Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

Table 1

Effect of various molecules on the toxicity induced by QUIN.

Compound	Mechanism of action	Reference
Melatonin	(i) Attenuates the convulsant effect of quinolinate; (ii) Partially protects against the increase of circling behavior; (iii) Protects against the increase in ROS and protein carbonyl levels as well as the inhibition of superoxide dismutase activity	[56–58]
Denepryl	(i) Acts as a potent-free radical scavenger; (ii) Increases the activity of endogenous antioxidant enzymes	[59]
𝛼-phenyl-t-butyl nitrone	(i) Presents cytoprotective effects	[60]
Polyamines such as spermine and spermidine	(i) Inhibit QUIN-induced TBARS production and have antioxidant properties	[61]
Deferoxamine (iron chelator)	(i) Reduces lipid peroxidation	[62]
Reduced glutathione	(i) Decreases lipid peroxidation and ROS formation in brain synaptosomes	[63]
Selenium	(i) Attenuates the QUIN-induced early reactive oxygen species formation and lipid peroxidation; (ii) Prevents loss of mitochondrial reductive capacity and morphological alterations in the striatum; (iii) Induces stimulation of striatal GPx activity; (iv) Prevents I𝜅B-𝛼 degradation; (v) Reduces the nuclear translocation of NF-𝜅B and inhibits the activity of caspase-3, resulting in internucleosomal DNA preservation; (vi) Induces an early stimulation of TrxR activity	[64–66]
Selenocompounds such as ebselen	(i) Inhibit TBARS production	[67]
Ksheerabala	(i) Decreases de lipid peroxidation and protein peroxidation; (ii) Increases the activity of antioxidant enzymes	[68]
Licofelone, Montelukast, and Pioglitazone	(i) Significantly improve body weight, locomotor activity, oxidative defense, activity of mitochondrial enzyme complex, rotarod performance, and balance beam walk	[69–71]
Dizocilpine (MK-801)	(i) Improves body weight, behavioral alterations (locomotor activity and rotarod performance) and attenuates oxidative damage and mitochondrial enzymes complexes dysfunction; (ii) Improves learning task in rats receiving chronic i.c.v, infusion of QUIN; (iii) Decreases release of lactate dehydrogenase (LDH) in NSC-34 cells after 48 h of QUIN	[72–74]
Nimesulide, rofecoxib, and caffeic acid	(i) Restore mitochondrial enzyme complex activities in striatum	[75, 76]
Memantine	(i) Significantly attenuates QUIN-mediated PARP activation, NAD^+ depletion, and LDH release in both neurons and astrocytes as well as decreases LDH release in NSC-34 cells induced by QUIN	[74, 77]
2-amino-5-phosphonopentanoic acid (APV)	(i) Decreases QUIN-induced LDH release in NSC-34 cell; (ii) Abolishes the release of aspartate and glutamate	[74, 78]
L-carnitine and acetyl L-carnitine	(i) Reduce lipid peroxidation; (ii) Prevent mitochondrial dysfunction in brain synaptosomes; (iii) Attenuate the behavioral alterations and striatal degeneration	[79–81]
Tolmetin and sulindac	(i) Reduce the generation of superoxide anions; (ii) Reduce the lipid peroxidation after an intrahippocampal injection of QUIN; (iii) Reduce the spatial memory deficit	[82, 83]
Acyclovir	(i) Inhibits the lipid peroxidation after in vitro and in vivo exposure to QUIN; (ii) Reduces necrosis of hippocampal neurons	[84]
Nitroarginine and L-arginine	(i) Prevent lipid peroxidation induced by QUIN	[85]
Iron metalloporphyrins such as Fe(TPFPP) and Fe(TPPS)	(i) Decrease 3-nitrotyrosine levels; (ii) Prevent lipid peroxidation and mitochondrial dysfunction; (iii) Reduce the DNA fragmentation and decreases caspase-3-like activation; (iv) Abolish the circling behavior; (v) Partially recover GABA levels; (vi) Reduce the immunochemical expression of IL-6 and iNOS	[86–88]
Safranal	(i) Inhibits lipid peroxidation; (ii) Inhibits oxidative DNA damage; (iii) Improves hippocampal antioxidant and thiol redox status	[89]
Polyphenols (epigallocatechin gallate, curcumin)	(i) Inhibit QUIN-induced nNOS activity and subsequent nitrite production; (ii) Reduce 3-nitrotyrosine production; (iii) Prevent DNA damage and PARP-1 activation; (iv) Attenuate QUIN-induced Ca^2+ influx	[90]

Thiobarbituric acid reactive species: TBARS; reactive oxygen species: ROS; thioredoxin reductase: TrxR; glutathione peroxidase: GPx; nuclear factor-kappaB: NF-𝜅B; quinolinic acid: QUIN; deoxyribonucleic acid: DNA; 𝛾-Aminobutyric acid: GABA; interleukin 6: IL-6; inducible nitric oxide synthase: iNOS.