Kynurenine 3‐mono‐oxygenase inhibitors attenuate post‐ischemic neuronal death in organotypic hippocampal slice cultures

Carpenedo, Raffaella; Meli, Elena; Peruginelli, Fiamma; Pellegrini‐Giampietro, Domenico E.; Moroni, Flavio

doi:10.1046/j.1471-4159.2002.01090.x

Cited by 57 publications

(29 citation statements)

References 34 publications

(89 reference statements)

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“…Even relatively small increases in extracellular KYNA in the brain are functionally significant, resulting in a reduction in extracellular glutamate levels (8). Interestingly, such moderate increases are also anticonvulsant and reduce neuronal vulnerability to ischemic and other excitotoxic insults (7,12,24,36,45,51,53), supporting the possible clinical relevance of fluctuations in brain KYNA.…”

Section: Vol 24 2004mentioning

confidence: 96%

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Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice

Yü

Prospero

Sapko

et al. 2004

Molecular and Cellular Biology

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Kynurenic acid (KYNA) can act as an endogenous modulator of excitatory neurotransmission and has been implicated in the pathogenesis of several neurological and psychiatric diseases. To evaluate its role in the brain, we disrupted the murine gene for kynurenine aminotransferase II (KAT II), the principal enzyme responsible for the synthesis of KYNA in the rat brain. mKat-2 ؊/؊ mice showed no detectable KAT II mRNA or protein. Total brain KAT activity and KYNA levels were reduced during the first month but returned to normal levels thereafter. In contrast, liver KAT activity and KYNA levels in mKat-2 ؊/؊ mice were decreased by >90% throughout life, though no hepatic abnormalities were observed histologically. KYNA-associated metabolites kynurenine, 3-hydroxykynurenine, and quinolinic acid were unchanged in the brain and liver of knockout mice. mKat-2 ؊/؊ mice began to manifest hyperactivity and abnormal motor coordination at 2 weeks of age but were indistinguishable from wild type after 1 month of age. Golgi staining of cortical and striatal neurons revealed enlarged dendritic spines and a significant increase in spine density in 3-week-old mKat-2 ؊/؊ mice but not in 2-month-old animals. Our results show that gene targeting of mKat-2 in mice leads to early and transitory decreases in brain KAT activity and KYNA levels with commensurate behavioral and neuropathological changes and suggest that compensatory changes or ontogenic expression of another isoform may account for the normalization of KYNA levels in the adult mKat-2 ؊/؊ brain.

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Section: Vol 24 2004mentioning

confidence: 96%

“…However, KYNA formation is influenced by the availability of 2-oxoacids (30), by cellular energy status (7,18,29,63), and by dopaminergic activity (47,49,67). Some of these regulatory processes are brain specific.…”

mentioning

confidence: 99%

Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice

Yü

Prospero

Sapko

et al. 2004

Molecular and Cellular Biology

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“…Therefore, KA might counteract the neurotoxic effect of QUIN. Indeed, blocking of the kynurenine pathway at the kynurenine hydroxylase stage reduced the neuronal damage after cerebral ischemia in vivo [61] and postischemic neuronal death in slice cultures [62].…”

Section: Possible Mechanisms Of Ido-mediated Tolerance Inductionmentioning

confidence: 97%

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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“…Procedures aimed at increasing KYNA concentrations in the brain cause sedation, reduce neuronal excitability, and excitotoxic or post-ischemic brain damage, both in vivo and in vitro (Russi et al, 1992;Carpenedo et al, 1994;Chiarugi et al, 1995;Cozzi et al, 1999;Wu et al, 2000). KYNA concentrations in the cerebrospinal fluid and in rat brain extracellular spaces are approximately 10-100 nM (Moroni et al, 1988;Turski et al, 1988;Swartz et al, 1990) and an increase of three times these concentrations is sufficient to exert a potent neuroprotective action (Cozzi et al, 1999;Carpenedo et al, 2002). However, KYNA affinity for the glycine site of NMDA receptors is relatively low (approximately 30 µM) (Stone, 2000) suggesting that KYNA neuroprotective action in the brain is likely not mediated by the antagonism of these receptors.…”

Section: Introductionmentioning

confidence: 99%

Kynurenic Acid Inhibits the Release of the Neurotrophic Fibroblast Growth Factor (FGF)-1 and Enhances Proliferation of Glia Cells, in vitro

et al. 2005

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1. Kynurenic (KYNA) and quinolinic (QUIN) acids are neuroactive tryptophan metabolites formed along the kynurenine pathway: the first is considered a non-competitive antagonist and the second an agonist of glutamate receptors of NMDA type. The affinity of these compounds for glutamate receptors is, however, relatively low and does not explain KYNA neuroprotective actions in models of post-ischemic brain damage. 2. We evaluated KYNA effects on the release of fibroblast growth factor (FGF)-1, a potent neurotrophic cytokine. Because KYNA exhibits a neuroprotective profile in vitro and in vivo, we anticipated that it could function as an autocrine/paracrine inducer of FGF-1 release. Studies were performed in several models of FGF-1 secretion (FGF-1 transfected NIH 3T3 cells exposed to heat shock, A375 melanoma cells exposed to serum starvation, growth factor deprived human endothelial cells). To our surprise, KYNA, at low concentration, inhibited FGF-1 release in all cellular models. QUIN, a compound having opposite effects on glutamate receptors, also reduced this release, but its potency was significantly lower than that of KYNA. 3. KYNA and QUIN also displayed a major stimulatory effect on the proliferation rate of mouse microglia and human glioblastoma cells, in vitro. 4. Our data suggest that minor changes of local KYNA concentration may modulate FGF-1 release, cell proliferation, and ultimately tissue damage in different pathological conditions.

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Kynurenine 3‐mono‐oxygenase inhibitors attenuate post‐ischemic neuronal death in organotypic hippocampal slice cultures

Cited by 57 publications

References 34 publications

Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice

Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice

IDO expression in the brain: a double-edged sword

Kynurenic Acid Inhibits the Release of the Neurotrophic Fibroblast Growth Factor (FGF)-1 and Enhances Proliferation of Glia Cells, in vitro

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