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Interacting effects of the MAM model of schizophrenia and antipsychotic treatment: Untargeted proteomics approach in adipose tissue

J. Kucera, K. Horska, P. Hruska, D. Kuruczova, V. Micale, J. Ruda-Kucerova, J. Bienertova-Vasku

. 2021 ; 108 (-) : 110165. [pub] 20201103

Language English Country Great Britain

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc22012405

Schizophrenia is a severe neuropsychiatric disease associated with substantially higher mortality. Reduced life expectancy in schizophrenia relates to an increased prevalence of metabolic disturbance, and antipsychotic medication is a major contributor. Molecular mechanisms underlying adverse metabolic effects of antipsychotics are not fully understood; however, adipose tissue homeostasis deregulation appears to be a critical factor. We employed mass spectrometry-based untargeted proteomics to assess the effect of chronic olanzapine, risperidone, and haloperidol treatment in visceral adipose tissue of prenatally methylazoxymethanol (MAM) acetate exposed rats, a well-validated neurodevelopmental animal model of schizophrenia. Bioinformatics analysis of differentially expressed proteins was performed to highlight the pathways affected by MAM and the antipsychotics treatment. MAM model was associated with the deregulation of the TOR (target of rapamycin) signalling pathway. Notably, alterations in protein expression triggered by antipsychotics were observed only in schizophrenia-like MAM animals where we revealed hundreds of affected proteins according to our two-fold threshold, but not in control animals. Treatments with all antipsychotics in MAM rats resulted in the downregulation of mRNA processing and splicing, while drug-specific effects included among others upregulation of insulin resistance (olanzapine), upregulation of fatty acid metabolism (risperidone), and upregulation of nucleic acid metabolism (haloperidol). Our data indicate that deregulation of several energetic and metabolic pathways in adipose tissue is associated with APs administration and is prominent in MAM schizophrenia-like model but not in control animals.

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$a Schizophrenia is a severe neuropsychiatric disease associated with substantially higher mortality. Reduced life expectancy in schizophrenia relates to an increased prevalence of metabolic disturbance, and antipsychotic medication is a major contributor. Molecular mechanisms underlying adverse metabolic effects of antipsychotics are not fully understood; however, adipose tissue homeostasis deregulation appears to be a critical factor. We employed mass spectrometry-based untargeted proteomics to assess the effect of chronic olanzapine, risperidone, and haloperidol treatment in visceral adipose tissue of prenatally methylazoxymethanol (MAM) acetate exposed rats, a well-validated neurodevelopmental animal model of schizophrenia. Bioinformatics analysis of differentially expressed proteins was performed to highlight the pathways affected by MAM and the antipsychotics treatment. MAM model was associated with the deregulation of the TOR (target of rapamycin) signalling pathway. Notably, alterations in protein expression triggered by antipsychotics were observed only in schizophrenia-like MAM animals where we revealed hundreds of affected proteins according to our two-fold threshold, but not in control animals. Treatments with all antipsychotics in MAM rats resulted in the downregulation of mRNA processing and splicing, while drug-specific effects included among others upregulation of insulin resistance (olanzapine), upregulation of fatty acid metabolism (risperidone), and upregulation of nucleic acid metabolism (haloperidol). Our data indicate that deregulation of several energetic and metabolic pathways in adipose tissue is associated with APs administration and is prominent in MAM schizophrenia-like model but not in control animals.
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$a Horska, Katerina $u Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic; Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University, Brno, Czech Republic
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$a Hruska, Pavel $u Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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$a Kuruczova, Daniela $u Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
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$a Micale, Vincenzo $u Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, University of Catania, Catania, Italy; National Institute of Mental Health, Klecany, Czech Republic
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$a Ruda-Kucerova, Jana $u Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. Electronic address: jkucer@med.muni.cz
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$a Bienertova-Vasku, Julie $u Research Centre for Toxic Compounds in the Environment (RECETOX), Faculty of Science, Masaryk University, Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic. Electronic address: julie.dobrovolna@recetox.muni.cz
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