Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression

Abstract

ObjectivesThe aim of this study was to repurpose a drug for the treatment of bipolar depression.MethodsA 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).ResultsThe 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.ConclusionCollectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Trimetazidine Improves Mitochondrial Dysfunction in SOD1G93A Cellular Models of Amyotrophic Lateral Sclerosis through Autophagy Activation

“…This study has therefore shed light on the neuroprotective function of TMZ, which has been poorly explored thus far. Most previous studies, indeed, have primarily focused on the role of TMZ in skeletal and cardiac muscle, while few papers highlighted the diverse effects of TMZ on the nervous system, including its neuroprotective properties, modulation of mitochondrial function and potential therapeutic applications in neurological conditions such as epilepsy, glaucoma and nerve injuries [ 46 , 47 , 48 , 49 , 50 , 51 ].…”

Exploring mood disorders and treatment options using human stem cells

“…Other studies using iPSC models of BD have demonstrated that inflammation plays a role in the manifestation and treatment of phenotypes associated with the disorder ( Vizlin-Hodzic et al, 2017 ), along with various molecular and electrophysiological differences compared to control groups ( Stern et al, 2018 , 2020a , b ; McGhee et al, 2021 ; Mishra et al., 2021 ; Vadodaria et al, 2021 ). More recently, researchers have used iPSC models to explore alternative pharmaceutical treatments for individuals with BD, focusing on lithium non-responders ( Paul et al, 2020 ; Stern et al ., 2020b ; Osete et al, 2021 ; Bortolasci et al, 2023 ). In addition, the novel data in Figure 2 demonstrate that targeting inflammatory responses correlated to BD, using anti-inflammatory compounds such as apigenin, could provide an alternative treatment for people suffering from the disorder.…”

“…Published studies report that BD patients have abnormalities in mitochondrial respiration ( Osete et al, 2021 ), a pathway that is known to be affected by trimetazidine. Although Bortolasci and colleagues ( Bortolasci et al ., 2023 ) did not strictly recapitulate the medication exposure in the iPSC models, the team was able to show that exposure to trimetazidine reduced BD-like symptoms in rats, showing the promise of iPSC modeling to address gaps in BD treatment plans.…”

“…A study by Bortolasci et al (2023 ) published a report using iPSC-derived neurons and astrocytes to screen for target genes associated with BD by producing a gene expression signature after exposure to BD medication and found that trimetazidine was an appropriate match in their analysis. The medication is known to work on the metabolic processes of the body and has a tendency to increase the production of adenosine triphosphate (ATP) ( Şekeroğlu et al, 2021 ), and ATP is thought to be a component of BD defects ( Jones et al, 2021 ).…”