Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk

Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 23-01-2023

Detalles Bibliográficos
Autor: Patel, Gaurangkumar
Tipo de recurso: tesis doctoral
Fecha de publicación:2023
País:España
Institución:Universidad Autónoma de Madrid
Repositorio:Biblos-e Archivo. Repositorio Institucional de la UAM
Idioma:inglés
OAI Identifier:oai:repositorio.uam.es:10486/706717
Acceso en línea:http://hdl.handle.net/10486/706717
Access Level:acceso abierto
Palabra clave:Biociencias Moleculares
Biología y Biomedicina / Biología
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spelling Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular riskPatel, GaurangkumarBiociencias MolecularesBiología y Biomedicina / BiologíaTesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 23-01-2023Esta tesis tiene embargado el acceso al texto completo hasta el 23-07-2024Second generation antipsychotics (SGAs) are preferred during chronic therapy for schizophrenic and psychotic patients due to less extrapyramidal side effects. On the other hand, they are associated with increased risk of cardiovascular diseases (CVDs), which is major cause of mortality among these patients. The SGAs are associated with metabolic side effects, where Olanzapine (Ola) is associated with increased metabolic risks; whereas Ari (Ari), less vigorously studied so far, is regarded as relatively safer. However, clear cause-effect relationships explaining such diverse metabolic profiles are yet to be established. Recently many drugs, including some SGAs, are found to induce mitochondrial dysfunction, which might be linked to metabolic and cardiovascular risks. Hence, we decided to evaluate role of mitochondrial function in development of cardiovascular risk due to SGAs in order to determine whether it can be used as risk predictor. In light of this, we investigated mitochondrial distribution of Ola and Ari in mice, as well as their effects on mitochondrial respiration clinically. We studied effects of subacute and chronic treatment with Ari and Ola on metabolic and cardiovascular functions in wild type (WT) and PGC-1α-deficient mice (KO), a model of mitochondrial dysfunction. We observed that both Ari and Ola enter mitochondria at significant levels. Ari reduced mitochondrial respiration efficiency, mitochondrial content, and cristae density severely and irreversibly; whereas Ola affected mitochondrial respiration and cristae density with compensatory recovery in mitochondrial content and respiration. Ari reduced whole body respiration and energy expenditure in vivo which was persistent and evident in both WT and KO mice, whereas Ola reduced respiration and energy expenditure which was dependent on genotype and tends to recover with time. In line with these observations, Ari found to cause glucose intolerance earlier than Ola with the effect being earlier and severe in KO mice compared to WT mice. Such metabolic changes coincided with profibrotic changes in cardiovascular structure especially in KO mice treated with Ari and Ola for long duration, which ultimately affects macrovascular function, and cardiac recovery after ischemia-reperfusion injury. Such detrimental effects of Ari and Ola on cardiovascular structure and functions were found to be dependent on mitochondrial function. The results indicate protective role of PGC-1α against drug-induced toxicity in cardiovascular system. These results could encourage potential use of drug screening for their mitochondrial effects during drug development. Also, evaluation of mitochondrial function in patients before and during therapy could be used to predict the risk of developing cardiovascular diseases and to guide selection of therapy as a part of personalised medicineThis work was supported by the grant ‘Horizon 2020 Marie Sklodowska-Curie Innovative Training Network of EU (Grant# 721236)’ to Dr. María Monsalve Pérez and Gaurangkumar PatelMonsalve Pérez, MaríaLamas Peláez, SantiagoDepartamento de BioquímicaFacultad de MedicinaInstituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)20232023-01-23doctoral thesishttp://purl.org/coar/resource_type/c_db06NAhttp://purl.org/coar/version/c_be7fb7dd8ff6fe43info:eu-repo/semantics/doctoralThesisapplication/pdfhttp://hdl.handle.net/10486/706717reponame:Biblos-e Archivo. Repositorio Institucional de la UAMinstname:Universidad Autónoma de MadridInglésengopen accesshttp://purl.org/coar/access_right/c_abf2info:eu-repo/semantics/openAccessoai:repositorio.uam.es:10486/7067172026-06-23T12:46:27Z
dc.title.none.fl_str_mv Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
title Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
spellingShingle Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
Patel, Gaurangkumar
Biociencias Moleculares
Biología y Biomedicina / Biología
title_short Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
title_full Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
title_fullStr Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
title_full_unstemmed Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
title_sort Role of antipsychotics-induced mitochondrial dysfunction in increased cardiovascular risk
dc.creator.none.fl_str_mv Patel, Gaurangkumar
author Patel, Gaurangkumar
author_facet Patel, Gaurangkumar
author_role author
dc.contributor.none.fl_str_mv Monsalve Pérez, María
Lamas Peláez, Santiago
Departamento de Bioquímica
Facultad de Medicina
Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM)
dc.subject.none.fl_str_mv Biociencias Moleculares
Biología y Biomedicina / Biología
topic Biociencias Moleculares
Biología y Biomedicina / Biología
description Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 23-01-2023
publishDate 2023
dc.date.none.fl_str_mv 2023
2023-01-23
dc.type.none.fl_str_mv doctoral thesis
http://purl.org/coar/resource_type/c_db06
NA
http://purl.org/coar/version/c_be7fb7dd8ff6fe43
dc.type.openaire.fl_str_mv info:eu-repo/semantics/doctoralThesis
format doctoralThesis
dc.identifier.none.fl_str_mv http://hdl.handle.net/10486/706717
url http://hdl.handle.net/10486/706717
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Biblos-e Archivo. Repositorio Institucional de la UAM
instname:Universidad Autónoma de Madrid
instname_str Universidad Autónoma de Madrid
reponame_str Biblos-e Archivo. Repositorio Institucional de la UAM
collection Biblos-e Archivo. Repositorio Institucional de la UAM
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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