A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia

Coughlin, Jennifer M.; Yang, Kun; Marsman, Anouk; Pradhan, Subechhya; Wang, Min; Ward, Rebecca; Bonekamp, Susanne; Ambinder, Emily B.; Higgs, Cecilia; Kim, Pearl K.; Edwards, Jamie A; Varvaris, Mark; Wang, Hongxing; Posporelis, Sotirios; Ma, Shuangchao; Tsujimura, Tsuyoshi; Edden, Richard A.E.; Pomper, Martin G.; Sedlak, Thomas W.; Fournier, Margot; Schretlen, David J.; Cascella, Nicola G.; Barker, Peter B.; Sawa, Akira

doi:10.1038/s41380-020-00901-5

Cited by 37 publications

(37 citation statements)

References 61 publications

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“…Nevertheless, it is unclear how biochemical changes in the periphery are related to neurochemical changes in the brain. There are few studies that point out a positive correlation between glutathione (which is the main intracellular non-enzymatic antioxidant) in plasma, with the levels of glutathione-dependent metabolites associated with glutamatergic transmission in the brains of schizophrenics, as compared to healthy controls [ 53 ]. The levels of these metabolites positively correlate with the neuropsychological assessment in patients with schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

Determinants of Schizophrenia Endophenotypes Based on Neuroimaging and Biochemical Parameters

et al. 2021

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Despite extensive research, there is no convincing evidence of a reliable diagnostic biomarker for schizophrenia beyond clinical observation. Disorders of glutamatergic neurotransmission associated with N-methyl-D-aspartate (NMDA) receptor insufficiency, neuroinflammation, and redox dysregulation are the principal common mechanism linking changes in the periphery with the brain, ultimately contributing to the emergence of negative symptoms of schizophrenia that underlie differential diagnosis. The aim of the study was to evaluate the influence of these systems via peripheral and cerebral biochemical indices in relation to the patient’s clinical condition. Using neuroimaging diagnostics, we were able to define endophenotypes of schizophrenia based on objective laboratory data that form the basis of a personalized approach to diagnosis and treatment. The two distinguished endophenotypes differed in terms of the quality of life, specific schizophrenia symptoms, and glutamatergic neurotransmission metabolites in the anterior cingulate gyrus. Our results, as well as further studies of the excitatory or inhibitory balance of microcircuits, relating the redox systems on the periphery with the distant regions of the brain might allow for predicting potential biomarkers of neuropsychiatric diseases, including schizophrenia. To the best of our knowledge, our study is the first to identify an objective molecular biomarker of schizophrenia outcome.

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Section: Introductionmentioning

confidence: 99%

Determinants of Schizophrenia Endophenotypes Based on Neuroimaging and Biochemical Parameters

et al. 2021

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“…To study the roles of LRRK2 in response to LPS, we used the human lymphoblasts that were generated by Dr. Akira Sawa’s group from blood lymphocytes of normal human subjects as described previously [ 36 ]. We found that endogenous LRRK2 was highly expressed in lymphoblasts ( Figure 1 a).…”

Section: Resultsmentioning

confidence: 99%

“…Human lymphoblasts were generated from normal human blood lymphocytes at the core facility, Johns Hopkins University, as described previously [ 36 ] by Dr. Akira Sawa’s group. Human lymphoblasts were grown in RPMI 1640 media containing 15% fetal bovine serum (FBS) and an antibiotic mixture.…”

Section: Methodsmentioning

confidence: 99%

“…This study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Johns Hopkins University School of Medicine (Project identification code, NA-00037204). All human subjects gave their informed consent for inclusion before they participated in the study as described in Dr. Sawa’s previous paper [ 36 ]. In this study, we only used lymphoblasts (without the identification information of human subjects) to perform in vitro studies.…”

Section: Methodsmentioning

confidence: 99%

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A LRRK2 GTP Binding Inhibitor, 68, Reduces LPS-Induced Signaling Events and TNF-α Release in Human Lymphoblasts

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et al. 2021

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Mutations in the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson’s disease (PD) and contribute to sporadic PD. Common genetic variation in LRRK2 modifies susceptibility to immunological disorders including Crohn’s disease and leprosy. Previous studies have reported that LRRK2 is expressed in B lymphocytes and macrophages, suggesting a role for LRRK2 in immunological functions. In this study, we characterized the LRRK2 protein expression and phosphorylation using human lymphoblasts. Lipopolysaccharide (LPS), a proinflammatory agent, induced the increase of LRRK2 expression and kinase activities in human lymphoblasts in a time-dependent manner. Moreover, LPS activated the Toll-like receptor (TLR) signaling pathway, increased TRAF6/LRRK2 interaction, and elevated the phosphorylation levels of MAPK (JNK1/2, p38, and ERK1/2) and IkBα. Treatment with LRRK2 inhibitor 68 reduced LPS-induced TRAF6/LRRK2 interaction and MAPK and IkBα phosphorylation, thereby reducing TNF-α secretion. These results indicate that LRRK2 is actively involved in proinflammatory responses in human lymphoblasts, and inhibition of GTP binding by 68 results in an anti-inflammation effect against proinflammatory stimuli. These findings not only provide novel insights into the mechanisms of LRRK2-linked immune and inflammatory responses in B-cell-like lymphoblasts, but also suggest that 68 may also have potential therapeutic value for LRRK2-linked immunological disorders.

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“…Because the stress-response system of Fig. 1 a is implicated in the pathology of schizophrenia [ [13] , [14] , [15] , [16] , [17] ], we also focused on a comparison between persons diagnosed with schizophrenia (SCZ; N=10) and healthy controls (HC; N=10) [ 18 ]. In that study, we employed the Trier Social Stress Test (TSST) protocol that is one of the most widely used laboratory stress tests to examine the effects of acute stress on psychological and physiological functioning in humans [ [19] , [20] , [21] , [22] , [23] , [24] , [25] ].…”

Section: Introductionmentioning

confidence: 99%

Association of acute psychosocial stress with oxidative stress: Evidence from serum analysis

et al. 2021

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Growing evidence implicates an association between psychosocial stress and oxidative stress (OxSt) although there are not yet reliable biomarkers to study this association. We used a Trier Social Stress Test (TSST) and compared the response of a healthy control group (HC; N=10) against the response of a schizophrenia group (SCZ; N=10) that is expected to have higher levels of OxSt. Because our previous study showed inconsistent changes in conventional molecular markers for stress responses in the neuroendocrine and immune systems, we analyzed the same serum samples using a separate reducing capacity assay that provides a more global measurement of OxSt. This assay uses the moderately strong oxidizing agent iridium (Ir) to probe a sample's reducing capacity. Specifically, we characterized OxSt by this Ir-reducing capacity assay (Ir-RCA) using two measurement modalities (optical and electrochemical) and we tuned this assay by imposing an input voltage sequence that generates multiple output metrics for data-driven analysis. We defined five OxSt metrics (one optical and four electrochemical metrics) and showed: (i) internal consistency among each metric in the measurements of all 40 samples (baseline and post TSST for N=20); (ii) all five metrics were consistent with expectations of higher levels of OxSt for the SCZ group (three individual metrics showed statistically significant differences); and (iii) all five metrics showed higher levels of OxSt Post-TSST (one metric showed statistically significant difference). Using multivariant analysis, we showed that combinations of OxSt metrics could discern statistically significant increases in OxSt for both the SCZ and HC groups 90 min after the imposed acute psychosocial stress.

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A multimodal approach to studying the relationship between peripheral glutathione, brain glutamate, and cognition in health and in schizophrenia

Cited by 37 publications

References 61 publications

Determinants of Schizophrenia Endophenotypes Based on Neuroimaging and Biochemical Parameters

Determinants of Schizophrenia Endophenotypes Based on Neuroimaging and Biochemical Parameters

A LRRK2 GTP Binding Inhibitor, 68, Reduces LPS-Induced Signaling Events and TNF-α Release in Human Lymphoblasts

Association of acute psychosocial stress with oxidative stress: Evidence from serum analysis

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