The kynurenine pathway storm in epilepsy: mechanisms and therapeutic implications.

The kynurenine pathway (KP) is the main route for tryptophan (TRP) degradation and plays a crucial role in neuroinflammation, oxidative stress and neurotransmission, which holds significant clinical significance. The dysregulation of this pathway is closely related to neurological disorders such as epilepsy, and its metabolic products can promote the occurrence of epileptic seizures and comorbid depression. This review aims to clarify the complex mechanisms of the KP in the occurrence and development of epilepsy and to explore its potential as a therapeutic target for epilepsy and comorbid depression. This is a narrative review and synthesis of the current literature. We reviewed animal experiments and clinical studies, elaborating in detail on how metabolites of the KP and their key enzymes function in the context of epilepsy by regulating neuroinflammation, oxidative stress, glutamatergic signaling, and the gut-brain axis. We also explored the interaction between antiseizure medications (ASMs) and the KP, and evaluated the potential value of targeting key enzymes (such as indoleamine 2,3-dioxygenase, IDO) as a new therapeutic strategy for epilepsy. This review particularly focuses on the promoting effect of KP imbalance on comorbid depression, clarifying how IDO-mediated TRP metabolism changes constitute a common mechanism basis, jointly leading to the occurrence of epilepsy and depression-like behaviors. The occurrence and development of epilepsy are closely related to the imbalance of the KP, specifically manifested as a decrease in kynurenic acid (KYNA) level and an increase in quinolinic acid (QA) level. The IDO-mediated shift of TRP metabolism towards the KP is established as a critical mechanism underlying depression comorbidity in epilepsy. Therapeutic modulation of this pathway, through targeting key enzymes like IDO and restoring the KYNA/QA balance, presents a viable strategy for improving the cerebral microenvironment. This approach holds promise for enhancing seizure control, counteracting drug resistance, and concurrently alleviating comorbid depressive symptoms.