Kynurenine pathway imbalance may drive seizures and depression in epilepsy

A new narrative review published in Acta Epileptologica argues that a single metabolic route, the kynurenine pathway, sits at the crossroads of epileptic seizures, drug resistance and the depression that burdens roughly a third of epilepsy patients. The authors, led by Yuxuan He and Liang Yu, synthesize animal experiments and clinical studies to describe how the breakdown of tryptophan, the amino acid best known for feeding serotonin production, can instead flood the brain with neuroactive metabolites that tip neurons toward hyperexcitability. Their central claim is striking: in epilepsy, levels of kynurenic acid, a neuroprotective metabolite, fall, while quinolinic acid, an excitotoxic compound, rises, and this imbalance may be a shared mechanism behind both seizures and comorbid depressive symptoms.

The kynurenine pathway is the main route for degrading tryptophan in the human body, consuming roughly 95 percent of the amino acid and generating neuroactive products along the way. The pathway begins when the enzyme indoleamine 2,3-dioxygenase, or IDO, catalyzes the conversion of tryptophan to kynurenine in extrahepatic tissues such as the brain and immune system, while the liver version of the enzyme, tryptophan 2,3-dioxygenase, performs the same step mostly within the liver. From kynurenine, metabolism flows along a main line through kynurenine monooxygenase, kynureninase and 3-hydroxyanthranilic acid 3,4-dioxygenase toward quinolinic acid and, ultimately, NAD plus. Four side branches divert intermediates toward kynurenic acid, xanthurenic acid, anthranilic acid and picolinic acid instead. Which direction the flux takes depends on the relative activities of the enzymes kynurenine monooxygenase and kynurenine aminotransferase, and this balance determines whether the brain receives protective or damaging chemistry.

Quinolinic acid is the pathway’s principal cytotoxic metabolite and is produced predominantly by activated microglia, the brain’s resident immune cells. It functions as an agonist of NMDA receptors, driving calcium overload, mitochondrial dysfunction and increased generation of reactive oxygen species. The review recounts classic experiments showing that intraventricular administration of quinolinic acid triggers convulsions in mice, with a dose of 3 nanomolar sufficient to induce electroencephalogram changes characterized by recurrent high-voltage sharp waves, while a higher dosage of 120 nanomolar is required to provoke epileptic seizures. Prolonged exposure to low concentrations of the compound, 100 nanomolar for seven weeks, induces excitotoxic injury in organotypic cultures of rat cortical-striatal tissue. Quinolinic acid also disrupts glutamate homeostasis by inhibiting astrocytic uptake of glutamate and down-regulating glutamine synthetase, and it can cause excessive phosphorylation of cytoskeletal proteins, impairing axonal transport and synaptic plasticity.

Kynurenic acid works in the opposite direction. Synthesized mainly in astrocytes by kynurenine aminotransferase II, it antagonizes the glycine binding site on NMDA receptors and, even at nanomolar concentrations, can reduce the brain’s glutamate level by approximately 30 to 40 percent. It also blocks alpha7 nicotinic acetylcholine receptors, activates GPR35 and the aryl hydrocarbon receptor, and lowers calcium mobilization, easing mitochondrial damage. Systemic administration of four classic convulsant agents, pentylenetetrazol, pilocarpine, lycorine and kainic acid, consistently elevated kynurenic acid levels in vivo, which the authors interpret as a negative feedback response against seizures. Yet the metabolite is a double-edged sword: antagonism at the glycine site can impair long-term potentiation and damage working memory, learning and information integration, a caveat the review flags for any therapeutic strategy that raises kynurenic acid.

The pathway’s entanglement with inflammation forms a self-reinforcing loop. Pro-inflammatory cytokines such as TNF-alpha, IFN-gamma and IL-6 induce excessive microglial activation, upregulate IDO1 expression and promote increased quinolinic acid synthesis, while astrocyte dysfunction reduces kynurenic acid production. Inflammatory factors including IL-1beta, IL-6, IL-8 and TNF-alpha are positively correlated with the activity of kynurenine monooxygenase, further steering metabolism toward the quinolinic acid branch. Quinolinic acid then triggers astrocytes to release monocyte chemoattractant protein-1, RANTES and IL-8, amplifying neuroinflammation. Reactive oxygen species generated downstream weaken GABAergic inhibition and enhance glutamatergic excitation, lowering the seizure threshold, and recurrent seizures in turn generate more reactive oxygen species. Clinical data support the picture: in the cerebrospinal fluid of epilepsy patients, kynurenine is significantly increased while kynurenic acid and tryptophan are significantly decreased, and in patients with status epilepticus, elevated quinolinic acid reflects a more severe seizure state.

Animal models reveal that IDO’s role is context-dependent rather than uniform. Knockout of IDO1 delays the onset of lithium-pilocarpine-induced status epilepticus and significantly reduces the frequency, duration and severity of spontaneous recurrent seizures in the chronic phase, apparently by diminishing kynurenine and downstream quinolinic acid generation. But in a viral encephalitis epilepsy model induced by Theiler’s murine encephalomyelitis virus, IDO1 knockout produced the opposite effect, resulting in a higher incidence of epilepsy, suggesting that in viral encephalitis the enzyme participates in early host defense. Global knockout of IDO2 had no effect on seizures in that model, whereas specific deletion of IDO2 in microglia significantly reduced epilepsy incidence, consistent with IDO2 driving a pro-inflammatory microglial phenotype. In the serum of patients with idiopathic generalized epilepsy, IDO activity remains elevated even without recent clinical seizures, hinting at an adaptive metabolic response.

The gut-brain axis adds another layer. Germ-free mice show suppressed conversion of tryptophan to kynurenine, and supplementation with Bifidobacterium increases plasma kynurenic acid in rats. During intestinal inflammation, IDO1 expression rises, and the resulting kynurenic acid acts on the aryl hydrocarbon receptor to dampen intestinal IL-1beta and TNF-alpha. Kynurenic acid also activates GPR35, a receptor highly expressed on vagal nerve endings, transmitting signals upward to the hypothalamus, amygdala and locus coeruleus, where the pathway can alleviate epileptic activity and activate the cholinergic anti-inflammatory reflex. Conversely, intestinal inflammation can increase permeability, allowing microbial products such as peptidoglycan fragments to cross the blood-brain barrier, stimulate microglia and degrade tight junction proteins, producing a leaky brain that lowers the seizure threshold. Clinical observations in children with epilepsy found that ketogenic diet treatment increases blood kynurenic acid, with the degree of increase positively correlated with clinical improvement.

These mechanisms suggest therapeutic openings. The IDO inhibitor 1-methyl-tryptophan exerted multiple beneficial effects in a temporal lobe epilepsy model, correcting overactivation of the BDNF/TrkB pathway, reducing oxidative stress, restoring mitochondrial complex I/IV activity and lowering seizure frequency and duration. Kynurenine monooxygenase inhibition shifts metabolic flux toward kynurenic acid; the inhibitor Ro 61-8048 significantly reduced the frequency and severity of epileptic seizures in mice while also improving depressive behavior and cognition, and diclofenac reduced quinolinic acid levels in a corneal kindling model. Existing antiseizure medications may partly act through this pathway: levetiracetam promotes production of anticonvulsant kynurenic acid and xanthurenic acid by astrocytes while inhibiting release of proconvulsant quinolinic acid and cinnabarinic acid, and carbamazepine, phenobarbital, felbamate, phenytoin and lamotrigine can all enhance kynurenic acid synthesis in brain cortex slices. Notably, analyses of resected tissue from drug-resistant patients suggest carbamazepine is metabolized by CYP3A4 within the blood-brain barrier into quinolinic acid, a provocative proposed mechanism for drug resistance that the authors themselves note remains theoretically inferred and awaits verification.

The depression connection runs through the same enzymatic gate. Tryptophan is the common precursor for serotonin and kynurenine metabolism, and inflammatory cytokines induce IDO to divert tryptophan toward the kynurenine pathway, raising quinolinic acid and 3-hydroxykynurenine while reducing serotonin synthesis. In a temporal lobe epilepsy model, recurrent seizures activated proinflammatory cytokines, promoted IDO upregulation and produced a decreased serotonin/tryptophan ratio and increased kynurenine/tryptophan ratio, culminating in depression-related behaviors. Sodium valproate reduced seizure severity but as monotherapy could not alleviate comorbid depressive symptoms, while 1-methyl-tryptophan reversed depressive behaviors without exacerbating seizures. Minocycline, agmatine, ferulic acid and quercetin also alleviated depressive symptoms in models by inhibiting IDO activation or restoring serotonin availability. The authors caution that current evidence mainly comes from animal models, that species differences in kynurenine metabolism may be significant, and that the safety of key enzyme inhibitors in humans requires focused study, since IDO is expressed in multiple organs. Still, they argue that profiling kynurenine metabolite ratios in cerebrospinal fluid or blood could eventually serve as biomarkers for epilepsy subtypes and predictors of treatment response, opening a route toward individualized therapy.

Subject of Research: The role of the kynurenine pathway in epilepsy mechanisms and therapy

Article Title: The kynurenine pathway storm in epilepsy: mechanisms and therapeutic implications

Article References: He, Y., Meng, J., Luo, W., Yu, M., Zhang, N., Chen, C., & Yu, L. (2026). The kynurenine pathway storm in epilepsy: mechanisms and therapeutic implications. Acta Epileptologica, 8(1), Article 12. https://doi.org/10.1186/s42494-026-00250-w

Image Credits: AI Generated

DOI: 10.1186/s42494-026-00250-w

Keywords: epilepsy, kynurenine pathway, tryptophan metabolism, quinolinic acid, kynurenic acid, IDO, neuroinflammation, gut-brain axis, antiseizure medications, drug resistance, comorbid depression, biomarkers