Long-term cuprizone administration resulted in cognitive decline and kynurenine metabolic disturbance: novel findings

The cuprizone (CPZ) animal model is suitable for studying the neurodegenerative processes of multiple sclerosis (MS). Cognitive decline is widespread in MS and markedly impacts patients' quality of life. Alterations in the kynurenine pathway (KP) of tryptophan degradation are also present in MS and its CPZ model. Our aim was to investigate the KP while analyzing cognitive abilities during long-term CPZ exposure and recovery. Mice were fed with 0.2% CPZ for 12 weeks followed by a 4-week recovery phase. At multiple time points during demyelination and remyelination, we analyzed cognitive ability using the Y-Maze test and examined KP metabolites in plasma and brain regions by UHPLC-MS/MS. We observed significant changes in neuroactive KP metabolites, such as kynurenic acid (KYNA), quinolinic acid (QUIN), picolinic acid (PA), and 3-hydroxykynurenine (3-HK), in response to CPZ treatment. As the treatment progressed, several metabolites decreased, while QUIN and PA showed dynamic changes. Metabolite levels tended to normalize during remyelination. In parallel, we detected notable cognitive decline in the CPZ-treated group. Our study firstly confirmed the link between kynurenine metabolite abnormalities in the CPZ model and MS, emphasizing the relevance of the kynurenine metabolite profile for understanding neurodegenerative processes.