Kynurenine Pathway in Epilepsy: Unraveling Its Role in Glutamate Excitotoxicity, GABAergic Dysregulation, Neuroinflammation, and Mitochondrial Dysfunction.

Abstract

Epilepsy is a chronic noncommunicable neurological disorder characterized by recurrent seizures and ranks as the seventh most prevalent neurological disease globally. According to the Global Burden of Disease report, 3.40 billion people were affected by epilepsy in 2021. The pathophysiology of epilepsy states that a disturbed balance between excitatory and inhibitory signaling at the synaptic level, which can cause seizure activity, is similar across epilepsies and includes mitochondrial dysfunction, neuroinflammation, and kynurenine metabolites such as kynurenic acid and quinolinic acid. The kynurenine pathway (KP) is the major metabolic pathway in which tryptophan (TRP) is the key precursor which is further converted into a variety of neuroactive substances that can have both neurotoxic metabolites (Quinolinic acid) and neuroprotective metabolites such as kynurenic acid, and picolinic acid. KP plays a significant role in the brain such as the metabolism of TRP, the production of metabolites, and its impact on aging. However, higher concentrations of kynurenine and its metabolites, such as quinolinic acid may increase the frequency and intensity of seizures, and dysregulation of the KP has been linked to the pathophysiology of epilepsy. Concurrently, glutamate and GABA signaling is altered by neuroinflammatory processes linked to epilepsy, which results in excitotoxic neuronal damage. This review aims to provide novel therapeutic strategies that might improve the prognosis of individuals with epilepsy and related disorders by elucidating the mechanisms underlying KP dysregulation in these circumstances. To develop targeted therapies for CNS disorders characterized by inflammation and seizures, it is essential to understand how kynurenine metabolites both promote and prevent excitotoxicity.