Effects of Epacadostat on Brain Extracellular Fluid Concentrations of Serotonin—an Intracerebral Microdialysis Study in Sprague-Dawley Rats

Zhang, Yan; Bowman, Kevin; Maleski, Janet; Diamond, Sharon; Yeleswaram, Swamy

doi:10.1124/dmd.118.084053

Cited by 3 publications

(6 citation statements)

References 18 publications

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“…The decrease of 5-HT level in peripheral blood can indirectly reflect the level of 5-HT, which may be closely related to indoleamine 2,3-dioxygenase 1 (IDO1) and metabolism of tryptophan. 39 Our results demonstrated that the level of 5-HT in serum of MDD patients was significantly decreased, and the ReHo in BA11 and BA9 regions of PFC was decreased, which was consistent with the reported study. 40 Second, we found that serum 5-HT level and ReHo value of BA11 and BA9 were negatively correlated with HAMD and SDS score.…”

Section: Discussionsupporting

confidence: 93%

“…It cannot pass directly through the blood–brain barrier unless with the help of ryptophan and transporters. The decrease of 5‐HT level in peripheral blood can indirectly reflect the level of 5‐HT, which may be closely related to indoleamine 2,3‐dioxygenase 1 (IDO1) and metabolism of tryptophan 39 . Our results demonstrated that the level of 5‐HT in serum of MDD patients was significantly decreased, and the ReHo in BA11 and BA9 regions of PFC was decreased, which was consistent with the reported study 40 .…”

Section: Discussionsupporting

confidence: 91%

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RETRACTED; Combined rs‐fMRI study on brain functional imaging and mechanism of RAGE‐DAMPs of depression: Evidence from MDD patients to chronic stress‐induced depression models in cynomolgus monkeys and mice

Yan

Xie

et al. 2021

Clinical & Translational Med

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More and more evidence show that major depressive disorder (MDD) is closely related to inflammation caused by chronic stress, which seriously affects human physical and mental health. However, the inflammatory mechanism of depression and its effect on brain function have not been clarified. Based on resting‐state functional magnetic resonance imaging (rs‐fMRI), we investigated change of brain functional imaging and the inflammatory mechanism of damage‐related molecular patterns (DAMPs)—receptor of advanced glycation protein end product (RAGE) in MDD patients and depressive‐like cynomolgus monkeys and mice models induced by chronic stress. The regional homogeneity (ReHo) and functional connectivity (FC) were analyzed using MATLAB and SPM12 software. We detected the expression of DAMPs‐RAGE pathway‐related proteins and mRNA in MDD peripheral blood and in serum and brain tissue of cynomolgus monkeys and mice. Meanwhile, RAGE gene knockout mice, RAGE inhibitor, and overexpression of AVV9 RAGE adeno‐associated virus were used to verify that RAGE is a reliable potential biomarker of depression. The results showed that the ReHo value of prefrontal cortex (PFC) in MDD patients and depressive‐like cynomolgus monkeys was decreased. Then, the PFC was used as a seed point, the FC of ipsilateral and contralateral PFC were weakened in depressive‐like mice. At the same time, qPCR showed that RAGE and HMGB1 mRNA were upregulated and S100β mRNA was downregulated. The expression of RAGE‐related inflammatory protein in PFC of depressive‐like monkeys and mice were consistent with that in peripheral blood of MDD patients. Moreover, the results were confirmed in RAGE –/– mice, injection of FPS‐ZM1, and overexpression of AAV9 RAGE in mice. To sum up, our findings enhance the evidence that chronic stress‐PFC‐RAGE are associated with depression. These results attempt to establish the links between brain functional imaging, and molecular targets among different species will help to reveal the pathophysiological mechanism of depression from multiple perspectives.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

RETRACTED; Combined rs‐fMRI study on brain functional imaging and mechanism of RAGE‐DAMPs of depression: Evidence from MDD patients to chronic stress‐induced depression models in cynomolgus monkeys and mice

Yan

Xie

et al. 2021

Clinical & Translational Med

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“…A possible explanation for the increased synthesis of serotonin in the TME is that inhibition of IDO1 may elevate Trp concentration systemically or locally and shunt catabolism toward the serotonin pathway. However, across 6 studies of EPA monotherapy and 22 studies of EPA in combination with other agents (a total of 2490 subjects), only four cases of suspected “serotonin syndrome” have been reported ( 35 ). Moreover, the effect of EPA on serotonin amounts in the brain extracellular fluid was minimal in rats ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, across 6 studies of EPA monotherapy and 22 studies of EPA in combination with other agents (a total of 2490 subjects), only four cases of suspected “serotonin syndrome” have been reported ( 35 ). Moreover, the effect of EPA on serotonin amounts in the brain extracellular fluid was minimal in rats ( 35 ). In the current study, we evaluated the impact of EPA on serotonin in the human TME.…”

Section: Discussionmentioning

confidence: 99%

Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses

et al. 2022

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To uncover underlying mechanisms associated with failure of indoleamine 2,3-dioxygenase 1 (IDO1) blockade in clinical trials, we conducted a pilot, window-of-opportunity clinical study in 17 patients with newly diagnosed advanced high-grade serous ovarian cancer before their standard tumor debulking surgery. Patients were treated with the IDO1 inhibitor epacadostat, and immunologic, transcriptomic, and metabolomic characterization of the tumor microenvironment was undertaken in baseline and posttreatment tumor biopsies. IDO1 inhibition resulted in efficient blockade of the kynurenine pathway of tryptophan degradation and was accompanied by a metabolic adaptation that shunted tryptophan catabolism toward the serotonin pathway. This resulted in elevated nicotinamide adenine dinucleotide (NAD + ), which reduced T cell proliferation and function. Because NAD + metabolites could be ligands for purinergic receptors, we investigated the impact of blocking purinergic receptors in the presence or absence of NAD + on T cell proliferation and function in our mouse model. We demonstrated that A2a and A2b purinergic receptor antagonists, SCH58261 or PSB1115, respectively, rescued NAD + -mediated suppression of T cell proliferation and function. Combining IDO1 inhibition and A2a/A2b receptor blockade improved survival and boosted the antitumor immune signature in mice with IDO1 overexpressing ovarian cancer. These findings elucidate the downstream adaptive metabolic consequences of IDO1 blockade in ovarian cancers that may undermine antitumor T cell responses in the tumor microenvironment.

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“…This degrader was based on the IDO1 inhibitor epacadostat, a holo-IDO1 inhibitor, and displayed a DC 50 = 2.8 μM that is significantly weaker than the IDO1-PROTAC, NU223612 , described here. There was also no in vivo evidence of IDO1-PROTAC effects combined with the known inability for epacadostat to enter the brain . Herein, we report the development of an IDO1-PROTAC library utilizing the existing BMS-986205 ( NU223618 ) apo-IDO1 inhibitor.…”

Section: Discussionmentioning

confidence: 99%

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

et al. 2022

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Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer. Here, we developed and characterized proteolysis targeting chimeras (PROTACs) that degrade the IDO1 protein. IDO1-PROTACs were tested for their effects on IDO1 enzyme and non-enzyme activities. After screening a library of IDO1-PROTAC derivatives, a compound was identified that potently degraded the IDO1 protein through cereblon-mediated proteasomal degradation. The IDO1-PROTAC: (i) inhibited IDO1 enzyme activity and IDO1-mediated NF-κB phosphorylation in cultured human glioblastoma (GBM) cells, (ii) degraded the IDO1 protein within intracranial brain tumors in vivo, and (iii) mediated a survival benefit in mice with well-established brain tumors. This study identified and characterized a new IDO1 protein degrader with therapeutic potential for patients with glioblastoma.

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Effects of Epacadostat on Brain Extracellular Fluid Concentrations of Serotonin—an Intracerebral Microdialysis Study in Sprague-Dawley Rats

Cited by 3 publications

References 18 publications

RETRACTED; Combined rs‐fMRI study on brain functional imaging and mechanism of RAGE‐DAMPs of depression: Evidence from MDD patients to chronic stress‐induced depression models in cynomolgus monkeys and mice

RETRACTED; Combined rs‐fMRI study on brain functional imaging and mechanism of RAGE‐DAMPs of depression: Evidence from MDD patients to chronic stress‐induced depression models in cynomolgus monkeys and mice

Metabolic adaptation of ovarian tumors in patients treated with an IDO1 inhibitor constrains antitumor immune responses

Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma

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