Tryptophan metabolism and neuronal injury in ischemic stroke: metabolic pathways, mechanisms of action, and advances in therapeutic interventions

Tryptophan is metabolized primarily through the kynurenine, indole, and serotonin pathways. Post-stroke inflammation, gut microbial dysbiosis, and altered barrier function can affect these pathways and modify the levels of neuroactive and immunoactive metabolites. Research has focused predominantly on the kynurenine pathway. Quinolinic acid and 3-hydroxykynurenine are associated with excitotoxicity, oxidative stress, and mitochondrial injury, whereas kynurenic acid can antagonize N-methyl-D-aspartate (NMDA) receptor signaling. Selected microbiota-derived indole metabolites can regulate aryl hydrocarbon receptor (AhR) signaling, inflammatory responses, and barrier function. The serotonin pathway and its downstream product melatonin also participate in post-stroke inflammation and cellular injury. Exogenous melatonin has shown protective effects in experimental models. This review examines alterations in these three pathways during ischemic stroke and their relationships with excitotoxicity, oxidative stress, apoptosis, ferroptosis, and other cell-death processes. It also summarizes advances in metabolite supplementation, kynurenine pathway modulation, and AhR-related interventions. By integrating metabolite sources, brain exposure, and cellular responses, this review provides a mechanistic framework for understanding post-stroke neuronal injury and identifying candidate intervention targets.