<scp>G</scp>enetic deletion of x<scp>CT</scp> attenuates peripheral and central inflammation and mitigates <scp>LPS</scp>‐induced sickness and depressive‐like behavior in mice

Albertini, Giulia; Deneyer, Lauren; Ottestad-Hansen, Sigrid; Zhou, Yun; Ates, Gamze; Walrave, Laura; Demuyser, Thomas; Bentea, Eduard; Sato, Hiroki; Bundel, Dimitri De; Danbolt, Niels Christian; Massie, Ann; Smolders, Ilse Julia

doi:10.1002/glia.23343

Cited by 27 publications

(23 citation statements)

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“…Inhibition of system x c − not only has anxiolytic, but also antidepressant potential, as evidenced by naive as well as LPS-injected xCT −/- mice showing a decreased immobility-time in the MTS and in the forced swim test ( Bentea et al, 2015 ; Albertini et al, 2018 ). Moreover, tumor-inoculated BALB/c mice showed reduced tumor-associated depressive-like behavior after chronic inhibition of system x c − using SAS ( Nashed et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, system x c − has been reported to drive neuroinflammation. Genetic xCT deletion shifts microglial cells towards a more anti-inflammatory, neuroprotective profile in a model for amyotrophic lateral sclerosis ( Mesci et al, 2015 ) and attenuates the (neuro)inflammatory response after a systemic injection of a sublethal dose of lipopolysaccharide (LPS) ( Albertini et al, 2018 ). Accordingly, xCT −/− mice have been shown to be protected in models for several neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

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Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

et al. 2021

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Despite ample evidence for the therapeutic potential of inhibition of the cystine/glutamate antiporter system xc− in neurological disorders and in cancer, none of the proposed inhibitors is selective. In this context, a lot of research has been performed using the EMA- and FDA-approved drug sulfasalazine (SAS). Even though this molecule is already on the market for decades as an anti-inflammatory drug, serious side effects due to its use have been reported. Whereas for the treatment of the main indications, SAS needs to be cleaved in the intestine into the anti-inflammatory compound mesalazine, it needs to reach the systemic circulation in its intact form to allow inhibition of system xc−. The higher plasma levels of intact SAS (or its metabolites) might induce adverse effects, independent of its action on system xc−. Some of these effects have however been attributed to system xc− inhibition, calling into question the safety of targeting system xc−. In this study we chronically treated system xc− - deficient mice and their wildtype littermates with two different doses of SAS (160 mg/kg twice daily or 320 mg/kg once daily, i.p.) and studied some of the adverse effects that were previously reported. SAS had a negative impact on the survival rate, the body weight, the thermoregulation and/or stress reaction of mice of both genotypes, and thus independent of its inhibitory action on system xc−. While SAS decreased the total distance travelled in the open-field test the first time the mice encountered the test, it did not influence this parameter on the long-term and it did not induce other behavioral changes such as anxiety- or depressive-like behavior. Finally, no major histological abnormalities were observed in the spinal cord. To conclude, we were unable to identify any undesirable system xc−-dependent effect of chronic administration of SAS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

et al. 2021

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“…Depression is a multifactorial disease which is regulated by genetic and environmental factors. As a systematic disease, it is a complex phenotype associated abnormalities ranging from central nervous system to many peripheral systems [30–32]. As an important component of the neuroendocrine system, HPA axis is a complex collection of direct influences and feedback interactions, and controls the response to stress and regulates many body processes including digestion, the immune system, mood and emotion, sexuality, energy storage and expenditure [33, 34].…”

Section: Discussionmentioning

confidence: 99%

Metabolomic signatures and microbial community profiling of depressive rat model induced by adrenocorticotrophic hormone

Song

et al. 2019

J Transl Med

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Background Adrenocorticotrophic hormone (ACTH)-treatment rat model has been utilized as a widely accepted model of treatment-resistant depression. Metabolomic signatures represent the pathophysiological phenotype of diseases. Recent studies in gut microbiota and metabolomics analysis revealed the dramatic role of microbiome in psychoneurological system diseases, but still, the mechanisms underlying gut microbiome–host interaction remain unclear. Methods Male Wistar rats were s.c . injection of ACTH fragment 1–24 for 14 days to induce treatment-resistant depression. Depression-related behavioral tests, analysis of serum monoamine neurotransmitters and hypothalamic–pituitary–adrenal (HPA) axis-related hormones were determined for assessment of ACTH-induced depression rat model. A gas chromatography-time-of-flight mass spectrometer based urinary metabolomic signatures integrated 16S rRNA sequence analysis based gut microbial profiling was performed, as well as Spearman’s correlation coefficient analysis was used to manifest the covariation between the differential urinary metabolites and gut microbiota of genus level. Results Chronic injection of ACTH-induced depression-like phenotype (increased immobility time in forced swimming test and tail suspension test) was accompanied by peripheral serotonin down-regulation and HPA axis overactivation (ACTH and corticosterone up-regulation). Urinary metabolomics analysis indicated that pyruvic acid, l -threonine, mannitol, d -gluconic acid, 4-hydroxybenzoic acid, d -arabitol, myo-inositol and ascorbic acid levels were reduced in ACTH-treated rats’ urine, while hippurate level was elevated. In addition, microbial community profiling revealed bacterial enrichment (e.g. Ruminococcus , Klebsiella ) and reduction (e.g. Akkermansia , Lactobacillus ) in the ACTH-induced depression rat model. Correlation analysis showed that Akkermansia and Lactobacillus were closely relevant to metabolites myo-inositol and hippurate, which were included in host inositol phosphate metabolism, and phenylalanine, tyrosine and tryptophan biosynthesis. Conclusions Depression rat model induced by ACTH is associated with disturbance of pyruvate metabolism, ascorbate and aldarate metabolism, inositol phosphate metabolism, glycine, serine and threonine metabolism, and glycolysis or gluconeogenesis, as well as changes in microbial community structure. Gut microbiota may participate in the mediation of systemic metabolomic changes in ACTH-induced depression model. Therefore, integrated metabolomic signatures and gut microbial community profiling would provide a basis for further studies on the pathogenesis of depression. Elect...

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“…3). Since the expression of xCT in astrocytes in LPS or 6-hydroxydopamine-treated animal model has been reported 36,37 , we also investigated the expression of xCT in astrocytes. The expression of xCT in astrocytes was also detected in later phase (Fig.…”

Section: Discussionmentioning

confidence: 99%

System xc− in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness

Kitagawa

Nakaso

Horikoshi

et al. 2019

Sci Rep

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Post-septic neurological and psychiatric illness (PSNPI) including dementia and depression may be observed after sepsis. However, the etiology of PSNPI and therapeutic treatment of PSNPI are unclear. We show that glutamate produced from microglia through the activity of system x c − plays a role in PSNPI. We established a mouse model of PSNPI by lipopolysaccharide (LPS) treatment that shows a disturbance of short/working memory and depression-like hypoactivity. Glutamate receptor antagonists (MK801 and DNQX) reduced these phenotypes, and isolated microglia from LPS-treated mice released abundant glutamate. We identified system x c − as a source of the extracellular glutamate. xCT, a component of system x c − , was induced and expressed in microglia after LPS treatment. In xCT knockout mice, PSNPI were decreased compared to those in wildtype mice. Moreover, TNF-α and IL-1β expression in wildtype mice was increased after LPS treatment, but inhibited in xCT knockout mice. Thus, system x c − in microglia may be a therapeutic target for PSNPI. The administration of sulfasalazine, an inhibitor of xCT, in symptomatic and post-symptomatic mice improved PSNPI. Our results suggest that glutamate released from microglia through system x c − plays a critical role in the manifestations of PSNPI and that system x c − may be a therapeutic target for PSNPI.

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Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS‐induced sickness and depressive‐like behavior in mice

Cited by 27 publications

References 62 publications

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

Chronic Sulfasalazine Treatment in Mice Induces System xc− - Independent Adverse Effects

Metabolomic signatures and microbial community profiling of depressive rat model induced by adrenocorticotrophic hormone

System xc− in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness

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