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Structural Evaluation and Electrophysiological Effects of Some Kynurenic Acid Analogs.

ABSTRACT: Kynurenic acid (KYNA), a metabolite of tryptophan, as an excitatory amino acid receptor antagonist is an effective neuroprotective agent in case of excitotoxicity, which is the hallmark of brain ischemia and several neurodegenerative processes. Therefore, kynurenine pathway, KYNA itself, and its derivatives came into the focus of research. During the past fifteen years, our research group has developed several neuroactive KYNA derivatives, some of which proved to be neuroprotective in preclinical studies. In this study, the synthesis of these KYNA derivatives and their evaluation with divergent molecular characteristics are presented together with their most typical effects on the monosynaptic transmission in CA1 region of the hippocampus of the rat. Their effects on the basic neuronal activity (on the field excitatory postsynaptic potentials: fEPSP) were studied in in vitro hippocampal slices in 1 and 200 ?M concentrations. KYNA and its derivative 4 in both 1 and 200 ?M concentrations proved to be inhibitory, while derivative 8 only in 200 ?M decreased the amplitudes of fEPSPs. Derivative 5 facilitated the fEPSPs in 200 ?M concentration. This is the first comparative study which evaluates the structural and functional differences of formerly and newly developed KYNA analogs. Considerations on possible relations between molecular structures and their physiological effects are presented.

SUBMITTER: Feher E

PROVIDER: S-EPMC6803921 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Structural Evaluation and Electrophysiological Effects of Some Kynurenic Acid Analogs.

Fehér Evelin E Szatmári István I Dudás Tamás T Zalatnai Anna A Farkas Tamás T Lőrinczi Bálint B Fülöp Ferenc F Vécsei László L Toldi József J

Molecules (Basel, Switzerland) 20190926 19

Kynurenic acid (KYNA), a metabolite of tryptophan, as an excitatory amino acid receptor antagonist is an effective neuroprotective agent in case of excitotoxicity, which is the hallmark of brain ischemia and several neurodegenerative processes. Therefore, kynurenine pathway, KYNA itself, and its derivatives came into the focus of research. During the past fifteen years, our research group has developed several neuroactive KYNA derivatives, some of which proved to be neuroprotective in preclinica ...[more]

PMID: 31561643

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Project description:Hypofunction of glutamatergic signaling is causally linked to neurodevelopmental disorders, including psychotic disorders like schizophrenia and bipolar disorder. Kynurenic acid (KYNA) has been found to be elevated in postmortem brain tissue and cerebrospinal fluid of patients with psychotic illnesses and may be involved in the hypoglutamatergia and cognitive dysfunction experienced by these patients. As insults during the prenatal period are hypothesized to be linked to the pathophysiology of psychotic disorders, we presently utilized the embryonic kynurenine (EKyn) paradigm to induce a prenatal hit. Pregnant Wistar dams were fed chow laced with kynurenine to stimulate fetal brain KYNA elevation from embryonic day 15 to embryonic day 22. Control dams (ECon) were fed unlaced chow. Plasma and hippocampal tissue from young adult (postnatal day 56) ECon and EKyn male and female offspring were collected at the beginning of the light (Zeitgeber time, ZT 0) and dark (ZT 12) phases to assess kynurenine pathway metabolites. Hippocampal tissue was also collected at ZT 6 and ZT 18. In separate animals, in vivo microdialysis was conducted in the dorsal hippocampus to assess extracellular KYNA, glutamate, and γ-aminobutyric acid (GABA). Biochemical analyses revealed no changes in peripheral metabolites, yet hippocampal tissue KYNA levels were significantly impacted by EKyn treatment, and increased in male EKyn offspring at ZT 6. Interestingly, extracellular hippocampal KYNA levels were only elevated in male EKyn offspring during the light phase. Decreases in extracellular glutamate levels were found in the dorsal hippocampus of EKyn male and female offspring, while decreased GABA levels were present only in males during the dark phase. The current findings suggest that the EKyn paradigm may be a useful tool for investigation of sex- and time-dependent changes in hippocampal neuromodulation elicited by prenatal KYNA elevation, which may influence behavioral phenotypes and have translational relevance to psychotic disorders.

Dataset Information

Structural Evaluation and Electrophysiological Effects of Some Kynurenic Acid Analogs.

Publications

Structural Evaluation and Electrophysiological Effects of Some Kynurenic Acid Analogs.

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