Quinolinic acid: an endogenous neurotoxin with multiple targets

Abstract

Quinolinic acid (QUIN), a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF) and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA) receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death.

Figure 1

Kynurenine pathway. NAD⁺= nicotinamide adenine dinucleotide.

Figure 2

Multiple mechanisms leading to QUIN cytotoxicity. One of the principal toxicity mechanism of QUIN is through the over stimulation of the NMDA receptor which is powered by the lack of uptake of QUIN from the extracellular space. Additionally, QUIN enhances the release of synaptosomal glutamate as a consequence of the inhibition of glutamate uptake into the astrocytes that will lead to overstimulation of receptors. Furthermore, QUIN can decrease the activity of antioxidant enzymes promoting ROS production and generating lipid peroxidation. Also, QUIN may inhibit the activity of mitochondrial complexes leading to energetic deficit, activating caspases and releasing cytochrome c. All these factors induce cytoskeleton destabilization, DNA damage, and cell death.