Access to the CNS: Biomarker Strategies for Dopaminergic Treatments

Abstract

Despite substantial research carried out over the last decades, it remains difficult to understand the wide range of pharmacological effects of dopaminergic agents. The dopaminergic system is involved in several neurological disorders, such as Parkinson’s disease and schizophrenia. This complex system features multiple pathways implicated in emotion and cognition, psychomotor functions and endocrine control through activation of G protein-coupled dopamine receptors. This review focuses on the system-wide effects of dopaminergic agents on the multiple biochemical and endocrine pathways, in particular the biomarkers (i.e., indicators of a pharmacological process) that reflect these effects. Dopaminergic treatments developed over the last decades were found to be associated with numerous biochemical pathways in the brain, including the norepinephrine and the kynurenine pathway. Additionally, they have shown to affect peripheral systems, for example the hypothalamus-pituitary-adrenal (HPA) axis. Dopaminergic agents thus have a complex and broad pharmacological profile, rendering drug development challenging. Considering the complex system-wide pharmacological profile of dopaminergic agents, this review underlines the needs for systems pharmacology studies that include: i) proteomics and metabolomics analysis; ii) longitudinal data evaluation and mathematical modeling; iii) pharmacokinetics-based interpretation of drug effects; iv) simultaneous biomarker evaluation in the brain, the cerebrospinal fluid (CSF) and plasma; and v) specific attention to condition-dependent (e.g., disease) pharmacology. Such approach is considered essential to increase our understanding of central nervous system (CNS) drug effects and substantially improve CNS drug development.

Spatiotemporal EEG microstate analysis in drug-free patients with Parkinson's disease

“…There are some studies have demonstrated that the patients with schizophrenia have the microstate class D matching the control group, but this kind of microstate has significantly shorter duration and lower occurrence than the normal level, which indicates that schizophrenic patients have similar abnormalities with PD patients. The lack of the typical microstate D in patients with schizophrenic is due to the lack of dopaminergic neurons up to a certain point (Johan et al., 2018). Relatedly, progressive degeneration of dopaminergic neurons in the substantia nigra is associated with the common motor symptoms of tremor, and bradykinesia in PD patients (Kalia, 2015), meanwhile literature (Serrano et al., 2018) indicates that the typical microstate class D matching the control group occurs in PD patients treated with dopamine.…”

EEG Microstates Change in Response to Increase in Dopaminergic Stimulation in Typical Parkinson’s Disease Patients

“…However, after levodopa intake there are differences, mainly in the microstate D. There are studies that demonstrate reduced duration ( Kikuchi et al, 2007 ; Nishida et al, 2013 ) and also a lower frequency of appearance ( Lehmann et al, 2010 ) of microstate D in patients with schizophrenia. Schizophrenia is believed to have a dopaminergic deficit up to a certain point that could explain this common finding in PD ( Van Den Brink et al, 2018 ). Consequently, it is to be expected that patients diagnosed with PD have a lower frequency of appearance of microstate D before taking the medication.…”

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

“…Although PK/PD modeling aims to predict single biomarker time courses, it appears that CNS drugs typically affect multiple biochemical pathways [59,60]. For example, risperidone affected multiple pathways including energy metabolism, antioxidant defense systems, neurotransmitter metabolism, fatty acid biosynthesis, and phospholipid metabolism [61].…”

“…Brain metabolic phenotypes are reflected in the periphery via three mechanisms: i) individual metabolites distribute to CSF, plasma and urine, and become integrated in the peripheral metabolic phenotype; ii) the brain metabolic phenotype affects the peripheral nervous signaling, thereby controlling the release of peripheral metabolites, such as acetylcholine or norepinephrine; iii) the brain metabolic phenotype influences the neuroendocrine system via the hypothalamus, modifying the pituitary hormone release. Modified from reference [59] with permission of Springer.…”

“…Of interest for the CNS-pharmacology are the energy substrates, neurotransmitters, amino acids, and structural lipids, all of which are involved in cell viability, signaling, and cell membrane function [2]. It was specifically observed that the corresponding pathways were overlapping among CNS drugs and diseases, indicating that multi-biomarker approaches are important for the evaluation of drug effects [2,59]. Several clinical studies have been performed utilizing pharmacometabolomics for the study of CNS drug effects, although the main focus has been on the disease rather than on the treatment [75].…”