Quinolinic Acid
General information
Quinolinic acid (2,3-pyridinedicarboxylic acid) is a metabolite of tryptophan and an essential link between the immune system and the brain (stimulations of inflammatory responses make macrophages release gamma-interferon). Quinolinic acid is a product of the kynurenine pathway and a highly potent excitotoxin for the CNS. It also has neurotoxic effects. The acid is an agonist of N-methyl-D-aspartate (NMDA) receptors. Quinolinic acid also inhibits glutamine synthetase (an enzyme in the glutamate-glutamine cycle) and increases the levels of glutamate, which is neurotoxic if presented at high levels for long periods of time and acts in synergy with high quinolinic acid. Besides, quinolinic acid may reduce the activity of antioxidant enzymes, which promote ROS production and cause lipid peroxidation. It interacts with 2-valent iron to form a complex that induces active O2 and nitrogen, causing severe oxidative stress (the levels of quinolinic acid should be monitored in patients with hemochromatosis and high ferritin).
Quinolinic acid may inhibit activity of mitochondrial complexes, thereby causing energy deficiency, activating caspases, and releasing cytochrome C. All these factors cause cytoskeleton destabilization, DNA damage, and cell death.
Quinolinic acid interacts with NMDA receptors of glutamatergic neurons that respond to pain and other peripheral signals. This biochemical event is an origin of typical pain symptoms of viral infections.

If these receptors are overstimulated, the neurons may degenerate with permanent loss of normal brain functions. That is called glutamate excitotoxicity. Toxicity of quinolinic acid is an etiological factor in Alzheimer’s disease.
The Figure demonstrates the neuronal release, glutamate binding and recycling. Toxicants (such as toxic metals, benzene, phthalate, etc.) may enhance sensitization of NMDA receptors and lower a threshold for quinolinate-induced neuronal loss. It’s interesting that rats exposed to methylmercury on gestational day 8 demonstrated significant elevations in quinolinic acid on day 21.
Biochemistry
A beneficial effect of converting tryptophan into quinolinic acid is production of nicotinic acid to maintain its cofactor form, NAD+. This stage requires the enzyme quinolinic acid phosphoribosyl transferase to bind the adenosyl moiety of NAD. The transferase has low activity in the brain resulting in the elevations in quinolinic acid as an unprocessed intermediate. Quinolinate tends to be converted into NAD+ in the liver.
Measles Vaccine and Quinolinate
Measles vaccination induces (enhances) gamma-interferon and causes stimulation of the enzyme IDO. IDO, in its turn, catalyzes initial oxidation of tryptophan including quinolinate production. IDO is stimulated by glucocorticoids, while estrogens react against this effect by means of a decrease in the rate of the kynurenine pathway and preservation of tryptophan. One of the ultimate outcomes of estrogen action is an elevation in tryptophan levels. Other cytokines may also have an impact on the extent and duration of the macrophagal kynurenine pathway reaction.
Intestine and Quinolinate
The intestine is often a source of chronic intoxication. Induction of inflammatory signals by gamma-interferon indicates that elevated levels of quinolinic acid may be the result of intestinal inflammation. In this case, it is recommended to check the ratio of quinolinic acid/kynurenic acid. If it is more than 2, neurotoxicity may be suspected.
Quinolinate and Brain
The hippocampus is a brain structure having a lot of NMDA receptors, which are sensitive to the neurotoxic effects of quinolinate. Since modulation of glutamatergic activity affects the excitation patterns of dopaminergic neurons, the process of motivation is compromised and the primary learning system is impaired. This often occurs during the episodes of viral infections, that’s why it is important to regard a viral infection as a metabolic event triggering impairments of various brain functions. Magnesium effectively competes for NMDA receptors to prevent calcium from entering a neuron (thus, magnesium sulfate infusion can be an effective and affordable way to reduce morbidity and mortality associated with acute glutamate toxicity). A similar protective effect of magnesium is found in prevention of deaths due to birth asphyxia. High levels of quinolinic acid often accompany chronic fatigue syndrome, which is caused by viral load in many cases. The levels of picolinic acid should also be checked.
E104 (quinoline yellow) is an additive causing elevations in quinolinic acid.
Elevated Levels
High levels of quinolinic acid lead to degeneration of the central nervous system. Quinolinic acid is elevated in the following cases:

  • High immune response of the body (especially, during viral load);
  • Chronically high levels of cortisol;
  • Beta-amyloid peptides of Alzheimer’s disease;
  • Overconsumption of tryptophan supplements;
  • Calcium channel dysfunction inhibiting neuronal functions;
  • Excessive exposure to phthalates. Quinolinic acid is as toxic as phthalates.

To correct the acid levels, it is necessary:

  • To stop taking tryptophan supplements;
  • To reduce viral/bacterial/fungal load;
  • Consider the use of immunomodulatory therapy;
  • To prevent exposure to plastic (water or food in plastic packaging).
Quinolinate-induced neuronal damage in the brain may be mitigated by means of supplementation with magnesium, acetyl-L-carnitine, melatonin, B6, curcumin, boswellia, olive leaf, physetin and pomegranate extract.
It is also recommended to consider the possibility of supplementation with B6 in the form of P-5-P (starting with small doses), L-carnitine (should be used if there is no intestinal dysbacteriosis), magnesium in various forms (malate, glycinate, threonate (passes through the BBB to the brain)), transdermal magnesium lotion and Epsom salt bath. It is not recommended to prescribe Omega-3 as this supplement may cause an increase in quinolinic acid (see "Picolinic Acid" for details).

Elevated levels of quinolinic acid are also observed in patients with inflammation in the central nervous system due to Lyme disease.

The following substances reduce the levels of quinolinic acid:

  • Selenium;
  • Melatonin;
  • Theanine;
  • Green tea polyphenols;
  • Curcumin and piperine.
Kynurenic Acid to Quinolinic Acid Ratio
Kynurenic acid obtained as a result of tryptophan processing is converted into quinolinic acid in the presence of B6 (P5P). While kynurenic acid has a calming effect, quinolinic acid is an excitotoxin, which may overstimulate the nervous system.

A high ratio indicates the following:

  • Excessive inflammation due to recurrent infections;
  • Tryptophan overconsumption;
  • Overstimulation of the immune system;
  • Excessive adrenal production of cortisol or excessive exposure to phthalates.

A low ratio indicates the following:

  • Impaired kynurenine metabolism leading to overproduction of quinolinic acid (see above).
Excessive tryptophan is processed in the liver via the kynurenine pathway with the production of nicotinic acid. That reduces the demand for dietary vitamin B3.
References
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