The excitotoxin quinolinic acid is present in the brain of several mammals and its cortical content increases during the aging process

Moroni, Flavio; Lombardi, Grazia; Moneti, Gloriano; Aldinio, C.

doi:10.1016/0304-3940(84)90385-9

Cited by 102 publications

(30 citation statements)

References 11 publications

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“…QA concentrations have also been shown to increase during the natural aging process in rats (Moroni et al, 1984). This metabolite of tryptophan metabolism has been shown to induce lipid peroxidation (Rios and Santamaria, 1991;Santamaria and Rios, 1993;RodriguezMartinez et al, 2000), causes the generation of the superoxide anion and reduces cell viability in neuronal cultures (Valencia and Moran, 2004).…”

Section: Discussionmentioning

confidence: 96%

Non-steroidal anti-inflammatory agents, tolmetin and sulindac attenuate quinolinic acid (QA)-induced oxidative stress in primary hippocampal neurons and reduce QA-induced spatial reference memory deficits in male Wistar rats

2007

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Section: Discussionmentioning

confidence: 96%

Non-steroidal anti-inflammatory agents, tolmetin and sulindac attenuate quinolinic acid (QA)-induced oxidative stress in primary hippocampal neurons and reduce QA-induced spatial reference memory deficits in male Wistar rats

2007

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“…QUIN is known to be associated with the neuropathogenesis of Alzheimer's disease (Guillemin and Brew 2002), Huntington's disease (Finkbeiner and Cuero 2006), amyotrophic lateral sclerosis (Guillemin et al 2005a), and human immunodeficiency virus (Guillemin et al 2005b;Heyes et al 1991;Heyes et al 1992). QUIN levels in the central nervous system also increase with age (Moroni et al 1984).…”

Section: Introductionmentioning

confidence: 97%

Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons

et al. 2009

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There is growing evidence implicating the kynurenine pathway (KP) and particularly one of its metabolites, quinolinic acid (QUIN), as important contributors to neuroinflammation in several brain diseases. While QUIN has been shown to induce neuronal and astrocytic apoptosis, the exact mechanisms leading to cell death remain unclear. To determine the mechanism of QUIN-mediated excitotoxicity in human brain cells, we measured intracellular levels of nicotinamide adenine dinucleotide (NAD(+)) and poly(ADP-ribose) polymerase (PARP) and extracellular lactate dehydrogenase (LDH) activities in primary cultures of human neurons and astrocytes treated with QUIN. We found that QUIN acts as a substrate for NAD(+) synthesis at very low concentrations (<50 nM) in both neurons and astrocytes, but is cytotoxic at sub-physiological concentrations (>150 nM) in both the cell types. We have shown that the NMDA ion channel blockers, MK801 and memantine, and the nitric oxide synthase (NOS) inhibitor, L-NAME, significantly attenuate QUIN-mediated PARP activation, NAD(+) depletion, and LDH release in both neurons and astrocytes. An increased mRNA and protein expression of the inducible (iNOS) and neuronal (nNOS) forms of nitric oxide synthase was also observed following exposure of both cell types to QUIN. Taken together these results suggests that QUIN-induced cytotoxic effects on neurons and astrocytes are likely to be mediated by an over activation of an NMDA-like receptor with subsequent induction of NOS and excessive nitric oxide (NO(*))-mediated free radical damage. These results contribute significantly to our understanding of the pathophysiological mechanisms involved in QUIN neuro- and gliotoxicity and are relevant for the development of therapies for neuroinflammatory diseases.

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“…QUIN occurs endogenously in the brain (86,182), and its excitatory effects, like those of its more potent homologue (Fig. 6), homoquinolinic acid (183) (HQUIN), are mediated predominantly by NMDA receptors (184) or, perhaps more likely, by a subtype of these (6,38).…”

Section: A Structural Relationshipsmentioning

confidence: 99%

Structural, conformational, and stereochemical requirements of central excitatory amino acid receptors

Hansen¹,

Krogsgaard‐Larsen²

1990

Medicinal Research Reviews

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The excitotoxin quinolinic acid is present in the brain of several mammals and its cortical content increases during the aging process

Cited by 102 publications

References 11 publications

Non-steroidal anti-inflammatory agents, tolmetin and sulindac attenuate quinolinic acid (QA)-induced oxidative stress in primary hippocampal neurons and reduce QA-induced spatial reference memory deficits in male Wistar rats

Non-steroidal anti-inflammatory agents, tolmetin and sulindac attenuate quinolinic acid (QA)-induced oxidative stress in primary hippocampal neurons and reduce QA-induced spatial reference memory deficits in male Wistar rats

Mechanism for Quinolinic Acid Cytotoxicity in Human Astrocytes and Neurons

Structural, conformational, and stereochemical requirements of central excitatory amino acid receptors

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