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.

The cells in the central nervous system (CNS) can adapt to injury and inflammation through structural and functional changes, many of which are mediated by the kynurenine pathway (KP). Studies using glia–neuron co-cultures showed that the biflavonoid agathisflavone (FAB), purified from the leaves of Cenostigma pyramidale Tul., a plant native to the Brazilian caatinga, exerts strong neuroprotective effects. This study evaluated whether agathisflavone (1 µM) modulates these responses in human and murine astrocytes and microglia exposed to inflammatory activation with lipopolysaccharide (LPS, 1 µg/mL), excitotoxic activation of NMDA receptors with quinolinic acid (QUIN, 500 µM), or inhibition of the KP rate-limiting enzyme indoleamine 2,3-dioxygenase 1 (IDO1) with 1-methyl tryptophan (1-MT, 1.5 μM). Co-treatment with FAB increased astrocyte viability relative to LPS, QUIN, or 1-MT alone, by up to 35% (p < 0.05), while reducing GFAP overexpression and other features of reactive astrogliosis. FAB decreased the proportion of Iba-1⁺ microglia, indicating anti-inflammatory effects. When combined with QUIN or 1-MT, FAB reversed the elevation of iNOS (p < 0.0001) and reduced IL1β upregulation. FAB also modulated KP activity in a cell type-specific manner. In astrocytes, FAB with QUIN or with 1-MT increased IDO activity, whereas in microglia, FAB alone reduced it. In microglia, kynurenine-3-monooxygenase (KMO) expression was significantly increased under FAB+QUIN or FAB+1-MT (p < 0.0001). Finally, astrocyte-conditioned medium from FAB-treated cells increased the viability of neuron-like PC12 cells by up to 40%. Collectively, these findings show that FAB confers cytoprotective and anti-inflammatory actions on glial cells, modulates KP signalling in a context-dependent manner, and supports neuronal survival under neuroinflammatory conditions.

Tryptophan (Trp) metabolism plays a central role in neuroimmune communication, integrating immune, metabolic, endocrine, and neural responses. In addition to serving as a precursor for serotonin and melatonin biosynthesis, Trp is metabolized by both host cells and the gut microbiota, generating bioactive metabolites that influence gut homeostasis, immune regulation, and brain function. Approximately 95% of free Trp is metabolized via the kynurenine pathway through indoleamine 2,3-dioxygenase-1 (IDO-1) and tryptophan 2,3-dioxygenase (TDO), a pathway considered inflammatory, producing neuroactive metabolites such as kynurenine (KYN), quinolinic acid (QUIN), kynurenic acid (KYNA), and 3-hydroxykynurenine (3-HK). In parallel, a portion of intestinal tryptophan is converted by the gut microbiota into indole and indole-derived metabolites, including indole-3-acetic acid (IAA), indole-3-propionic acid (IPA), and indole-3-aldehyde (IAld). These microbial metabolites contribute to intestinal barrier integrity, immune homeostasis, and gut-brain axis signaling, primarily through activation of the aryl hydrocarbon receptor (AhR). Growing evidence indicates that inflammatory signals mediated by Toll-like receptors (TLRs), interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-1 beta (IL-1β) induce IDO-1 activity, redirecting tryptophan metabolism to the kynurenine pathway and promoting the accumulation of neurotoxic metabolites at the expense of neuroprotective indole-derived compounds. Furthermore, environmental factors such as heavy metals, pesticides, air pollutants, and microplastics can trigger gut dysbiosis and neuroinflammation, thus disrupting tryptophan metabolism and gut-brain communication. This review discusses the mechanisms by which TLR activation, environmental toxins, gut dysbiosis, and dysregulation of the kynurenine and indole pathways contribute to neuroinflammation and neurodegeneration. Additionally, we highlight emerging therapeutic targets, including IDO-1 inhibitors and modulation of kynurenine monooxygenase (KMO), sensitization of AhR, GPR35, and microbiota-derived metabolites, as promising strategies for the prevention and treatment of neurodegenerative disorders.