A novel kynurenic acid analog (SZR104) inhibits pentylenetetrazole-induced epileptiform seizures. An electrophysiological study

Demeter, I.; Nagy, K.; Gellért, Levente; Vécsei, László; Fülöp, Ferenc; Toldi, József

doi:10.1007/s00702-011-0755-x

Cited by 27 publications

(31 citation statements)

References 21 publications

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“…Kynurenine 3-monooxygenase inhibitors such as JM6 and Ro-61-8048 do not cross the blood-brain barrier but, after oral administration, change concentrations of extracellular KYN metabolites in the brain and exert neuroprotection in animal models of neurodegenerative diseases (30,31). Plasma KA is not expected to affect brain pools of KA significantly as only a small portion crosses the blood-brain barrier (32) and KA has to be synthesized locally from KYN via kynurenine aminotransferase. This fact and our data argue for similar profiles of KYN and KA in the plasma and hippocampus and relatively unrestricted conversion of KYN to KA.…”

Section: Kyn Pathway and Related Metabolitesmentioning

confidence: 99%

Regulation of kynurenine metabolism by a ketogenic diet

Heischmann

Gano

Quinn

et al. 2018

Journal of Lipid Research

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Ketogenic diets (KDs) are increasingly utilized as treatments for epilepsy, other neurological diseases, and cancer. Despite their long history in suppressing seizures, the distinct molecular mechanisms of action of KDs are still largely unknown. The goal of this study was to identify key metabolites and pathways altered in the hippocampus and plasma of rats fed a KD versus control diet (CD) either ad libitum or calorically restricted to 90% of the recommended intake. This was accomplished using a combination of targeted methods and untargeted MS-based metabolomics analyses. Various metabolites of and related to the tryptophan (TRP) degradation pathway, such as kynurenine (KYN), kynurenic acid as well as enzyme cofactors, showed significant changes between groups fed different diets and/or calorie amounts in plasma and/or the hippocampus. KYN was significantly downregulated in both matrices in animals of the CD-calorically restricted, KD-ad libitum, and KD-calorically restricted groups compared with the CD-ad libitum group. Our data suggest that the TRP degradation pathway is a key target of the KD.

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Section: Kyn Pathway and Related Metabolitesmentioning

confidence: 99%

Regulation of kynurenine metabolism by a ketogenic diet

Heischmann

Gano

Quinn

et al. 2018

Journal of Lipid Research

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“…Since these gene products may direct the catabolism of KYN, which is also influenced by neuroinflammation, targeted treatments in individuals at risk for psychopathological symptoms (e.g., KATII T-carriers), by decreasing neuroinflammation and increasing KYNA, might reduce depressive symptoms in HIV. For example, KYNA analogs that are already being investigated for the treatment of migraine (Knyihar-Csillik et al 2008), seizures (Demeter et al 2012), and cognitive deficits in HIV (Baran and Kepplinger 2014), may also be useful in the treatment of psychopathological symptoms, and ultimately improved the quality of life in HIV patients.…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of Kynurenine Pathway-Related Genes, Kynurenic Acid, and Psychopathological Symptoms in HIV

Douet

Tanizaki

Franke

et al. 2016

J Neuroimmune Pharmacol

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HIV-infection is associated with neuroinflammation and greater psychopathological symptoms, which may be mediated by imbalances in the kynurenic pathway (KP). Two key KP enzymes that catabolize kynurenine include kynurenine-aminotransferase II (KATII), which yields antioxidative kynurenine acid [KYNA] in astrocytes, and kynurenine-3-monooxygenase (KMO), which produces neurotoxic metabolites in microglia. The relationships between polymorphisms in KMO and KATII, psychopathological symptoms, and cerebrospinal fluid (CSF) [KYNA] were evaluated in subjects with and without HIV-infection. Seventy-two HIV-positive and 72-seronegative (SN) participants were genotyped for KATII-rs1480544 and KMO-rs1053230. Although our participants were not currently diagnosed with depression or anxiety, they were assessed for psychopathological distress with Center for Epidemiologic Studies-Depression scale and Symptom Checklist-90-Revised. CSF-[KYNA] was also measured in 100 subjects (49 HIV/51 SN). HIV-participants had more psychopathological distress than SN, especially for anxiety. KATII-by-HIV interactions were found on anxiety, interpersonal sensitivity and obsessive compulsivity; KATII-C-carriers had lower scores than TT-carriers in SN but not in HIV. In contrast, the KMO-polymorphism had no influence on psychopathological symptoms in both groups. Overall, CSF-[KYNA] increased with age independently of HIV-serostatus, except KATII-TT-carriers tended to show no age-dependent variations. Therefore, the C-allele in KATII-rs1480544 appears to be protective against psychopathological distress in SN but not in HIV individuals, who had more psychopathological symptoms and likely greater neuroinflammation. The age-dependent increase in CSF-[KYNA] may reflect a compensatory response to age-related inflammation, which may be deficient in KATII-TT-carriers. Targeted treatments that decrease neuroinflammation and increase KYNA in at risk KATII-TT-carriers may reduce psychopathological symptoms in HIV.

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“…One possibility could be the use of a prodrug such as L-kynurenine or its derivates [153][154][155]; whereas shifting the pathway towards the production of KYNA with different enzyme inhibitors would represent another possible therapeutic strategy [156][157]. During the last years, our research group has synthesized several different KYNA derivates that have proven to be effective in animal models of cerebral ischemia [158], Huntington's disease [159], epilepsy [160], and rat models of trigeminovascular activation [68,[161][162]. The chemical structures of these KYNA analogues have been previously presented.…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%