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.
Highlights
Methylphenidate (MPH) is a widely used stimulant for pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD)
The 98 differentially expressed proteins (DEP) identified were analyzed in the context of biological pathways to provide a comprehensive overview of which systems are affected by MPH administration
We were able to reinforce the relevance of some findings in a clinical sample of adults with ADHD, for which we found suggestive evidence on the association between MPH treatment response and genetic variability in pathways related to neurotransmitter release and GABA transmission
Summary
Methylphenidate (MPH) is a widely used stimulant for pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). Several other pathways such as those involved in neuronal plasticity, energy metabolism, cell differentiation, circadian rhythm, and ubiquitinda Silva et al Translational Psychiatry (2019)9:308 dependent protein degradation are affected by MPH, as evidenced by transcriptomics and candidate gene/ protein expression studies[10,11,12,13,14,15,16,17] These studies used different methodologies, including in vivo and in vitro treatments, the overall evidence indicates that MPH actions involve a complex biological scenario, but the most relevant mechanisms for treatment response are still unclear. MPH treatment influences ventral frontostriatal functional connectivity without tasks[20], as well as activates prefrontal cortex, basal ganglia, and cerebellum during tasks[21,22] This set of evidence suggests that MPH effects involve mainly frontal and striatal regions, and a comprehensive investigation of the changes induced by MPH in such regions can provide a better understanding of its pharmacological effects
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