Quinolinic Acid - Production in Vivo

Production in Vivo

Quinolinic acid is a byproduct of the kynurenine pathway which is responsible for catabolism of tryptophan in mammals. This pathway is important for its production of the coenzyme nicotinamide adenine dinucleotide (NAD+) and produces several neuroactive intermediates including quinolinic acid, kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HANA). Quinolinic acid's neuroactive and excitatory properties are a result of NMDA receptor agonism in the brain. It also acts as a neurotoxin, gliotoxin, proinflammatory mediator, and pro-oxidant molecule.

Quinolinic acid is unable to pass through the blood-brain barrier (BBB) and must be produced within the brain microglial cells or macrophages which have passed the BBB. While quinolinic acid cannot pass the BBB, kyurenic acid, tryptophan and 3-hydroxykynurenine do and subsequently act as precursors to the production of quinolinic acid in the brain. The quinolinic acid produced in microglia is then released and stimulates NMDA receptors resulting in excitatory neurotoxiticity. While astrocytes are not able to produce quinolinic acid directly, they are capable of producing KYNA, which when released from the astrocytes can be taken in by migroglia which can in turn increase quinolinic acid production.

Microglia and macrophages produce the vast majority of quinolinic acid present in the body. This production is increased during an immune response. It is suspected that this is a result of activation of indoleamine dioxygenases (specifically IDO-1 and IDO-2) as well as tryptophan 2,3-dioxygenase (TDO) stimulation by inflammatory cytokines (mainly IFN-gamma, but also IFN-beta and IFN-alpha).

IDO-1, IDO-2 and TDO are present in microglia and macrophages. Under inflammatory conditions and conditions of T cell activation, leukocytes are retained in the brain by cytokine and chemokine production which can lead to the breakdown of the BBB thus increasing the quinolinic acid which enters the brain. Furthermore, quinolinic acid has been shown to play a role in destabilization of the cytoskeleton within astrocytes and brain endothelial cells contributing to the degradation of the BBB which results in higher concentrations of quinolinic acid in the brain.