Abstract 14258: Modulation of Kynurenine Pathway to Prevent Brain Injury After Cardiac Arrest and Cardiopulmonary Resuscitation in Mice

Abstract

Introduction: Kynurenine pathway (KP) is emerging as one of the potential components affecting cardiac arrest (CA) outcomes. The aim of this study is to evaluate the effects of KP inhibition through genetic deletion of the rate-limiting enzyme of the KP, indoleamine-2,3-dyoxygenase (IDO) on survival and neurological outcome after CA. Methods and Results: Sixteen adult male wild-type (WT) and IDO-deleted (IDO -/- ) mice were subjected to 8 min untreated CA followed by resuscitation. At baseline heart rate and mean arterial pressure (MAP) did not differ among groups. At the time of return of spontaneous circulation, 30 and 60 min later, MAP was higher in the IDO -/- group compared to the WT one (p=0.0005). IDO -/- mice showed higher survival compared to WT at 7 days after CA (68.5% in IDO -/- vs 37.5% in WT; log rank p=0.036). Neurological function was higher in IDO -/- than in WT mice during the 7 days following CA (p=0.0124). IDO -/- mice also showed an improved locomotor function compared to WT mice (p=0.037). Brain magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) sequences showed a reduction in fractional anisotropy in the external capsule of the corpus callosum in WT mice compared to IDO -/- mice at 7 days after resuscitation (p=0.015). We then treated additional IDO -/- mice with L-kyn 15 min before CA, to revert the IDO -/- phenotype. Brain MRI with diffusion-weighted imaging (DWI) sequences and histological analysis were performed 24h after CA in WT, IDO -/- , and IDO -/- +L-Kyn mice. Brain MRI revealed restriction of water diffusivity 24h after CA in WT mice. IDO-deletion reduced water diffusion abnormalities while the beneficial effect was reverted in the L-kyn group (p=0.01). Degenerating neurons in the frontal cortex, represented as Fluoro-Jade B positive cells, were more numerous in WT compared to IDO -/- mice; L-kyn halted this IDO deletion-induced reduction in degenerating cells (p=0.05). Conclusion: KP inhibition improves survival and neurological outcome after CA. The neuroprotective effect of IDO-deletion was associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema. Reversal of these beneficial effects by L-kyn administration in IDO -/- mice further confirm the KP role in CA outcome.

Evaluation of the genetic architecture of human blood metabolites on sudden cardiac arrest: A Mendelian randomization analysis

“…With the development of metabolomics, research on the metabolomics of SCA is steadily increasing. At the animal level, researchers observed that targeting metabolic pathways such as kynurenine pathway 9 , ketone pathway 10 , mitochondrial energy 11 can attenuate brain injury after SCA, improve prognosis, and prolong survival in mice. Previous studies have also reported several circulating metabolite biomarkers in SCA patients: N-acetylaspartate/creatinine ratios, lactate levels, glucose level served as predictive indicators for unfavorable outcomes 12,13 .…”