Quinurenina, ¿una vía enzimática estresante?

Kynurenine, a stressful enzymatic pathway?

Stress-related regulation through the kynurenine pathway is relevant to neuropsychiatric and neurodegenerative disorders.

The kynurenine pathway (KP), which is activated during stress and infection, has been implicated in the pathophysiology of neurodegenerative and psychiatric disorders.

Activation of this tryptophan metabolism pathway produces neuroactive metabolites that have the potential to interfere with normal neuronal functioning, which may contribute to altered neuronal transmission and the emergence of symptoms of these brain disorders.

This review investigates the involvement of kynurenine in a variety of neurological disorders, examining recent in vitro, in vivo, and clinical findings, and highlights evidence indicating that the enzyme is a potential therapeutic target in neuropsychiatric, neurodegenerative, and stress-related disorders.

How does kynurenine work?

To demonstrate how it works, a group of researchers worked with rodents that underwent a mild/chronic stress procedure in certain situations.

These procedures resulted in peripheral and brain alterations in the kynurenine pathway (KP) on every occasion.

  • The present study tested whether disturbances in this pathway are associated with differences in anxiety- and depression-like behaviors in stressed and non-stressed rodents
  • In the experiment, both groups underwent the elevated plus maze test and the forced swim test.

Upon completion of the tests, biological assays were conducted to quantify tryptophan (TRP), serotonin (5-HT), and TRP-kynurenine (KYN) metabolites in two “corticolimbic” structures involved in mood regulation (cingulate cortex = CC; amygdala = AMY).

This study demonstrated that an elevated peripheral KYN/TRP ratio (lung) correlates with the magnitude of anxiety- and depression-like phenotypes only in stressed rodents.

These results suggest that elevated peripheral kynurenine could underlie biochemical changes in the brain and, consequently, could be involved in the modulation of behavior induced by chronic stress; undoubtedly, a modulated pathway plays a crucial role in mood.

Where does tryptophan come into play?

Tryptophan is an essential dietary amino acid required for protein synthesis, but it also serves as a precursor to serotonin.

However, in addition to these biological functions, tryptophan also serves as a precursor to the kynurenine pathway, which has neurotoxic metabolites (quinolinic acid) and neuroprotective metabolites (kynurenic acid).

Glucocorticoid hormones and inflammatory mediators, both of which are increased by stress, have been shown to divert tryptophan along the kynurenine pathway and away from serotonin synthesis.

Although little published data exist on the effects of stress on the enzymes that regulate this pathway regionally throughout the brain, time-dependent changes were found in differential enzymes along the kynurenine metabolism pathway, particularly those involved in the production of quinolinic acid, within the amygdala, hypothalamus, and medial prefrontal cortex, with no changes in the hippocampus.

These regional differences may provide mechanistic insight into the processes that become chronically dysregulated in stress-related disorders.

Have you been feeling very stressed lately?

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