Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons

Linderholm, Klas R.; Tufvesson-Alm, Maximilian; Larsson, Magnus; Olsson, Sara K.; Goiny, Michel; Hajós, Mihály; Erhardt, Sophie; Engberg, Göran

doi:10.1016/j.neuropharm.2015.10.028

Cited by 35 publications

(29 citation statements)

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“…Decreased concentration of KYNA may be important not only for cognition but also for psychosis because increased KYNA concentration may be associated with psychosis [103-105]. Furthermore, inhibition of kynurenine aminotransferase II was associated with a marked reduction in dopamine firing activity in the ventral tegmental area [106]. KP modulations may be potential targets of novel antipsychotics [107].…”

Section: Kynurenine Pathwaymentioning

confidence: 99%

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

Koola¹

2018

Complex Psychiatry

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Schizophrenia is, in part, a cognitive illness. There are no approved medications for cognitive impairments associated with schizophrenia (CIAS) and primary negative symptoms. Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine (α-7nACh) and N-methyl-D-aspartate (NMDA) receptors, kynurenic acid (KYNA), and mismatch negativity have been implicated in the pathophysiology of CIAS and negative symptoms. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is a noncompetitive NMDA receptor antagonist. Galantamine and memantine alone and in combination were effective for cognition in animals and people with Alzheimer’s disease. The objective of this article is to critically dissect the published randomized controlled trials with galantamine and memantine for CIAS to highlight the efficacy signal. These studies may have failed to detect a clinically meaningful efficacy signal due to limitations, methodological issues, and possible medication nonadherence. There is evidence from a small open-label study that the galantamine-memantine combination may be effective for CIAS with kynurenine pathway metabolites as biomarkers to detect the severity of cognitive impairments. Given that there are no available treatments for cognitive impairments and primary negative symptoms in schizophrenia, testing of this “five-pronged strategy” (quintuple hypotheses: dopamine, nicotinic-cholinergic, glutamatergic/NMDA, GABA, and KYNA) is a “low-risk high-gain” approach that could be a major breakthrough in the field. The galantamine-memantine combination has the potential to treat positive, cognitive, and negative symptoms, and targeting the quintuple hypotheses concurrently may lead to a major scientific advancement – from antipsychotic treatment to antischizophrenia treatment.

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Section: Kynurenine Pathwaymentioning

confidence: 99%

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

Koola¹

2018

Complex Psychiatry

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“…Based on previous suggestions that chronic excessive alcohol consumption leads to activation of the immune system (92) involving TLR4 (100), it is tempting to suggest that the LPS translocated from the gut following CI EtOH could produce a neuroinflammatory response, leading to the induction of IDO activity, which results in the observed increase in brain Kyn levels. Supporting this, preclinical studies showed that peripheral LPS injection produces an increase in central proinflammatory cytokines and IDO expression (101–103) as well as in Kyn concentration in brain tissue (104).…”

Section: Discussionmentioning

confidence: 86%

Changes in brain kynurenine levels via gut microbiota and gut‐barrier disruption induced by chronic ethanol exposure in mice

et al. 2019

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Inflammatory processes have been shown to modify tryptophan (Trp) metabolism. Gut microbiota appears to play a significant role in the induction of peripheral and central inflammation. Ethanol (EtOH) exposure alters gut permeability, but its effects on Trp metabolism and the involvement of gut microbiota have not been studied. We analyzed several parameters of gut‐barrier and of peripheral and central Trp metabolism following 2 different EtOH consumption patterns in mice, the binge model, drinking in the dark (DID), and the chronic intermittent (CI) consumption paradigm. Antibiotic treatment was used to evaluate gut microbiota involvement in the CI model. Mice exposed to CI EtOH intake, but not DID, show bacterial translocation and increased plasma LPS immediately after EtOH removal. Gut‐barrier permeability to FITC‐dextran is increased by CI, and, furthermore, intestinal epithelial tight‐junction (TJ) disruption is observed (decreased expression of zonula occludens 1 and occludin) associated with increased matrix metalloproteinase (MMP)‐9 activity and iNOS expression. CI EtOH, but not DID, increases kynurenine (Kyn) levels in plasma and limbic forebrain. Intestinal bacterial decontamination prevents the LPS increase but not the permeability to FITC‐dextran, TJ disruption, or the increase in MMP‐9 activity and iNOS expression. Although plasma Kyn levels are not affected by antibiotic treatment, the elevation of Kyn in brain is prevented, pointing to an involvement of microbiota in CI EtOH‐induced changes in brain Trp metabolism. Additionally, CI EtOH produces depressive‐like symptoms of anhedonia, which are prevented by the antibiotic treatment thus pointing to an association between anhedonia and the increase in brain Kyn and to the involvement of gut microbiota.—Giménez‐Gómez, P., Pérez‐Hernández, M., O'Shea, E., Caso, J. R., Martín‐Hernández, D., Cervera, L. A., Centelles. M. L. G.‐L., Gutiérrez‐Lopez, M. D., Colado, M. I. Changes in brain kynurenine levels via gut microbiota and gut‐barrier disruption induced by chronic ethanol exposure in mice. FASEB J. 33, 12900–12914 (2019). http://www.fasebj.org

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“…The dose and route for PF‐04859989 administration were chosen based on previous publication (Linderholm et. al., ). Neurological function was evaluated at 24 hr after SBI after which brain samples were collected for western blot.…”

Section: Methodsmentioning

confidence: 97%

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model

Zakhary

Sherchan

et al. 2019

J of Neuroscience Research

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Neurosurgical procedures result in surgically induced brain injury (SBI) that causes postoperative complications including brain edema and neuronal apoptosis in the surrounding brain tissue. SBI leads to the release of cytokines that indirectly cause the stimulation of kynurenine 3‐monooxygenase (KMO) and the release of neurotoxic quinolinic acid (QUIN). This study tested a KMO inhibitor, RO 61‐8048, to prevent postoperative brain edema and consequent neuronal apoptosis in an in vivo model of SBI. A rodent model of SBI was utilized which involves partial resection of the right frontal lobe. A total of 127 Sprague‐Dawley male rats (weight 275–325 g) were randomly divided into the following groups: Sham surgical group, SBI, SBI + DMSO, SBI + RO 61‐8048 (10 mg/kg), SBI + RO 61‐8048 (40 mg/kg), and SBI + RO 61‐8048 (40 mg/kg) + KAT II inhibitor PF‐04859989 (5 mg/kg). RO 61‐8048 was administered by intraperitoneal injection after SBI. Postoperative assessment at different time points included brain water content (brain edema), neurological scoring, and western blot. SBI increased brain water content (ipsilateral frontal lobe), decreased neurological function, and increased apoptotic markers compared with sham animals. Treatment with RO 61‐8048 (40 mg/kg) reduced brain water content and improved long‐term neurological function after SBI. RO 61‐8048 increased the expression of kynurenic acid while reducing QUIN and apoptotic markers in the surrounding brain tissue after SBI. These neuroprotective effects were reversed by PF‐04859989. This study suggests KMO inhibition via RO 61‐8048 as a potential postoperative therapy following neurosurgical procedures.

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Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons

Cited by 35 publications

References 50 publications

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

Changes in brain kynurenine levels via gut microbiota and gut‐barrier disruption induced by chronic ethanol exposure in mice

Modification of kynurenine pathway via inhibition of kynurenine hydroxylase attenuates surgical brain injury complications in a male rat model

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