The antipsychotic medications aripiprazole, brexpiprazole and cariprazine are off-target respiratory chain complex I inhibitors
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Published:2023-08-01
Issue:1
Volume:18
Page:
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ISSN:1745-6150
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Container-title:Biology Direct
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language:en
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Short-container-title:Biol Direct
Author:
Hardy Rachel E.,Chung Injae,Yu Yizhou,Loh Samantha H. Y.,Morone Nobuhiro,Soleilhavoup Clement,Travaglio Marco,Serreli Riccardo,Panman Lia,Cain Kelvin,Hirst Judy,Martins Luis M.,MacFarlane Marion,Pryde Kenneth R.
Abstract
AbstractAntipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies for other prevalent psychiatric conditions, including bipolar disorder and major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority of patients. The majority of antipsychotic drugs function as dopamine receptor antagonists in the brain while the most recent ‘third’-generation, such as aripiprazole, act as partial agonists. Despite showing good clinical efficacy, these newer agents are still associated with EPS in ~ 5 to 15% of patients. However, it is not fully understood how these movement disorders develop. Here, we combine clinically-relevant drug concentrations with mutliscale model systems to show that aripiprazole and its primary active metabolite induce mitochondrial toxicity inducing robust declines in cellular ATP and viability. Aripiprazole, brexpiprazole and cariprazine were shown to directly inhibit respiratory complex I through its ubiquinone-binding channel. Importantly, all three drugs induced mitochondrial toxicity in primary embryonic mouse neurons, with greater bioenergetic inhibition in ventral midbrain neurons than forebrain neurons. Finally, chronic feeding with aripiprazole resulted in structural damage to mitochondria in the brain and thoracic muscle of adultDrosophila melanogasterconsistent with locomotor dysfunction. Taken together, we show that antipsychotic drugs acting as partial dopamine receptor agonists exhibit off-target mitochondrial liabilities targeting complex I.
Funder
Medical Research Council
Publisher
Springer Science and Business Media LLC
Subject
Applied Mathematics,General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology,Modeling and Simulation,Ecology, Evolution, Behavior and Systematics,Immunology
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