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. 2023 Jan 17;133(2):e164577.
doi: 10.1172/JCI164577.

The kynurenine pathway implicated in patient delirium: possible indications for indoleamine 2,3 dioxygenase inhibitors

Amy B Heimberger, Rimas V Lukas

The kynurenine pathway implicated in patient delirium: possible indications for indoleamine 2,3 dioxygenase inhibitors

Amy B Heimberger et al. J Clin Invest. .

Abstract

Tryptophan (Trp) metabolism plays a central role in sleep, mood, and immune system regulation. The kynurenine pathway (KP), which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO), which catalyze the conversion of Trp to kynurenine (Kyn), facilitates immune regulation and influences neurocognition. Notably, Kyn metabolites bind the N-methyl-d-aspartate receptor (NMDAR), essential for memory encoding, and in turn, cognition. Aberrant NMDAR activity through agonist binding influences excitability and cell death. In this issue of the JCI, Watne and authors demonstrate that KP pathway end products were elevated in the serum and the cerebrospinal fluid (CSF) of subjects with delirium. This observation provides insight regarding the basis of a variety of commonly observed clinical conditions including sundowning, abnormal sleep-wake cycles in hospitalized patients, neurodegenerative cognitive impairment, radiation-induced cognitive impairment, neurocognitive symptomatology related to COVID-19, and clinical outcomes observed in patients with CNS tumors, such as gliomas.

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Conflict of interest statement

Conflict of interest: ABH serves on the advisory board of Caris Life Sciences and the WCG Oncology Advisory Board; receives royalty and milestone payments from DNAtrix for the licensing of the patent “Biomarkers and combination therapies using oncolytic virus and immunomodulation” (no. 11,065,285); and is supported by research grants from Celularity, Alnylam, and AbbVie. She additionally has active granted patents titled “miRNA for treating cancer and for use with adoptive immunotherapies” (no. 9,675,633) and “Concurrent chemotherapy and immunotherapy” (no. 9,399,662), with a patent pending, “Low intensity ultrasound combination cancer therapies” (international applications PCT/US2022/019435 and US 63/158,642). RVL serves on a scientific advisory board for Merck and speakers’ bureaus for Merck and Novocure and received research support from BMS.

Figures

Figure 1
Figure 1. Trp metabolism and the KP associate with delirium.
Trp can be metabolized into melatonin, serotonin, and Kyn. While the KP plays a role in suppressing the immune system, the QA metabolite also shows evidence of direct neurotoxicity. Both Trp metabolism and KP mechanisms may account for the cognitive impairment that associates with various conditions, including hospitalized delirium (4). Modulating the KP via IDO or TDO inhibition may mitigate negative neurocognitive outcomes associated with a variety of conditions.
See this image and copyright information in PMC

Comment on

  • Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip fracture patients

References

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