Year: 2019
Type: article
Abstract: Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < -1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.
Source: Translational Psychiatry
Authors: Bruna S. da Silva, Douglas T. Leffa, Walter O. Beys-da-Silva, Iraci L. S. Torres, Diego L. Rovaris, Marcelo M. Victor, Luis A. Rohde, Nina R. Mota, Carla de Oliveira, Markus Berger, John R. Yates, Renuka Sabnis, Ramón Díaz Peña, Alexandre Rosa Campos, Eugenio H. Grevet, Lucelia Santi, Claiton H. D. Bau, Verônica Contini
Institutions: Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Scripps Research Institute, Sanford Burnham Prebys Medical Discovery Institute, Univates
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,095
Funders: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Conselho Nacional de Desenvolvimento Científico e Tecnológico, Hospital de Clínicas de Porto Alegre, Fundação Instituto de Pesquisas Econômicas, National Institutes of Health, Horizon 2020 Framework Programme, National Institute of Mental Health, National Cancer Institute, National Institute of General Medical Sciences
Awards: G1124005961, G176435288, G1950895571, G2783655308, G2932042871, G3623864585, Quantitative Proteome Analysis of Brain Development, G4420342495, G589077160, G5905040377, G7539200513, G8415331640, G8442129070, G8858395165, G9000083079, G9000102658, G9000147135, G9000313974, G9000316514, G949115552
OpenAlex ID: W2985827412