The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine

Eastman, Clifford L.; Guilarte, Tomás R.

doi:10.1007/bf01101711

Cited by 108 publications

(67 citation statements)

References 26 publications

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“…According to some early studies, the proposed deleterious effects of 3-OH-L-KYN, a metabolite produced by kynurenine 3-monooxygenase (KMO), are mediated by free radicals and not glutamate receptors, and some of its detrimental actions may be due to its metabolite, 3-OH-ANA, via its auto-oxidation, leading to the production of superoxide anion [218][219][220][221].…”

Section: -Hydroxy-l-kynurenine and 3-hydroxyanthranilic Acidmentioning

confidence: 99%

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: -Hydroxy-l-kynurenine and 3-hydroxyanthranilic Acidmentioning

confidence: 99%

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 second neurotoxic Trp metabolite is 3-HAA, which is unstable under physiological conditions. Upon spontaneous auto-oxidation, 3-HAA produces reactive radical species, which in turn induce oxidative stress and apoptosis in neurons [57][58][59].…”

Section: Possible Mechanisms Of Ido-mediated Tolerance Inductionmentioning

confidence: 99%

IDO expression in the brain: a double-edged sword

2007

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The tryptophan-catabolizing enzyme indoleamine-2,3-dioxygenase (IDO) initiates the first and ratelimiting step of the kynurenine pathway. It is induced by proinflammatory cytokines such as interferon-β and interferon-γ and has established effects in the control of intracellular parasites. The recent detection of its decisive function in immune tolerance at the maternal-fetal interface stimulated various studies unraveling its regulatory effect on T cells in many pathologies. In the brain, IDO can be induced in microglia by interferon-γ-producing T helper (Th) 1 cells, thereby initiating a negative feedback loop which downmodulates neuroinflammation in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). This protective effect could to be counteracted by the production of neurotoxic metabolites of the kynurenine pathway such as quinolinic acid, which are produced upon IDO induction. Some metabolites of the kynurenine pathway can pass the blood-brain barrier and thus could act as neurotoxins, e.g., during systemic infection. In this paper, we give a brief overview on established immune regulatory functions of IDO, review recent data on IDO expression in the brain, and propose that autoimmune neuroinflammation and the increasingly appreciated neuronal damage in MS are linked by Th1-mediated IDO induction through subsequent synthesis of toxic metabolites of tryptophan.

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“…All the above syndromes are characterized by severe neurological dysfunctions. Moreover, earlier studies using a neuronal hybrid cell line have shown that 3-HK exerts cytotoxicity and causes cell lysis (9,10). Nevertheless, the argument that 3-HK may be involved in brain pathogenesis has long been dismissed (11).…”

mentioning

confidence: 99%

Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

Okuda

Nishiyama

Saito

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

262

215

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The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine

Cited by 108 publications

References 26 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

IDO expression in the brain: a double-edged sword

Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine.

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