Tryptophan metabolism through the kynurenine pathway in glial cells

Deivison Silva Argolo, Lucas Matheus Gonçalves de Oliveira, Gilles J. Guillemin, George E. Barreto, Arthur Morgan Butt, Silvia Lima Costa*, Maria de Fátima Dias Costa*

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

The central nervous system (CNS) relies on complex and dynamic interactions between neurons and glial cells. Among glial cells, astrocytes regulate the chemical environment surrounding neurons and supply essential nutrients for brain metabolism whereas microglia, the resident macrophages of the CNS, play critical roles in homeostasis, defense, and responses to injury. Both microglia and astrocytes contribute to the regulation of excitotoxicity and inflammation mediated by the metabolism of tryptophan (Trp) via the kynurenine pathway. Trp metabolism generates several bioactive metabolites, including quinolinic acid (QUIN) and kynurenic acid (KYNA), which have opposing effects. QUIN, produced by activated microglia, acts as an agonist for NMDA receptors; excessive stimulation of these receptors can lead to excitotoxicity and neuronal death. Conversely, KYNA, primarily produced by astrocytes via kynurenine 2,3-aminotransferases (KAT), acts as an NMDA receptor antagonist, conferring neuroprotection by mitigating excitotoxicity. Dysregulation of the Trp metabolism is implicated in many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and amyotrophic lateral sclerosis, as well as in various neuropsychiatric disorders. This review examines the cellular and molecular mechanisms underlying Trp metabolism in glial cells, highlighting the unique contributions of each glial phenotype, the implications for CNS pathologies, and the potential biomarkers and therapeutic targets for restoring homeostasis and preventing disease progression.

Original languageEnglish
Article number14
Pages (from-to)1-21
Number of pages21
JournalNeuroglia
Volume6
Issue number1
DOIs
Publication statusPublished - 12 Mar 2025

Keywords

  • Astrocytes
  • inflammation
  • kynurenine pathway
  • microglia
  • neurodegeneration

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