Sex Differences in Tryptophan Metabolism via the Kynurenine Pathway in Acute Ischemic Stroke.

Abstract

Purpose: Females are at increased lifetime risk of stroke and experience worse outcomes compared with males. Tryptophan metabolism through the kynurenine pathway, resulting in decreased tryptophan concentrations, is associated with poor outcomes (larger infarct volume, higher National Institutes of Health Stroke Scale [NIHSS] score, and increased early mortality). This metabolic pathway activity varies by sex in healthy adults. However, evaluation of potential sex differences in tryptophan metabolism after an acute ischemic stroke (AIS) is lacking and could contribute to the disparate outcomes by sex. This study characterized sex differences in tryptophan metabolism via the kynurenine pathway in patients with AIS.

Methods: Whole blood from patients with AIS enrolled in the University of Colorado Health Emergency Medicine Specimen Bank was analyzed using high-throughput mass spectrometry-based metabolomics at the time of arrival to the emergency department and at 12, 24, and 48 hours thereafter. Descriptive statistics characterized the cohort and metabolite levels. Potential sex differences in tryptophan metabolites at individual time points and their change over time were estimated using linear regression models to control for known factors influencing metabolite levels, initial NIHSS score, therapeutic interventions, and time to last known well (or symptom onset). A multivariable linear regression model examined the interaction effect between sex and metabolite level (at 12 hours after admission) on 24-hour NIHSS score while controlling for initial metabolite level, initial NIHSS score, time to last known well, factors influencing metabolite level, and factors influencing neurologic outcomes.

Findings: After adjusting for covariates, females with AIS had significantly lower levels of tryptophan at 12 hours after admission compared with males (point estimate, -5.80; P = 0.03). Females and males neither differ in levels of tryptophan, kynurenine, quinolinic acid, or kynurenic acid at any other time point nor did they differ in change in metabolite concentration over time. Only increased quinolinic acid levels across both sexes at 12 hours after admission were associated with increased 24-hour NIHSS scores (point estimate, 0.49; P = 0.0002).

Implications: Overall, females and males have similar levels and changes in tryptophan and kynurenine pathway metabolites after an AIS. However, females have lower levels of tryptophan early after a stroke. Increased quinolinic acid levels across both sexes were associated with worsening neurologic function as measured by an NIHSS score. Future evaluation of alternative metabolic pathways downstream of tryptophan is needed to explain differences in tryptophan levels but similar levels of downstream kynurenine metabolites in females and males with AIS.