Quinolinic acid is a potent lipid peroxidant in rat brain homogenates

Rı́os, Camilo; Santamarı́a, Abel

doi:10.1007/bf00966592

Cited by 239 publications

(148 citation statements)

References 31 publications

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“…Indeed, QUIN occurs naturally in the mammalian brain, although the low QUIN content of cerebral tissue (50 -1000 nM) is difficult to reconcile with its low receptor affinity (ED 50 Ͼ100 M). It appears that the remarkably high in vivo potency of QUIN, particularly as an excitotoxin, is caused by a combination of factors, including the absence of effective removal mechanisms for extracellular QUIN , its ability to readily generate damage-promoting free radicals (Rios and Santamaria, 1991), and, possibly, its specific interaction with the NR2A and NR2B NMDA receptor subtypes (de Carvalho et al, 1996). These and other characteristics distinguish QUIN from other excitotoxins, such as NMDA itself, and might account for the compound's unique neuroexcitatory and neurotoxic profile (Foster and Schwarcz, 1989;Stone, 1993).…”

Section: Neuroactive Tryptophan Metabolitesmentioning

confidence: 99%

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Schwarcz

Pellicciari²

2002

J Pharmacol Exp Ther

500

418

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Degradation of the essential amino acid tryptophan along the kynurenine pathway (KP) yields several neuroactive intermediates, including the free radical generator 3-hydroxykynurenine, the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist quinolinic acid, and the NMDA and ␣7 nicotinic acetylcholine receptor antagonist kynurenic acid. The ambient levels of these compounds are determined by several KP enzymes, which in the brain are preferentially localized in astrocytes and microglial cells. Normal fluctuations in the brain levels of neuroactive KP intermediates might modulate several neurotransmitter systems. Impairment of KP metabolism is functionally significant and occurs in a variety of diseases that affect the brain. Pharmacological agents targeting specific KP enzymes are now available to manipulate the concentration of neuroactive KP intermediates in the brain. These compounds can be used to normalize KP defects, show remarkable efficacy in animal models of central nervous system disorders, and offer novel therapeutic opportunities. Neuroactive Tryptophan MetabolitesIn mammals, the vast majority of dietary tryptophan is metabolized via the kynurenine pathway (KP) (Scheme 1), which is initiated by the oxidative opening of the indole ring and eventually produces the ubiquitous enzyme cofactor NAD ϩ . This catabolic cascade is notable for the fact that it contains three neuroactive intermediates, all of which derive directly or indirectly from L-kynurenine (L-KYN), the primary major degradation product of tryptophan. One of the three compounds, kynurenic acid (KYNA), is formed in a "dead end" side-arm of the pathway, whereas the other two, 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN), are synthesized from L-KYN en route to NAD ϩ . Although all kynurenines-the collective term used for KP intermediates shown in Scheme 1-are found in high concentration in urine (hence the name), none of them has so far been assigned an important physiological function in peripheral organs.The first indication that kynurenines might play a role in the brain was provided by Lapin (1978), who noted convulsions after an intracerebroventricular QUIN injection in mice. Soon thereafter, ionophoretically applied QUIN was found to excite rat cortical neurons (Stone and Perkins, 1981), and intracerebrally injected QUIN was shown to cause excitotoxic lesions in rat brain (Schwarcz et al., 1983). Both QUIN-induced excitation and neurotoxicity are mediated by N-methyl-D-aspartate (NMDA) receptors, leading to the suggestion that endogenous QUIN might participate in physiological and pathological processes that are associated with NMDA receptor activation. Indeed, QUIN occurs naturally in the mammalian brain, although the low QUIN content of cerebral tissue (50 -1000 nM) is difficult to reconcile with its low receptor affinity (ED 50 Ͼ100 M). It appears that the remarkably high in vivo potency of QUIN, particularly as an excitotoxin, is caused by a combination of factors, including the absence of effective removal mech...

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Section: Neuroactive Tryptophan Metabolitesmentioning

confidence: 99%

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Schwarcz

Pellicciari²

2002

J Pharmacol Exp Ther

500

418

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“…The first is the activation of NMDA receptors by Quinolinic acid (Guillemin et al 2004), which is already known to mediate neuronal apoptosis with caspase-3 activation (Tenneti and Lipton 2000;Stone 2001). The second possibility, which represent another important aspect of Quinolinic acid toxicity, is lipid peroxidation (Rios and Santamaria 1991). Quinolinic acid in concentration as low as 120 nM, induces lipid peroxidation and formation of free radicals leading to neuronal death (Behan et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of some tropical green leafy vegetables on key enzymes linked to Alzheimer’s disease and some pro-oxidant induced lipid peroxidation in rats’ brain

et al. 2011

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This study sought to investigate the inhibitory effect of some commonly consumed Nigerian green leafy vegetables (raw and blanched) on acetylcholinesterase and butyrylcholinesterase (key enzyme linked to Alzheimer's disease) activities and some pro-oxidants (FeSO 4 , Sodium nitroprusside and Quinolinic acid) induced lipid peroxidation in rat brain in vitro. Three commonly consumed green leafy vegetables in Nigeria [Amarantus cruentus (Arowojeja), Struchium sparganophora (Ewuro-odo) and Telfairia occidentalis (Ugwu] were blanched in hot water for 10 min, and the extracts of the raw and blanched vegetables were prepared and used for subsequent analysis. The result revealed that all the vegetables inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity as well as the pro-oxidants induced lipid peroxidation in rat brain in a dose dependent manner; however, Amarantus cruentus extract (EC 50 =97.9 μg/ml) had the highest inhibitory effect on acetylcholinesterase activity while Telfairia occidentalis extract (EC 50 =52.7 μg/ml) had the highest inhibitory effect on butyrylcholinesterase activity. However, blanching of the vegetables caused a significant (P<0.05) decrease in the inhibitory effect of the vegetables on AChE activities while it enhanced the inhibition of the pro-oxidants induced lipid peroxidation in rat brain in vitro. Therefore, some of the possible mechanism by which green leafy vegetables exert their neuroprotective activities could be through the inhibition of acetylcholinesterase and butyrylcholinesterase activities and prevention of lipid peroxidation in the brain. However, blanching of the vegetables could reduce their ability to inhibit acetylcholinesterase and butyrylcholinesterase activity.

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“…Quinolinate selectively activates NMDA receptors, which can lead to excitotoxicity, and intrastriatal injections of this metabolite lead to axon-sparing neuronal lesions proximal to the site of injection [13,14]. Quinolate has been also related to mitochondrial dysfunction [15]) and has been demonstrated to cause neurodegeneration in cultures of rat corticostriatal system [16]. In fact, alterations in the levels of the kynurenine pathway metabolites have been implicated in several neurodegenerative diseases, including Alzheimer's, and PD and modulation of neuroactive kynurenine metabolites has been proposed as desirable for neuroprotection [9].…”

Section: Discussionmentioning

confidence: 99%

A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson’s Disease

Vilas

Fernández‐Santiago

Sánchez

et al. 2017

JPD

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Abstract.Background: Common genetic variability in the ACMSD gene has been associated with increased risk for Parkinson's disease (PD) but ACMSD mutations in clinical cases of PD have so far not been reported. Objective: To describe a case of sporadic PD carrying a novel ACMSD mutation. Methods: As part of a genetic study to identify potential pathogenic gene defects related to PD in the Mediterranean island Menorca, an initial group of 62 PD patients underwent mutational screening using a panel-based sequencing approach. Results: We report a 74-years-old man with sporadic PD who developed tremor in his right hand and slowness. On examination, moderate rigidity, asymmetric bradykinesia, and bilateral action tremor were present. He was started on levodopa with significant improvement. Two years later, he developed wearing off phenomena. The genetic study in the patient identified a novel ACMSD mutation resulting in p.Glu298Lys amino-acid change which was not present in neurologically normal population. Conclusions: Our data suggest that not only common genetic variability but also rare variants in ACMSD alone or in combination with other risk factors might increase the risk of PD.

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Quinolinic acid is a potent lipid peroxidant in rat brain homogenates

Cited by 239 publications

References 31 publications

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Manipulation of Brain Kynurenines: Glial Targets, Neuronal Effects, and Clinical Opportunities

Inhibitory effect of some tropical green leafy vegetables on key enzymes linked to Alzheimer’s disease and some pro-oxidant induced lipid peroxidation in rats’ brain

A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson’s Disease

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