Kynurenines, Gender and Neuroinflammation; Showcase Schizophrenia

Bie, Josien de; Lim, Chai K.; Guillemin, Gilles J.

doi:10.1007/s12640-016-9641-5

Cited by 18 publications

(19 citation statements)

References 66 publications

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“…These effects could also play a role in enhanced inflammation with sleep-loss 54 , and contribute to misbalance in the KP in health and disease processes 12 , 55 . Importantly, our present data draw additional attention to sex as an important biological variable in KP studies 12 , 13 , 56 , 57 , and introduce a novel interplay between the HPA responses to sleep deprivation and downstream KP metabolism. The specific mechanisms governing the causes and physiological ramifications of these responses will be further explored and clarified in future studies.…”

Section: Discussionmentioning

confidence: 67%

Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats

Baratta

Buck

Buchla

et al. 2018

Sci Rep

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Inadequate sleep is a prevalent problem within our society that can result in cognitive dysfunction. Elevations in kynurenic acid (KYNA), a metabolite of the kynurenine pathway (KP) of tryptophan degradation known to impact cognition, in the brain may constitute a molecular link between sleep loss and cognitive impairment. To test this hypothesis, we investigated the impact of 6 hours of sleep deprivation on memory and KP metabolism (brain and plasma) in male and female rats. Sleep-deprived males were impaired in a contextual memory paradigm, and both sexes were impaired in a recognition memory paradigm. After sleep deprivation, hippocampal KYNA levels increased significantly only in males. The response in hippocampal KYNA levels to sleep loss was suppressed in gonadectomized males, delineating a role of circulating gonadal hormones. Circulating corticosterone, which has previously been linked to KP metabolism, correlated negatively with hippocampal KYNA in sleep-deprived females, however the relationship was not significant in male animals. Taken together, our study introduces striking sex differences in brain KYNA formation and circulating corticosterone in response to sleep deprivation. Relating these findings to sex differences in cognitive outcomes after sleep deprivation may further advance the development of novel therapeutic agents to overcome sleep loss-induced cognitive dysfunction.

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Section: Discussionmentioning

confidence: 67%

Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats

Baratta

Buck

Buchla

et al. 2018

Sci Rep

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“…Such antagonism caused Th1 effector cells to produce less IL-2 and IFN-γ, whereas it affected Th2 cells to produce more interleukin (IL-) 10 and IL-13. As proposed by a recent review, this interaction suggests a kynurenine pathway-immune feedback loop that may be disrupted in schizophrenia [81]. We suggest that the competition between the pro-inflammatory QUIN (an NMDA receptor agonist produced by microglia) and the immunosuppressant KYNA (an NMDA receptor antagonist) may determine the inflammatory status and/or the clinical picture of certain psychiatric diseases related with neuroinflammation.…”

Section: Kynurenine Pathway and Inflammationmentioning

confidence: 60%

“…However, a recent review postulated that in some cases, kynurenine pathway metabolism is likely to be rerouted from KYNA to QUIN production in brain tissue in states of inflammation with microglial activation and macrophage infiltration [81]. Microglial activation was only found in a small percentage of schizophrenia patients and seems to be more pronounced in chronic schizophrenia patients [79].…”

Section: Cellular Substrates Regulating Interactions Between Kynurenimentioning

confidence: 99%

Effects of inflammation on the kynurenine pathway in schizophrenia — a systematic review

Pedraz-Petrozzi

Elyamany

Rummel

et al. 2020

J Neuroinflammation

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Background: In the last decade, there has been growing evidence that an interaction exists between inflammation and the kynurenine pathway in schizophrenia. Additionally, many authors found microglial activation in cases of schizophrenia due to inflammatory mechanisms related mostly to an increase of pro-inflammatory cytokines. In order to gain new insights into the pathophysiology of schizophrenia, it is important to incorporate the latest published evidence concerning inflammatory mechanisms and kynurenine metabolism. This systematic review aims to collect reliable recent findings within the last decade supporting such a theory. Methods: A structured search of electronic databases was conducted for publications between 2008 and 2018 to identify eligible studies investigating patients with schizophrenia/psychosis and the relationship between inflammation and kynurenine pathway. Applicable studies were systematically scored using the NIH Quality Assessment Tools. Two researchers independently extracted data on diagnosis (psychosis/schizophrenia), inflammation, and kynurenine/tryptophan metabolites. Results: Ten eligible articles were identified where seven studies assessed blood samples and three assessed cerebrospinal fluid in schizophrenic patients. Of these articles: Four investigated the relationship between immunoglobulins and the kynurenine pathway and found correlations between IgA-mediated responses and levels of tryptophan metabolites (i.e., kynurenine pathway). Five examined the correlation between cytokines and kynurenine metabolites where three showed a relationship between elevated IL-6, TNF-α concentrations, and the kynurenine pathway. Only one study discovered correlations between IL-8 and the kynurenine pathway. Two studies showed correlations with lower concentrations of IL-4 and the kynurenine pathway. Moreover, this systematic review did not find a significant correlation between CRP (n = 1 study), IFN-γ (n = 3 studies), and the kynurenine pathway in schizophrenia.

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“…Further, the current study observed a strong interaction effect between NAL and gender on KP metabolites that may be attributed to the influence of sex hormones on the enzymes involved within the KP 35 . For example, testosterone has been reported to have an inhibitory effect on the KP (via TDO/IDO1 by reducing NAD production in favour of KYNA formation) 36 , 37 while oestrogen has been reported to induce (via TDO/IDO1 favouring NAD + production, precluding KYNA formation) 38 as well as inhibit the KP (by inhibiting immune system activation) 39 . However, the incidence of ageing-related hormonal changes prevalent within the KARVIAH cohort and the complex interplay and feedback mechanisms between the various KP metabolites also need to be considered with regard to observations in this study.…”

Section: Discussionmentioning

confidence: 99%

Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load: A pilot study

Chatterjee

Goozee

Lim

et al. 2018

Sci Rep

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The kynurenine pathway (KP) is dysregulated in neuroinflammatory diseases including Alzheimer’s disease (AD), however has not been investigated in preclinical AD characterized by high neocortical amyloid-β load (NAL), prior to cognitive impairment. Serum KP metabolites were measured in the cognitively normal KARVIAH cohort. Participants, aged 65–90 y, were categorised into NAL+ (n = 35) and NAL− (n = 65) using a standard uptake value ratio cut-off = 1.35. Employing linear models adjusting for age and APOEε4, higher kynurenine and anthranilic acid (AA) in NAL+ versus NAL− participants were observed in females (kynurenine, p = 0.004; AA, p = 0.001) but not males (NALxGender, p = 0.001, 0.038, respectively). To evaluate the predictive potential of kynurenine or/and AA for NAL+ in females, logistic regressions with NAL+/− as outcome were carried out. After age and APOEε4 adjustment, kynurenine and AA were individually and jointly significant predictors (p = 0.007, 0.005, 0.0004, respectively). Areas under the receiver operating characteristic curves were 0.794 using age and APOEε4 as predictors, and 0.844, 0.866 and 0.871 when kynurenine, AA and both were added. Findings from the current study exhibit increased KP activation in NAL+ females and highlight the predictive potential of KP metabolites, AA and kynurenine, for NAL+. Additionally, the current study also provides insight into he influence of gender in AD pathogenesis.

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Kynurenines, Gender and Neuroinflammation; Showcase Schizophrenia

Cited by 18 publications

References 66 publications

Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats

Sex Differences in Hippocampal Memory and Kynurenic Acid Formation Following Acute Sleep Deprivation in Rats

Effects of inflammation on the kynurenine pathway in schizophrenia — a systematic review

Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load: A pilot study

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