Are Kynurenines Accomplices or Principal Villains in Dementia? Maintenance of Kynurenine Metabolism

Abstract

Worldwide, 50 million people suffer from dementia, a group of symptoms affecting cognitive and social functions, progressing severely enough to interfere with daily life. Alzheimer's disease (AD) accounts for most of the dementia cases. Pathological and clinical findings have led to proposing several hypotheses of AD pathogenesis, finding a presence of positive feedback loops and additionally observing the disturbance of a branch of tryptophan metabolism, the kynurenine (KYN) pathway. Either causative or resultant of dementia, elevated levels of neurotoxic KYN metabolites are observed, potentially upregulating multiple feedback loops of AD pathogenesis. Memantine is an N-methyl-D-aspartate glutamatergic receptor (NMDAR) antagonist, which belongs to one of only two classes of medications approved for clinical use, but other NMDAR modulators have been explored so far in vain. An endogenous KYN pathway metabolite, kynurenic acid (KYNA), likewise inhibits the excitotoxic NMDAR. Besides its anti-excitotoxicity, KYNA is a multitarget compound that triggers anti-inflammatory and antioxidant activities. Modifying the KYNA level is a potential multitarget strategy to normalize the disturbed KYN pathway and thus to alleviate juxtaposing AD pathogeneses. In this review, the maintenance of KYN metabolism by modifying the level of KYNA is proposed and discussed in search for a novel lead compound against the progression of dementia.

Keywords: Alzheimer’s disease; antioxidant molecules; dementia; kynurenic acid; kynurenines; multitarget agents; neuroprotective agents.

Figure A1

Flow diagram of qualitative synthesis adopted from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

Figure 1

Positive feedback loops of amyloid β hypothesis of Alzheimer’s disease in connection with disturbance of the kynurenine pathway. The amyloid beta (Aβ) cascade, inflammation, tau phosphorylation, and neuroplasticity hypotheses lie in one downward cascade, and the glutamate and calcium hypotheses lie in another branched downward cascade of pathological events leading to dementia. Positive feedback loops are located between inflammation and increased Aβ accumulation, between increased oxidative stress and increased Aβ accumulation, and increased glutamate and decreased cadherin 1 CDh1). Kynurenine (KYN) pathway enzymes are activated by inflammation: the tryptophan dioxygenase (TDO) by the glucocorticoid stress hormone, cortisol and indolamine-2,3-dioxygenase (IDO1) by pro-inflammatory cytokines, interferon (IFN)-α, interleukin (IL)-1β, IFN-γ, and tumor necrosis factor (TNF)-α. IFN-γ also activates formamidase and kynurenine-3-monooxygenase (KMO) in human microglia and macrophages. KYN pathway metabolites, 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) are highly reactive free radicals. In addition, QUIN is an N-methyl-d-aspartate receptor (NMDAR) agonist, causing excitotoxicity. Thus, disturbance of the KYN pathway potentiates inflammation, oxidative free radical attack, and excitotoxic glutamate production (partly adopted from Doig, 2018).

Figure 2

Kynurenine Branch of Tryptophan Metabolism. More than 95% of tryptophan is metabolized in the kynurenine (KYN) pathway except for serotonin metabolism and protein synthesis. Tryptophan (TRP) is converted to KYN by the hepatic rate-limiting tryptophan 2,3-dioxygenase (TDO) and ubiquitous rate-limiting indoleamine 2, 3-oxygenase (IDO) 1, each of which is induced by cortisol, and interferon (IFN)-α, IFN-γ, and tumor necrosis factor (TNF)-α, respectively. KYN is converted to anthranilic acid (AA) by the kynureninase, 3-hydroxy-L-kynurenine (3-HK) is converted by the KYN-3-monooxygenase (KMO), and kynurenic acid (KYNA) is converted by KYN aminotransferases (KATs). KYNA is an antagonist at the NMDA receptor. AA and 3-HK are converted to 3-hydroxyanthranillic acid (3-HAA) and further to picolinic acid (PIC) and quinolinic acid (QUIN). 3-HK and QUIN are agonists at the NMDA receptor. QUIN is converted to nicotinamide adenine dinucleotide (NAD⁺), which is a feedback inhibitor of TDO. Neurotoxic KYNs are shown in orange, and neuromodulartory KYNs are shown in green.

Figure 3

Disturbance of Kynurenine Metabolism Wires Multiple Positive Feedback Loops of Alzheimer’s Disease. Hypotheses of Alzheimer’s disease (AD) pathogenesis derived from anatomical, clinical, and medicinal findings are closely connected to each other, and many positive feedback loops exist to exacerbate the disease. Disturbance of a branch of tryptophan metabolism, kynurenine (KYN) pathway lies in a close connection with various pathogeneses of dementia. Increased neurotoxic KYN metabolites and decreased neuroprotective kynurenic acid (KYNA) may potentiate multiple feedback loops of AD pathogenesis.