Over the last two decades, evidence for the involvement of quinolinic acid (QUIN) in neuroinflammatory diseases has been exponentially increasing. Within the brain, QUIN is produced and released by infiltrating macrophages and activated microglia, the very cells that are prominent during neuroinflammation. QUIN acts as an agonist of the N-methyl-D-aspartate receptor and as such is considered to be a brain endogenous excitotoxin. Since the discovery of the excitotoxic activity of QUIN in the early 1980s, several other cytotoxic mechanisms have been identified. We know today that QUIN acts as a neurotoxin, gliotoxin, proinflammatory mediator, pro-oxidant molecule and can alter the integrity and cohesion of the blood-brain barrier. This paper aims to review some of the most recent findings about the effects of QUIN and its mode of action.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1742-4658.2012.08485.x

Quinolinic acid, the inescapable neurotoxin.

There is good evidence that the kynurenine pathway (KP) and one of its end products, quinolinic acid (QUIN) play a role in the pathogenesis of several major neurological diseases. While QUIN has been shown to be produced in neurotoxic concentrations by macrophages and microglia, the capacity of astrocytes and neurons to produce QUIN is controversial. Using interferon gamma (IFN-γ)-stimulated primary cultures of human mixed brain cells, we assayed expression of the KP regulatory enzyme indoleamine 2,3-dioxygenase (IDO) and QUIN production by immunocytochemistry. Using IFN-γ-stimulated purified cultures of neurons, astrocytes, microglia and macrophages, we studied IDO expression by RT-PCR and production of QUIN using mass spectrometry. We found that astrocytes, neurons, and microglia expressed IDO but only microglia were able to produce detectable amounts of QUIN. However, astrocytes and neurons had the ability to catabolize QUIN. This study also provides the first evidence of IDO expression and lack of production of QUIN in culture of primary human neurons. © 2004 Wiley-Liss, Inc.

Expression of indoleamine 2,3-dioxygenase and production of quinolinic acid by human microglia, astrocytes, and neurons.

Quinolinic acid and other kynurenines in the central nervous system.

There is good evidence that the kynurenine pathway (KP) and one of its products, quinolinic acid (QUIN) play a role in the pathogenesis of neurological diseases. Monocytic cells are known to be the major producers of QUIN. However, macrophages have the ability to produce approximately 20 to 30-fold more QUIN than microglia. The molecular origin of this difference has not been clarified yet. Using unstimulated and IFN-y-stimulated cultures of human fcetal microglia and adult macrophages, we assayed mRNA expression of 8 key enzymes of the KP using RT-PCR and QUIN production using GC-MS. We found that after stimulation with IFN-y microglia producedde novo20-fold less QUIN than macrophages. This quantitative difference in the ability to produce QUIN appears to be associated with a lower expression of 3 important enzymes of the KP in microglia: indoleamine 2,3-dioxygenase (IDO), kynureninase (KYNase) and kynurenine hydroxylase (KYN(OH)ase). These results suggest that activated infiltrating macrophages are the most potent QUIN producers during brain inflammatory diseases with playing a lesser role.

Expression of the kynurenine pathway enzymes in human microglia and macrophages.

The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid (QUIN), is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. Alzheimer's disease is the major dementing disorder of the elderly that affects over 20 million peoples world-wide. Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the KP being associated with Alzheimer's disease. Disturbances of the KP have already been described in Alzheimer's disease. Recently, we demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of QUIN, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of QUIN toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease. Together, these data imply that QUIN may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the KP and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of QUIN neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation.

https://www.tandfonline.com/doi/pdf/10.1179/135100002125000550

Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease.

When introduced intracerebroventricularly, quinolinic acid appeared to be the only kynurenine metabolite among those tested (L- and DL-kynurenine sulfate, kynurenic and nicotinic acids, nicotinamide) which induced locomotor excitement and clonic scizures in rats; in high dosage all exhibited convulsant action in mice. L-Kynurenine sulfate (500μg) induced continuous rotation in rats around a longitudinal axis in one or other direction. It also potentiated the convulsant effect of strychnine sulfate and caffeine. Neither the excitatory amino acids, L-glutamic and L-aspartic acids nor the inhibitory amino acids, GABA, glycine and taurine induced excitement or scizures in rats but did in mice. In rats, GABA, glycine and taurine induced sedation, side position and discoordination. The convulsants, strychnine sulfate and pentylenetetrazole, induced scizures both in rats and mice. Differences between species may derive from the better access of intracerebroventricularly administered drugs to mouse hippocampus. Thus mice may be preferable for studies of this type on excitatory amino acids (including kynurenine pathway metabolites) and rats for those on inhibitory amino acids.

Excitatory effects of kynurenine and its metabolites, amino acids and convulsants administered into brain ventricles: differences between rats and mice.

The effect of pretreatment with drugs on generalized clonic-tonic seizures induced by intracerebroventricular (i.c.v.) administration of the endogenous convulsant quinolinic acid (QUIN, 50 micrograms) was studies in rats. Of the inhibitory amino acids tested, only 1-glycine (50 and 100 micrograms, i.c.v.) diminished the number of animals with seizures while taurine and GABA were ineffective. Of the kynurenine metabolites, only kynurenic acid (50 micrograms, i.c.v.) prevented seizures and lethality. Picolinic acid, nicotinic acid and nicotinamide were ineffective. The standard anticonvulsants phenobarbital, diphenylhydantoin and primidone were effective antagonists of QUIN-induced seizures at doses which did not influence pentylenetetrazol seizures. However, the only drug which completely prevented QUIN-induced seizures was diazepam (10 mg/kg). It also prevented pentylenetetrazol seizures in rats in a four times lower dose. The GABA derivatives sodium hydroxybutyrate and phenibut (beta-phenyl-GABA), which are effective QUIN-antagonists in mice, were found to be ineffective in rats. Species differences between rats and mice in the efficacy of antagonists QUIN are discussed.

Antagonism of seizures induced by the administration of the endogenous convulsant quinolinic acid into rat brain ventricles

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Excitatory effects of kynurenine and its metabolites, amino acids and convulsants administered into brain ventricles: differences between rats and mice.

Antagonism of seizures induced by the administration of the endogenous convulsant quinolinic acid into rat brain ventricles