Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid

Miranda, Alejandra; Boegman, R.J.; Beninger, Richard J.; Jhamandas, K

doi:10.1016/s0306-4522(96)00655-0

Cited by 124 publications

(66 citation statements)

References 39 publications

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“…It is lower though, than after in vivo application of KYNA precursor, L-kynurenine together with probenecid, reported to increase brain KYNA several-fold (Miranda et al 1997;Shepard et al 2003). Yet, having in mind that already nanomolar levels of KYNA block a7 nicotinic receptors and reduce the presynaptic release of glutamate (Carpenedo et al 2001;Hilmas et al 2001;Luccini et al 2007), found enhancement of KYNA synthesis evoked by BHB seems to be clinically relevant, especially as regards potential neuroprotective effects of ketone bodies.…”

Section: Discussionmentioning

confidence: 88%

Novel Aspect of Ketone Action: β-Hydroxybutyrate Increases Brain Synthesis of Kynurenic Acid In Vitro

et al. 2010

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Ketone bodies formed during ketogenic diet or non-treated diabetes mellitus may exert neuroprotective and antiepileptic effects. Here, we assessed the influence of ketone body, β-hydroxybutyrate (BHB) on the brain synthesis of kynurenic acid (KYNA), an endogenous antagonist of glutamatergic and α7-nicotinic receptors. In brain cortical slices and in primary glial cultures, BHB enhanced KYNA production. KT 5270, an inhibitor of protein kinase A, has prevented this action. At hypoglycemia, under pH 7.0 and 7.4, profound (15 mM BHB), but not mild (3 mM) ketosis increased synthesis of KYNA. In paradigm resembling diabetic ketoacidosis in vitro (30 mM glucose, pH 7.0), neither mild nor profound ketosis influenced the production of KYNA. At pH 7.4 and in 30 mM glucose though, both mild and severe ketonemia evoked an increase of KYNA production. The activity of KYNA biosynthetic enzymes, KAT I and KAT II, in cortical homogenate was not altered by BHB (0.05-10.0 mM). However, in cultured glial cells exposed to BHB (10 mM), the activity of KATs increased. This effect was reversed by the co-incubation of cells with KT 5270. Presented data reveal a novel mechanism of action of BHB. Increased synthesis of KYNA in the presence of BHB is most probably mediated by protein kinase A-dependent stimulation of KATs expression/activity leading to an increase of KYNA formation. Ensuing attenuation of the excessive excitatory glutamate-mediated neurotransmission may, at least in part, explain the neuroprotective actions of BHB.

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Section: Discussionmentioning

confidence: 88%

Novel Aspect of Ketone Action: β-Hydroxybutyrate Increases Brain Synthesis of Kynurenic Acid In Vitro

et al. 2010

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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%

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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“…The first such inhibitor, nicotinylalanine (NICALA), a kynurenine analogue introduced by Decker et al (1963), was successfully demonstrated to increase brain KYNA content and to produce sedative and anticonvulsant effects in rats (Connick et al, 1992;Russi et al, 1992). These findings suggested that NICALA may have a neuroprotectant action and we evaluated this possibility, in two in vivo models of excitotoxin-induced damage -the nigrostratial dopamine model (Miranda et al, 1997) and the striatal NADPH-diaphorase and GABA neuron model (Harris et al, 1998) -using the strategy represented in Fig. 3.…”

Section: Kyna-based Neuroprotectionmentioning

confidence: 98%

Excitotoxicity of quinolinic acid: Modulation by endogenous antagonists

et al. 2000

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Quinolinic acid (QUIN), a product of tryptophan metabolism by the kynurenine pathway, produces excitotoxicity by activation of NMDA receptors. Focal injections of QUIN can deplete the biochemical markers for dopaminergic, cholinergic, gabaergic, enkephalinergic and NADPH diaphorase neurons, which differ in their sensitivity to its neurotoxic action. This effect of QUIN differs from that of other NMDA receptor agonists in terms of its dependency on the afferent glutamatergic input and its sensitivity to the receptor antagonists. The enzymatic pathway yielding QUIN produces metabolites that inhibit QUIN-induced neurotoxicity. The most active of these metabolites, kynurenic acid (KYNA), blocks NMDA and non-NMDA receptor activity. Treatment with kynurenine hydroxylase and kynureinase inhibitors increases levels of endogenous KYNA in the brain and protects against QUIN-induced neurotoxicity. Other neuroprotective strategies involve reduction in QUIN synthesis from its immediate precursor, or endogenous synthesis of 7-chloro-kynurenic acid, a NMDA antagonist, from its halogenated precursor. Several other tryptophan metabolites--quinaldic acid, hydroxyquinaldic acid and picolinic acid--also inhibit excitotoxic damage but their presence in the brain is uncertain. Picolinic acid is of interest since it inhibits excitotoxic but not neuroexcitatory responses. The mechanism of its anti-excitotoxic action is unclear but might involve zinc chelation. Neurotoxic actions of QUIN are modulated by nitric oxide (NO). Treatment with inhibitors of NO synthase can augment QUIN toxicity in some models of excitotoxicity suggesting a neuroprotective potential of endogenous NO. In recent studies, certain nitroso compounds which could be NO donors, have been reported to reduce the NMDA receptor-mediated neurotoxicity. The existence of endogenous compounds which inhibit excitotoxicity provides a basis for future development of novel and effective neuroprotectants.

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Protection against quinolinic acid-mediated excitotoxicity in nigrostriatal dopaminergic neurons by endogenous kynurenic acid

Cited by 124 publications

References 39 publications

Novel Aspect of Ketone Action: β-Hydroxybutyrate Increases Brain Synthesis of Kynurenic Acid In Vitro

Novel Aspect of Ketone Action: β-Hydroxybutyrate Increases Brain Synthesis of Kynurenic Acid In Vitro

Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice

Excitotoxicity of quinolinic acid: Modulation by endogenous antagonists

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