KMO Inhibition Improves Seizures and Depressive-like Behaviors Without Aggravating Cognitive Impairment in Epileptic...

The objective of this study is to investigate the effects of kynurenine-3-monooxygenase (KMO) inhibition on seizures, depressive-like behaviors, and cognitive functions in epileptic mice, and to elucidate its impact on the kynurenine metabolic pathway. Male Kunming (KM) mice were randomized into four groups: the epileptic model (EM), epileptic model treated with Ro 61-8048 (RM), healthy control (HC), and healthy control treated with Ro 61-8048 (RC). Chronic epilepsy was induced in the EM and RM groups via an intraperitoneal pilocarpine injection (225 mg/kg). The RM and RC groups received Ro 61-8048 (42 mg/kg). The seizure frequency was monitored continuously using a 24 h video recording. Depressive-like behaviors were assessed with the sucrose preference test (SPT) and forced swim test (FST); cognitive function was evaluated with the Y-maze test and open field test (OFT). The concentrations of kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), and 3-hydroxyanthranilic acid (3-HANA) were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Compared to the EM group, the RM group exhibited a reduced seizure frequency and severity (p < 0.05), ameliorated depressive-like behaviors (increased sucrose preference in SPT, and decreased immobility time in FST, p < 0.05), and enhanced cognitive performance (elevated spontaneous alternation and reduced non-sequential alternation in a Y-maze, and increased time and distance in a central open field area, p < 0.05). Mechanistically, compared to the RC group, the RM group showed an increased KYNA/KYN ratio, and a decreased 3-HK/KYN ratio (p < 0.05) KMO inhibition rectifies the neurotoxic-neuroprotective imbalance in the kynurenine pathway (downregulating the 3-HK/3-HANA ratio and upregulating the KYNA/KYN ratio), thereby decreasing seizures, depressive-like behaviors, and cognitive deficits. These findings suggest KMO inhibition is a potential therapeutic strategy for epilepsy-associated depression. A further investigation of its mechanisms and clinical applicability is warranted.