Increased breakdown of kynurenine towards its neurotoxic branch in bipolar disorder

Abstract

IntroductionBipolar disorder (BD) is a chronic psychiatric disease which can take most different and unpredictable courses. It is accompanied by unspecific brainstructural changes and cognitive decline. The neurobiological underpinnings of these processes are still unclear. Emerging evidence suggests that tryptophan catabolites (TRYCATs), which involve all metabolites of tryptophan towards the kynurenine (KYN) branch, are involved in the etiology as well as in the course of BD. They are proposed to be mediators of immune-inflammation and neurodegeneration. In this study we measured the levels of KYN and its main catabolites consisting of the neurotoxic hydroxykynurenine (3-HK), the more neuroprotective kynurenic acid (KYNA) and anthranilic acid (AA) and evaluated the ratios between end-products and substrates as proxies for the specific enzymatic activity (3-HK/KYN, KYNA/KYN, AA/KYN) as well as 3-HK/KYNA as a proxy for neurotoxic vs. neuroprotective end-product relation in individuals with BD compared to healthy controls (HC).MethodsWe took peripheral TRYCAT blood levels of 143 euthymic to mild depressive BD patients and 101 HC. For statistical analyses MANCOVA’s controlled for age, sex, body mass index, cardiovascular disease and smoking were performed.ResultsThe levels of KYNA (F = 5,579; p <.05) were reduced in BD compared to HC. The enzymatic activity of the kynurenine-3-monooxygenase (KMO) reflected by the 3-HK/KYN ratio was increased in BD individuals compared to HC (F = 5,394; p <.05). Additionally the ratio of 3-HK/KYNA was increased in individuals with BD compared to healthy controls (F = 11,357; p <.01).DiscussionIn conclusion our findings subserve the concept of KYN -pathway alterations in the pathophysiology of BD. We present evidence of increased breakdown towards the neurotoxic branch in KYN metabolism even in a euthymic to mild depressive state in BD. From literature we know that depression and mania are accompanied by inflammatory states which should be capable to produce an even greater imbalance due to activation of key enzymes in the neurotoxic direction of KYN -conversion. These processes could finally be involved in the development of unspecific brain structural changes and cognitive deficits which are prevalent in BD. Further research should focus on state dependent changes in TRYCATs and its relation to cognition, brain structure and staging parameters.

A mood state‐specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder

“…In line with our findings, studies using peripheral blood samples showed unchanged or decreased KYNA levels in patients with a history of mania or psychosis . Decreased peripheral KYNA levels have also been shown in euthymic and depressive patients with BD . As further discussed below, this discrepancy between central and peripheral results may reflect the difficult passage of KYNA across the blood–brain barrier (BBB).…”

“…8,12,16 Decreased peripheral KYNA levels have also been shown in euthymic and depressive patients with BD. 16,20,21 As further discussed below, this discrepancy between central and peripheral results may reflect the difficult passage of KYNA across the blood-brain barrier (BBB). Secondly, a negative correlation between inflammatory markers and the neuroprotective ratios are found in patients only and appear across all mood states.…”

“…Savitz found a decreased neuroprotective ratio KYNA/QA in patients with bipolar depression, but no differences in absolute kynurenine metabolite levels. Decreased KYNA and increased neurotoxic ratios also have been reported in euthymic to mild depressive patients with BD . A recent meta‐analysis on kynurenine metabolites in mood disorders found no significant differences between patients with BD and controls, but included a limited number of studies with high heterogeneity.…”

“…Decreased KYNA and increased neurotoxic ratios also have been reported in euthymic to mild depressive patients with BD. 16,20,21 A recent meta-analysis on kynurenine metabolites in mood disorders found no significant differences between patients with BD and controls, 22 but included a limited number of studies with high heterogeneity.…”

The Mystery of Chemotherapy Brain: Kynurenines, Tubulin and Biophoton Release

“…Rats receiving intrastriatal injections of quinolinic acid experience alterations of microtubule-associated protein-2 and cytoskeletal disruption (95). Another tryptophan metabolite, 3hydroxykynurenine, can cause hallucinations and is thought to play a role in the development of schizophrenia and bipolar disorder (96,97). High levels of 3-hydroxykynurenine correlate strongly with increased schizophrenic symptoms.…”