AbstractThe enzyme indoleamine 2,3 dioxygenase 1 (IDO1) catalyzes the rate‐limiting step in the kynurenine pathway (KP) which produces both neuroprotective and neurotoxic metabolites. Neuroinflammatory signals produced as a result of pathological conditions can increase production of IDO1 and boost its enzymatic capacity. IDO1 and the KP have been implicated in behavioral recovery after human traumatic brain injury (TBI), but their roles in experimental models of TBI are for the most part unknown. We hypothesized there is an increase in KP activity in the fluid percussion injury (FPI) model of TBI, and that administration of an IDO1 inhibitor will improve neurological recovery. In this study, adult male Sprague Dawley rats were subjected to FPI or sham injury and received twice‐daily oral administration of the IDO1 inhibitor PF‐06840003 (100 mg/kg) or vehicle control. FPI resulted in a significant increase in KP activity, as demonstrated by an increased ratio of kynurenine: tryptophan, in the perilesional neocortex and ipsilateral hippocampus 3 days postinjury (DPI), which normalized by 7 DPI. The increase in KP activity was prevented by PF‐06840003. IDO1 inhibition also improved memory performance as assessed in the Barnes maze and anxiety behaviors as assessed in open field testing in the first 28 DPI. These results suggest increased KP activity after FPI may mediate neurological dysfunction, and IDO1 inhibition should be further investigated as a potential therapeutic target to improve recovery.

01 Oct 2023·Current Alzheimer Research

Development and Optimization of a Target Engagement Model of Brain IDO Inhibition for Alzheimer’s Disease

Article

Author: Weaver, Donald F ; Yang, Seung-Pil ; Lee, Sanghyun ; López Vásquez, Lucía M ; Pasangulapati, Jagadeesh P ; Goodwin-Tindall, Jake ; Reed, Mark A ; Damian, Andreea C ; Stafford, Paul M ; Barden, Christopher J ; Stover, Kurt R

Background:Indoleamine 2,3-dioxygenase (IDO1) inhibition is a promising target as an Alzheimer’s disease (AD) Disease-modifying therapy capable of downregulating immunopathic neuroinflammatory processes.Methods:To aid in the development of IDO inhibitors as potential AD therapeutics, we optimized a lipopolysaccharide (LPS) based mouse model of brain IDO1 inhibition by examining the dosedependent and time-course of the brain kynurenine:tryptophan (K:T) ratio to LPS via intraperitoneal dosing.Results:We determined the optimal LPS dose to increase IDO1 activity in the brain, and the ideal time point to quantify the brain K:T ratio after LPS administration. We then used a brain penetrant tool compound, EOS200271, to validate the model, determine the optimal dosing profile and found that a complete rescue of the K:T ratio was possible with the tool compound.Conclusion:This LPS-based model of IDO1 target engagement is a useful tool that can be used in the development of brain penetrant IDO1 inhibitors for AD. A limitation of the present study is the lack of quantification of potential clinically relevant biomarkers in this model, which could be addressed in future studies.

01 Aug 2021·Cardiovascular ToxicologyQ4 · MEDICINE

RETRACTED ARTICLE: Indoleamine 2,3-Dioxygenase 1 (IDO1) Promotes Cardiac Hypertrophy via a PI3K-AKT-mTOR-Dependent Mechanism

Q4 · MEDICINE

Article

Author: Li, Shuangjia ; Tan, Qingyun ; Li, Yanmei ; Li, Shuang ; Wang, Qingdong ; Gao, Zhanqun ; Wang, Dongwei ; Liu, Yang

AbstractIndoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme for tryptophan metabolism, involved in immune cell differentiation/maturation and cancer biology. IDO1 is also expressed in cardiomyocytes, but its roles in the cardiovascular system are not fully understood. Here, we reported the functions of IDO1 during cardiac hypertrophy. Quantitative real-time PCR and Western blot experiments demonstrated the upregulation of IDO1 mRNA and protein levels in human and hypertrophic mouse hearts, as well as in angiotensin II (Ang II)-induced hypertrophic rat cardiomyocytes. IDO1 activity and metabolite product kynurenine were upregulated in rodent hypertrophic hearts and cardiomyocytes. Inhibition of IDO1 activity with PF-06840003 reduced Ang II-induced cardiac hypertrophy and rescued cardiac function in mice. siRNA-mediated knockdown of Ido1 repressed Ang II-induced growth in cardiomyocyte size and overexpression of hypertrophy-associated genes atrial natriuretic peptide (Anp or Nppa), brain natriuretic peptide (Bnp or Nppb), β-myosin heavy chain (β-Mhc or Myh7). By contrast, adenovirus-mediated rat Ido1 overexpression in cardiomyocytes promoted hypertrophic growth induced by Ang II. Mechanism analysis showed that IDO1 overexpression was associated with PI3K-AKT-mTOR signaling to activate the ribosomal protein S6 kinase 1 (S6K1), which promoted protein synthesis in Ang II-induced hypertrophy of rat cardiomyocytes. Finally, we provided evidence that inhibition of PI3K with pictilisib, AKT with perifosine, or mTOR with rapamycin, blocked the effects of IDO1 on protein synthesis and cardiomyocyte hypertrophy in Ang II-treated cells. Collectively, our findings identify that IDO1 promotes cardiomyocyte hypertrophy partially via PI3K-AKT-mTOR-S6K1 signaling.

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Indication	Highest Phase	Country/Location	Organization	Date
Astrocytoma	Phase 1	US	Pfizer Inc.	09 Sep 2016
Oligodendroglioma	Phase 1	US	Pfizer Inc.	09 Sep 2016
Neoplasms	Preclinical	US	iTeos Therapeutics, Inc.	15 Jul 2016

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT02764151 (Pubmed \| Invest New Drugs) Manual	Phase 1	Recurrent Malignant Glioma	17	PF-06840003	(yclpzfdahu) = 12.5% (1/8) at 500 mg BID qotqpnyyqw (kwmtigkfyy ) View more	Positive	01 Dec 2020
NCT02764151 (CTgov)	Phase 1	Astrocytoma \| Oligodendroglioma	17	PF-06840003 (PF-06840003 125 MG QD)	hiyrbuuwhg(xdipujuakt) = inttyavmhd pylpzgfirr (gowbwnsfma, hsdeyheesx - dqiznzzopb) View more	-	27 Jan 2020
NCT02764151 (CTgov)	Phase 1	Astrocytoma \| Oligodendroglioma	17	PF-06840003 (PF-06840003 250 MG QD)	hiyrbuuwhg(xdipujuakt) = ycwusasysd pylpzgfirr (gowbwnsfma, gaqebpvbog - nrocjknnff) View more	-	27 Jan 2020

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