Quinolinic Acid - Toxicity

Toxicity

Quinolinic acid is an excitotoxin in the CNS. It reaches pathological levels in response to inflammation in the brain which activates resident microglia and macrophages. High levels of quinolinic acid can lead to hindered neuronal function or even apoptotic death. Quinolinic acid produces its toxic effect through several mechanisms; primarily as its function as an NMDA receptor agonist, which triggers a chain of deleterious effects, but also through lipid peroxidation, and cytoskeletal destabilization. The gliotoxic effects of quinolinic acid further amplify the inflammatory response. Quinolinic acid mainly affects neurons located in the hippocampus, striatum, and neocortex, due to the selectivity towards quinolinic acid by the specific NMDA receptors residing in those regions.

When inflammation occurs, quinolinic acid is produced in excessive levels through the kyurinene pathway. This leads to over excitation of the NMDA receptor, which results in an influx of Ca2+ into the neuron. High levels of Ca2+ in the neuron trigger an activation of destructive enzymatic pathways including protein kinases, phospholipases, NO synthase, and proteases. These enzymes will degenerate crucial proteins in the cell and increase NO levels, leading to an apoptotic response by the cell, which results in cell death.

In normal cell conditions, astrocytes in the neuron will provide a glutamate-glutamine cycle which results in reuptake of glutamate from the synapse into the pre-synaptic cell to be recycled, keeping glutamate from accumulating to lethal levels inside the synapse. When quinolinic acid is at pathological concentrations, a reduction of glutamine synthetase, a critical enzyme in the glutamate-glutamine cycle occurs.

This results in a loss of function of the cycle, and results in an accumulation of glutamate. This glutamate further stimulates the NMDA receptors, thus acting synergistically with quinolinic acid to increase its neurotoxic effect by increasing the levels of glutamate, as well as inhibiting its uptake. In this way, quinolinic acid self-potentiates its own toxicity. Furthermore, quinolinic acid results in changes of the biochemistry and structure of the astrocytes themselves, resulting in an apoptotic response. A loss of astrocytes results in a pro-inflammatory effect, further increasing the initial inflammatory response which initiates quinolinic acid production.

Quinolinic acid can also exert neurotoxicity through lipid peroxidation, as a result of its pro-oxidant properties. Quinolinic acid can interact with Fe(II) to form a complex which induces a reactive oxygen and nitrogen species (ROS/RNS), notably the hydroxyl radical •OH. This free radical causes oxidative stress by further increasing glutamate release and inhibiting its reuptake, and results in the breakdown of DNA in addition to lipid peroxidation. Quinolinic acid has also been noted to increase phosphorylation of proteins involved in cell structure, leading to destabilization of the cytoskeleton.