What is the significance of Kynurenine pathway dominance?

From the Guidelines

Kynurenine pathway dominance is significantly associated with cognitive impairment and neuroinflammation.

Key Findings

• The kynurenine pathway is activated in long COVID, leading to the production of metabolites such as quinolinic acid, 3-hydroxyanthranilic acid, and kynurenine, which are associated with cognitive impairment 1.
• The kynurenine pathway is also involved in the regulation of immune responses, including the differentiation of regulatory T cells (Tregs) 1.
• Activation of the kynurenine pathway has been linked to neuroinflammation, damage to blood vessels, and injury to neurons, which can contribute to cognitive impairment and other neurological symptoms 1.
• The kynurenine pathway may also play a role in the development of myeloid-derived suppressor cells (MDSCs), which can contribute to immune suppression and tumor growth 1.

Mechanisms

• The kynurenine pathway is activated by the enzyme indolamine 2,3-dioxygenase (IDO), which is induced by inflammatory cytokines and other stimuli 1.
• The production of kynurenine metabolites, such as quinolinic acid, can lead to neuroinflammation and oxidative stress, which can damage neurons and contribute to cognitive impairment 1.
• The kynurenine pathway may also interact with other immune regulatory pathways, such as the TGF-β signaling pathway, to modulate immune responses and contribute to disease pathogenesis 1.

Clinical Implications

• The activation of the kynurenine pathway may be a therapeutic target for the treatment of cognitive impairment and other neurological symptoms associated with long COVID and other diseases 1.
• Further research is needed to fully understand the mechanisms by which the kynurenine pathway contributes to disease pathogenesis and to develop effective therapeutic strategies for modulating this pathway 1.

From the Research

Significance of Kynurenine Pathway Dominance

The kynurenine pathway is a major route of tryptophan degradation in mammalian cells, and its dominance has been implicated in various diseases and disorders. Some of the key points related to the significance of kynurenine pathway dominance include:

• The kynurenine pathway is involved in the regulation of the immune response, with the first enzyme of the pathway, indoleamine-2,3-dioxygenase, being strongly stimulated by inflammatory molecules, particularly interferon gamma 2
• The depletion of tryptophan and generation of kynurenines play a key modulatory role in the immune response, and some of the kynurenines, such as quinolinic acid, 3-hydroxykynurenine, and kynurenic acid, are neuroactive 2
• The kynurenine pathway has been demonstrated to be involved in many diseases and disorders, including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, AIDS dementia complex, malaria, cancer, depression, and schizophrenia, where imbalances in tryptophan and kynurenines have been found 2, 3, 4
• The kynurenine pathway is also involved in the regulation of neuroplasticity and exerting neurotoxic effects, and has been implicated in psychiatric illness in the context of inflammation 5
• The kynurenine pathway is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems 5
• The kynurenine pathway is dysregulated in inflammation and immune activation, and tryptophan-kynurenine pathway is positively associated with inflammation, oxidative stress, endothelial dysfunction, and carotid artery intima-media thickness values in end-stage renal disease patients 6

Key Metabolites and Enzymes

Some of the key metabolites and enzymes involved in the kynurenine pathway include:

• Kynurenic acid (KYNA)
• Quinolinic acid (QUIN)
• 3-hydroxykynurenine (3-HK)
• Picolinic acid (PIC)
• Indoleamine-2,3-dioxygenase (IDO)
• Tryptophan 2,3-dioxygenase

Therapeutic Considerations

The kynurenine pathway has been identified as a potential therapeutic target for various diseases and disorders, including:

• Alzheimer's disease
• Amyotrophic lateral sclerosis
• Huntington's disease
• AIDS dementia complex
• Malaria
• Cancer
• Depression
• Schizophrenia
• Multiple sclerosis
• Novel therapeutic approaches targeting the kynurenine pathway are being developed, including analogs of neuroprotective metabolites and small molecule enzyme inhibitors preventing the formation of neurotoxic compounds 4, 5