NextGen Brain Microdialysis: Applying Modern Metabolomics Technology to the Analysis of Extracellular Fluid in the Central Nervous System

Kao, Chi-Ya; Anderzhanova, Elmira; Asara, John M.; Wotjak, Carsten T.; Turck, Christoph W.

doi:10.1159/000381855

Cited by 18 publications

(25 citation statements)

References 34 publications

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“…A brain microdialysis metabolomics study in live mice enabled in vivo investigation of metabolites (at baseline) as predictors of subsequent sensitivity or resilience to PTSD-like behaviors in a foot-shock model (107). At day 2 after a stress event, behavioral symptoms (hyperarousal) in shocked mice were predicted by the enrichment of the TCA cycle and glyoxylate and dicarboxylate metabolism in the medial prefrontal cortex prior to foot shock.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Metabolism, Metabolomics, and Inflammation in Posttraumatic Stress Disorder

Mellon

Gautam

Hammamieh

et al. 2018

Biological Psychiatry

145

114

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Posttraumatic stress disorder (PTSD) is defined by classic psychological manifestations, although among the characteristics are significantly increased rates of serious somatic comorbidities, such as cardiovascular disease, immune dysfunction, and metabolic syndrome. In this review, we assess the evidence for disturbances that may contribute to somatic pathology in inflammation, metabolic syndrome, and circulating metabolites (implicating mitochondrial dysfunction) in individuals with PTSD and in animal models simulating features of PTSD. The clinical and preclinical data highlight probable interrelated features of PTSD pathophysiology, including a proinflammatory milieu, metabolomic changes (implicating mitochondrial and other processes), and metabolic dysregulation. These data suggest that PTSD may be a systemic illness, or that it at least has systemic manifestations, and the behavioral manifestations are those most easily discerned. Whether somatic pathology precedes the development of PTSD (and thus may be a risk factor) or follows the development of PTSD (as a result of either shared pathophysiologies or lifestyle adaptations), comorbid PTSD and somatic illness is a potent combination placing affected individuals at increased physical as well as mental health risk. We conclude with directions for future research and novel treatment approaches based on these abnormalities.

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Section: Preclinical Studiesmentioning

confidence: 99%

Metabolism, Metabolomics, and Inflammation in Posttraumatic Stress Disorder

Mellon

Gautam

Hammamieh

et al. 2018

Biological Psychiatry

145

114

View full text Add to dashboard Cite

show abstract

“…glutamate, alanine, aspartate, glyoxylate, citric acid cycle and dicarboxylate metabolism pathways were involved in the hyperarousal among shocked mice [41] . Furthermore, metabolites, such as sarcosine, kynurenic acid, nicotinate and xanthurenic acid were correlated with behavioral changes in stressed mice [40] , while intermediates involved in the process of citric acid cycle, such as citric, isocitric, aconitic, succinic and oxalacetic acids were decreased in shocked mice [41] . To our knowledge, only one preliminary study [42] analyzed metabolites in a small number of PTSD subjects: in 20 PTSD patients and 18 controls.…”

Section: Depressionmentioning

confidence: 99%

Short overview on metabolomic approach and redox changes in psychiatric disorders

et al. 2018

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Schizophrenia, depression and posttraumatic stress disorder (PTSD) are severe mental disorders and complicated diagnostic entities, due to their phenotypic, biological and genetic heterogeneity, unknown etiology, and poorly understood alterations in biological pathways and biological mechanisms. Disturbed homeostasis between overproduction of oxidant species, overcoming redox regulation and a lack of cellular antioxidant defenses, resulting in free radical-mediated pathology and subsequent neurotoxicity contributes to development of depression, schizophrenia and PTSD, their heterogeneous clinical presentation and resistance to treatment. Metabolomics is a discipline that combines different strategies with the aim to extract, detect, identify and quantify all metabolites that are present in a biological sample and might provide mechanistic insights into the etiology of various psychiatric disorders. Therefore, oxidative stress research combined with metabolomics might offer a novel approach in dissecting psychiatric disorders, since these data-driven but not necessarily hypothesis-driven methods might identify new targets, molecules and pathways responsible for development of schizophrenia, depression or PTSD. Findings from the oxidative research in psychiatry together with metabolomics data might facilitate development of specific and validated prognostic, therapeutic and clinical biomarkers. These methods might reveal bio-signatures of individual patients, leading to individualized treatment approach. In reviewing findings related to oxidative stress and metabolomics in selected psychiatric disorders, we have highlighted how these novel approaches might make a unique contribution to deeper understanding of psychopathological alterations underlying schizophrenia, depression and PTSD.

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“…It allows longitudinal sampling within a single individual to follow the treatment response over time. Moreover, since microdialysis allows the collection of molecules with a molecular weight below 20 kD, it is highly suitable for pharmacometabolomics analysis [104,105]. Notably, microdialysis, for ethical reasons, is limited in humans.…”

Section: Prediction Of the Human Brain Pharmacometabolomics Responsesmentioning

confidence: 99%

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

Brink

Hankemeier

Graaf

et al. 2018

Expert Opinion on Drug Discovery

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Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion: It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species.

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NextGen Brain Microdialysis: Applying Modern Metabolomics Technology to the Analysis of Extracellular Fluid in the Central Nervous System

Cited by 18 publications

References 34 publications

Metabolism, Metabolomics, and Inflammation in Posttraumatic Stress Disorder

Metabolism, Metabolomics, and Inflammation in Posttraumatic Stress Disorder

Short overview on metabolomic approach and redox changes in psychiatric disorders

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

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