolar Disord ; 25(8): 661-670, 2023 12.
Article en En | MEDLINE | ID: mdl-36890661
OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trimetazidina / Trastorno Bipolar Límite: Animals / Humans Idioma: En Revista: Bipolar Disord Asunto de la revista: PSIQUIATRIA Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Dinamarca
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trimetazidina / Trastorno Bipolar Límite: Animals / Humans Idioma: En Revista: Bipolar Disord Asunto de la revista: PSIQUIATRIA Año: 2023 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Dinamarca