Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice

Abstract

Background The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post-cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome, through genetic deletion of the rate-limiting enzyme of the pathway, indoleamine-2,3-dyoxygenase(IDO). Methods Wild-type (WT) and IDO-deleted (IDO -/-) mice were subjected to 8 min cardiac arrest. Survival, neurological outcome, and locomotor activity were evaluated following resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia/macrophage activation and neurofilament light chain measurements. Results IDO-/- mice showed higher survival compared to WT mice (IDO-/- 11/16, WT 6/16, log-rank p=0.036). Neurological function was higher in IDO-/- mice than in WT mice following cardiac arrest (IDO-/- 9±1, WT 7±1, p=0.012, n=16). IDO-deletion preserved locomotor function while maintaining physiologic circadian rhythm after cardiac arrest. Brain magnetic resonance imaging with diffusion tensor imaging showed an increase in mean fractional anisotropy in the corpus callosum (IDO-/- 0.68±0.01, WT 0.65±0.01, p=0.010, n=5-4) and in the external capsule (IDO -/- 0.47±0.01, WT 0.45±0.01, p=0.006, n=5-4) in IDO-/- mice compared to WT ones. Increased release of neurofilament light chain was observed in WT mice compared to IDO-/- (median concentrations (IQR), pg/mL: WT 1138 (678–1384), IDO-/- 267 (157–550), p<0.001, n=3-4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 hours after cardiac arrest in WT mice, IDO-deletion prevented water diffusion abnormalities, which was reverted in IDO-/- mice receiving L-kynurenine (Apparent Diffusion Coefficient, μm2/ms: WT 0.48±0.07, IDO-/- 0.59±0.02, IDO-/- +L-Kynurenine 0.47±0.08, p=0.007, n=6). Conclusions Kynurenine pathway represents a novel target to prevent post-cardiac arrest brain injury. The neuroprotective effects of IDO-deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema.

The novel imaging methods in diagnosis and assessment of cerebrovascular diseases: an overview

“…DTI has various applications in cerebrovascular diseases. It allows for the assessment of white matter integrity and provides insights into the structural changes occurring due to ischemic or hemorrhagic stroke ( 40 ). By reconstructing white matter tracts, DTI enables the study of connectivity patterns in the brain, providing valuable information about how cerebrovascular diseases affect the overall neural network ( 41 ).…”

The role of the kynurenine pathway in cardiovascular disease

“…Additionally, during the early stages of cardiac arrest, activation of the KP in plasma indicates adverse neurological outcomes. The application of IDO1 inhibitors can mitigate brain damage after cardiac arrest and improve survival rates following cardiac resuscitation (109). Although research on IDO1 inhibitors has progressed to phase III clinical trials, the controversy surrounding their mechanisms in cardiovascular disease has prevented clinical trials using IDO1 inhibitors for treating cardiovascular diseases.…”