Epilepsy as a Disorder of Neuroimmune Metabolism: The Kynurenine Pathway as a Link Between Cognitive and Psychiatric...

In this narrative review we summarise some of the roles played by glutamate and its receptors in both epilepsy and schizophrenia, before presenting the kynurenine pathway of tryptophan metabolism as a generator of compounds acting at least partly by modulating those receptors. Increasing evidence indicates that epilepsy involves interactions between neuronal excitability, cellular metabolism and immune system signalling. The kynurenine pathway of tryptophan metabolism occupies a central position within this neuroimmune-metabolic network through its regulation of glutamatergic neurotransmission and both innate and adaptive arms of the immune response. The modulation of glutamate receptors is achieved by activating NMDA-sensitive sites by quinolinic acid and the blockade of all glutamate ionotropic receptors by kynurenic acid. In addition, emerging evidence is discussed which implicates the GRIA3-mediated AMPA receptor subunit GluA3 function in epilepsy and schizophrenia, and observations suggesting antagonistic actions of 3-hydroxykynurenine at kainate receptors. The evidence reviewed suggests that the modulation of the kynurenine pathway metabolism may be relevant to the development of agents which increase understanding of the mechanisms involved in epilepsy, while also addressing the psychiatric and systemic inflammatory disorders that frequently accompany it. A dysregulation of neuroimmune metabolism represents a framework for improved understanding of epilepsy and its associated neuropsychiatric comorbidities, while highlighting opportunities and challenges for therapies targeting glutamatergic and immunometabolic pathways.