DYSREGULATION OF THE TRYPTOPHAN-KYNURENINE PATHWAY AND ITS IMPLICATIONS FOR SEIZURE SUSCEPTIBILITY IN TEMPORAL LOBE EPILEPSY

Temporal lobe epilepsy (TLE) is characterized by recurrent seizures, hippocampal hyperexcitability, and chronic neuroinflammation. Studies from our lab highlighted dysregulation of the tryptophan-kynurenine pathway (TKP) in patients with Mesial Temporal Lobe Epilepsy with hippocampal sclerosis (MTLE-HS) and acute TLE model, identifying Kynurenic acid (KYNA) as a key endogenous neuroprotective and anti-inflammatory metabolite. Elucidating kynurenine pathway alterations and their therapeutic relevance in chronic TLE is critical to understand long-term epileptogenesis and network remodeling. The present study focused on investigating the role of TKP dysregulation in chronic TLE. A lithium-Pilocarpine chronic rat model of TLE was developed and recurrent seizures were observed through video-monitoring. After 30 days, hippocampus and ATL tissues were resected and H & E staining revealed significant neuronal degradation in chronic hippocampus. Significant alterations in the apical and basal dendritic length of hippocampus and ATL neurons were observed utilising Golgi-cox staining, suggesting region specific modulation in chronic TLE. The TKP pathway metabolites were quantified through HPLC where significant disruption of the kynurenine pathway, marked by alterations in the hippocampal KYNA levels were observed, accompanied by alterations in the mRNA expression of key pathway enzymes, including IDO, KAT-II and PNPO. Dysregulation of the kynurenine pathway, reflected by altered KYNA levels, was closely associated with enhanced NMDA receptor–mediated excitotoxicity. Together, these findings highlight the kynurenine pathway, particularly KYNA, as a key contributor in mediating hyperexcitability in TLE, suggesting its potential as a therapeutic target for TLE.