Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study

Demeter, I.; Nagy, K.; Farkas, Tamás; Kis, Zsolt; Kocsis, Krisztián; Knapp, Levente; Gellért, Levente; Fülöp, Ferenc; Vécsei, László; Toldi, József

doi:10.1016/j.neulet.2013.08.028

Cited by 16 publications

(15 citation statements)

References 36 publications

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“…At the dose capable of exerting these neuroprotective effects, the KYNA analog did not demonstrate any significant systemic side effects, i.e., it did not alter locomotor activity, working memory performance, and long-lasting, consolidated reference memory in contrast to the observed indirect side-effects following KYN administration [312][313][314]. These results are supported by the findings that instead of decreasing LTP as it might be expected from its potential NMDAR antagonistic properties, it rather facilitated the potentiation of field excitatory postsynaptic potentials [315].…”

Section: Kynurenic Acidmentioning

confidence: 53%

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Zádori

Veres

Szalárdy

et al. 2018

JAD

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The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathwayrelated alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.3

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Section: Kynurenic Acidmentioning

confidence: 53%

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Zádori

Veres

Szalárdy

et al. 2018

JAD

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“…It is interesting to note that structures that are altered in the CNS, PNS, exocrine glands, and cornea (based on image exams) of SS patients are also sensitive to changes in the KP caused by trauma or ischemic damage (Table 1). These observations suggest that common inflammatory events are shared in autoimmune and non-immune inflammatory diseases, such as the synapses of the sensorial fibers, in the dorsal ganglion root, hippocampus, thalamus, and LFU [2,12,13,20,29,40,53,93,105,106,107,108] (Table 1). Those locations must be investigated in future studies addressing the anatomic correlations of clinical and biochemical changes in SS.…”

Section: Autoimmunity Neuropathy and Chronic Painmentioning

confidence: 99%

Neurological and Inflammatory Manifestations in Sjögren’s Syndrome: The Role of the Kynurenine Metabolic Pathway

Oliveira

Fantucci

Adriano

et al. 2018

IJMS

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For decades, neurological, psychological, and cognitive alterations, as well as other glandular manifestations (EGM), have been described and are being considered to be part of Sjögren’s syndrome (SS). Dry eye and dry mouth are major findings in SS. The lacrimal glands (LG), ocular surface (OS), and salivary glands (SG) are linked to the central nervous system (CNS) at the brainstem and hippocampus. Once compromised, these CNS sites may be responsible for autonomic and functional disturbances that are related to major and EGM in SS. Recent studies have confirmed that the kynurenine metabolic pathway (KP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating indoleamine 2,3-dioxygenase (IDO) in SS. This pathway interferes with serotonergic and glutamatergic neurotransmission, mostly in the hippocampus and other structures of the CNS. Therefore, it is plausible that KP induces neurological manifestations and contributes to the discrepancy between symptoms and signs, including manifestations of hyperalgesia and depression in SS patients with weaker signs of sicca, for example. Observations from clinical studies in acquired immune deficiency syndrome (AIDS), graft-versus-host disease, and lupus, as well as from experimental studies, support this hypothesis. However, the obtained results for SS are controversial, as discussed in this study. Therapeutic strategies have been reexamined and new options designed and tested to regulate the KP. In the future, the confirmation and application of this concept may help to elucidate the mosaic of SS manifestations.

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“…In these experiments, it did not impair the cognitive functions of the brain [ 90 ]. Furthermore, an electrophysiological study of the effects of this analog on the cognitive functions revealed that did not decrease LTP as might have been expected from its NMDA antagonistic properties, but rather facilitated the potentiation of field excitatory postsynaptic potentials [ 91 ]. The explanation of this somewhat paradoxical effect may be the observation that the elevation of KYNA levels results in a preferential inhibition of the extrasynaptic NMDA receptors and presynaptic nicotinic acetylcholine receptors, whereas the synaptic NMDA and AMPA receptor-mediated currents are relatively spared (reviewed in [ 92 ]).…”

Section: Kynurenic Acidmentioning

confidence: 99%

Memantine and Kynurenic Acid: Current Neuropharmacological Aspects

Majláth¹,

Török²,

Toldi³

et al. 2016

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Glutamatergic neurotransmission, of special importance in the human brain, is implicated in key brain functions such as synaptic plasticity and memory. The excessive activation of N-methyl- D-aspartate (NMDA) receptors may result in excitotoxic neuronal damage; this process has been implicated in the pathomechanism of different neurodegenerative disorders, such as Alzheimer’s disease (AD). Memantine is an uncompetitive antagonist of NMDA receptors with a favorable pharmacokinetic profile, and is therefore clinically well tolerated. Memantine is approved for the treatment of AD, but may additionally be beneficial for other dementia forms and pain conditions. Kynurenic acid (KYNA) is an endogenous antagonist of NMDA receptors which has been demonstrated under experimental conditions to be neuroprotective. The development of a well-tolerated NMDA antagonist may offer a novel therapeutic option for the treatment of neurodegenerative disease and pain syndromes. KYNA may be a valuable candidate for future drug development.

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Paradox effects of kynurenines on LTP induction in the Wistar rat. An in vivo study

Cited by 16 publications

References 36 publications

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Neurological and Inflammatory Manifestations in Sjögren’s Syndrome: The Role of the Kynurenine Metabolic Pathway

Memantine and Kynurenic Acid: Current Neuropharmacological Aspects

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