Altered kynurenine pathway metabolite levels in toddlers and preschool children with autism spectrum disorder

Bi̇lgi̇ç, Ayhan; Abuşoğlu, Sedat; Çelikkol, Çağla; Oflaz, Mehmet Burhan; Akça, Ömer Faruk; Sivrikaya, Abdullah; Baysal, Tamer; Ünlü, Ali

doi:10.1080/00207454.2020.1841187

Cited by 14 publications

(34 citation statements)

References 49 publications

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“…As TNF and other pro‐inflammatory cytokines can increase indoleamine 2,3‐dioxygenase (IDO), leading to tryptophan being driven down the kynurenine pathway and away from serotonin and melatonin synthesis, 4 it will be important to determine IDO and kynurenine pathway products in correlation with TNF, and aMT6s in future research. Given the alterations in the kynurenine pathway in ASD, 69 and the ability of kynurenine and kynurenic acid to activate the aryl hydrocarbon receptor (AhR), a susceptibility gene for ASD severity, 70 the integration of the kynurenine pathway, AhR, and their impacts on neuronal and immune system function with the immune‐pineal axis will be important to evaluate.…”

Section: Discussionmentioning

confidence: 99%

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances

Cruz‐Machado

Campos

Fadini

et al. 2021

Journal of Pineal Research

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Autism spectrum disorder (ASD) is characterized by persistent alterations in social interactions across multiple contexts, communication deficits, and restricted repetitive behaviors, interests, or activities. 1 This neurodevelopmental condition is four times more frequent in boys than girls, 2 and its susceptibility is attributed to heterogeneous genetic influences and a combination of environmental, autoimmune, metabolic, and inflammatory factors. 3-6 Social communication impairment in ASD is linked to the desynchronization of physiological and behavioral responses to environmental cues. 7,8 The night-time release of pineal melatonin significantly modulates cells of the peripheral circulation and the cerebrospinal fluid, thereby synchronizing central and peripheral clocks, including the circadian rhythm of the endocrine and

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Section: Discussionmentioning

confidence: 99%

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances

Cruz‐Machado

Campos

Fadini

et al. 2021

Journal of Pineal Research

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“…These are all considered risk factors for ASD [ 204 , 205 , 206 ]. Even though single compound changes of KP are still controversial in each clinical study ( Table 1 ) [ 1 , 2 , 8 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 , 215 , 216 , 217 , 218 , 219 ], it is clear that an abnormal balance of KP metabolites may be associated with adverse fetal neurodevelopment and the pathogenesis of ASD.…”

Section: Perinatal Kp Metabolismmentioning

confidence: 99%

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder

Murakami

Imamura

Kasahara

et al. 2023

Cells

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Several studies show that genetic and environmental factors contribute to the onset and progression of neurodevelopmental disorders. Maternal immune activation (MIA) during gestation is considered one of the major environmental factors driving this process. The kynurenine pathway (KP) is a major route of the essential amino acid L-tryptophan (Trp) catabolism in mammalian cells. Activation of the KP following neuro-inflammation can generate various endogenous neuroactive metabolites that may impact brain functions and behaviors. Additionally, neurotoxic metabolites and excitotoxicity cause long-term changes in the trophic support, glutamatergic system, and synaptic function following KP activation. Therefore, investigating the role of KP metabolites during neurodevelopment will likely promote further understanding of additional pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). In this review, we describe the changes in KP metabolism in the brain during pregnancy and represent how maternal inflammation and genetic factors influence the KP during development. We overview the patients with ASD clinical data and animal models designed to verify the role of perinatal KP elevation in long-lasting biochemical, neuropathological, and behavioral deficits later in life. Our review will help shed light on new therapeutic strategies and interventions targeting the KP for neurodevelopmental disorders.

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“…On the other hand, 3-HAA may have a neuroprotective activity by suppressing the immune and inflammatory activity. 45,51 As a matter of fact, both KYNA and QA are considered relevant modulatory compounds of neuronal circuits, acting in different ways in specific brain areas during the development of CNS, 52 as highlighted by many studies that stressed their function in synaptogenesis. [53][54][55] Noticeably, it was reported that, while KYN pathway may modulate the inflammatory response, inflammatory processes through several cytokines may induce, in a vicious circle, the TRP metabolism through the KYN pathway enhancing IDO and TDO activities.…”

Section: Introductionmentioning

confidence: 99%

“…44 This intermediate is then metabolized by the KYN formamidase into L-KYN, which opens the way to 2 different possible pathways: the so-called "neurotoxic branch" and the "neuroprotective branch." The "neuroprotective branch," via the enzyme KYN aminotransferase (KAT), 33,45 ends with the production of KYNA. 46 KYNA is known to exert a neuroprotective effect in various ways: first, it is an antagonist of N-methyl-D-aspartate (NMDA) receptors, being involved in the modulation of excitotoxicity linked to glutamate transmission.…”

Section: Introductionmentioning

confidence: 99%

“…KYNA is also an antagonist of kainate and α-7 nicotinic acetyl choline receptors. 33,45 Moreover, KYNA can induce the amyloid degrading enzyme, scavenge free radicals, and act as an antioxidant; as an agonist of G-protein coupled receptor (GPR35), KYNA may promote the inhibition of the Ntype Ca channels in the neural tissues and the regulation of the production of cyclic adenosine monophosphate (c-AMP). 33,45 Lastly, KYNA also seems to exert an agonistic activity on the aryl hydrocarbon receptor which interrupts the release of cytokines in macrophages and other kinds of cells.…”

Section: Introductionmentioning

confidence: 99%

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Kynurenine pathway and autism spectrum phenotypes: an investigation among adults with autism spectrum disorder and their first-degree relatives

et al. 2022

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Background Increasing literature highlighted alterations of tryptophan (TRP) metabolism and kynurenine (KYN) pathway in children with autism spectrum disorder (ASD). However, no study specifically focused on adult samples. Meanwhile, several authors stressed the relevance of investigating neurobiological correlates of adult forms of ASD and of those subthreshold ASD manifestations frequently found in relatives of ASD probands, known as broad autism phenotype (BAP). This work aimed to evaluate circulating levels of TRP and metabolites of KYN pathway in a sample of ASD adults, their first-degree relatives and controls (CTLs), investigating also the correlations between biochemical variables’ levels and ASD symptoms. Methods A sample of ASD adults, together with a group of first-degree relatives (BAP group) and unrelated CTLs were assessed by means of psychometric scales. Circulating levels of TRP, KYN, quinolinic acid (QA), and kynurenic acid (KYNA) were assessed in all subjects. Results ASD patients reported significantly higher total scores than the other groups on all psychometric scales. BAP subjects scored significantly higher than CTLs. ASD patients reported significantly lower TRP levels than BAP and CTL groups. Moreover, significantly lower levels of KYNA were reported in both ASD and BAP groups than in CTLs. Specific patterns of associations were found between autism symptoms and biochemical variables. Conclusions Our findings confirm in adult samples the presence of altered TRP metabolism through KYN pathway. The intermediate alterations reported among relatives of ASD patients further stress the presence of a continuum between subthreshold and full-threshold ASD phenotypes also from a biochemical perspective.

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Altered kynurenine pathway metabolite levels in toddlers and preschool children with autism spectrum disorder

Cited by 14 publications

References 49 publications

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances

Disrupted nocturnal melatonin in autism: Association with tumor necrosis factor and sleep disturbances

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder

Kynurenine pathway and autism spectrum phenotypes: an investigation among adults with autism spectrum disorder and their first-degree relatives

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