- Quinolinic acid (QA) is a neuroactive metabolite produced in the Kynurenine Pathway of tryptophan degradation, which is the primary route of tryptophan catabolism in mammals.
- It is an endogenous agonist at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, with high affinity for the NR2A and NR2B subunits.
- Under normal physiological conditions, QA levels in the brain and cerebrospinal fluid are tightly regulated and kept low by a balance between its production—mainly in activated microglia and macrophages—and its degradation by quinolinate phosphoribosyltransferase (QPRT) into nicotinamide adenine dinucleotide (NAD⁺). This homeostatic control is crucial because QA is a potent excitotoxin that can cause severe neuronal injury when present in excess.
- Biochemically, QA exerts its neurotoxic effects primarily by overstimulating NMDA receptors, leading to excessive calcium influx into neurons. This calcium overload triggers a cascade of deleterious events, including activation of proteases, generation of reactive oxygen and nitrogen species, mitochondrial dysfunction, lipid peroxidation, and DNA damage. In addition to receptor-mediated toxicity, QA can contribute to oxidative stress by promoting the formation of free radicals through Fenton chemistry and by impairing antioxidant defenses. These combined mechanisms result in neuronal swelling, dendritic beading, and eventual cell death, typically through necrosis or apoptosis depending on exposure severity.
- Pathophysiologically, elevated QA levels have been implicated in several neurodegenerative and neuroinflammatory disorders, including Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and HIV-associated neurocognitive disorders. In these conditions, chronic activation of microglia leads to overproduction of QA, overwhelming the degradative capacity of QPRT. The excitotoxic and inflammatory effects of QA contribute to progressive neuronal loss, synaptic dysfunction, and disruption of neural networks. In experimental research, stereotaxic intrastriatal injection of QA in rodents is a well-established model for studying Huntington’s disease-related excitotoxicity, because it selectively destroys medium spiny neurons in the striatum while sparing most interneurons and glia.
- Beyond its neurotoxic role, QA also serves important physiological and metabolic functions. It is an intermediate in the de novo synthesis of NAD⁺, an essential cofactor in cellular energy metabolism and redox balance. This dual nature—being both a crucial metabolic intermediate and a potent neurotoxin—highlights the importance of tight regulatory control over QA biosynthesis and degradation. Under normal immune surveillance, QA production may have antimicrobial benefits, as certain pathogens are sensitive to changes in tryptophan metabolism and NAD⁺ availability. However, in chronic inflammation or persistent infection, dysregulated QA production shifts its role from protective to pathological.
- Therapeutically, strategies to modulate QA levels or block its downstream toxic effects are an active area of research. Approaches include NMDA receptor antagonists to dampen excitotoxic signaling, inhibitors of upstream kynurenine pathway enzymes such as indoleamine 2,3-dioxygenase (IDO) or kynurenine 3-monooxygenase (KMO) to reduce QA synthesis, and enhancement of QPRT activity to accelerate QA clearance. Additionally, antioxidants and mitochondrial protectants have been explored to counteract QA-induced oxidative damage. Such interventions have shown promise in preclinical models, but translation into clinical practice remains challenging due to the widespread physiological importance of the kynurenine pathway and the potential for off-target metabolic effects.
