Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest
Aurora Magliocca1, Carlo Perego2, Francesca Motta2
1Department of Pathophysiology and Transplants, University of Milan, Milan, Italy; and Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
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-dioxygenase.
Methods:
Wild-type and indoleamine 2,3-dioxygenase-deleted (IDO-/-) mice were subjected to 8-min cardiac arrest. Survival, neurologic outcome, and locomotor activity were evaluated after resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia and macrophage activation and neurofilament light chain measurements.
Results:
IDO-/- mice showed higher survival compared to wild-type mice (IDO-/- 11 of 16, wild-type 6 of 16, log-rank P = 0.036). Neurologic function was higher in IDO-/- mice than in wild-type mice after cardiac arrest (IDO-/- 9 ± 1, wild-type 7 ± 1, P = 0.012, n = 16). Indoleamine 2,3-dioxygenase 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, wild-type 0.65 ± 0.01, P = 0.010, n = 4 to 5) and in the external capsule (IDO-/- 0.47 ± 0.01, wild-type 0.45 ± 0.01, P = 0.006, n = 4 to 5) in IDO-/- mice compared with wild-type ones. Increased release of neurofilament light chain was observed in wild-type mice compared to IDO-/- (median concentrations [interquartile range], pg/mL: wild-type 1,138 [678 to 1,384]; IDO-/- 267 [157 to 550]; P < 0.001, n = 3 to 4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 h after cardiac arrest in wild-type mice; indoleamine 2,3-dioxygenase deletion prevented water diffusion abnormalities, which was reverted in IDO-/- mice receiving l-kynurenine (apparent diffusion coefficient, μm2/ms: wild-type, 0.48 ± 0.07; IDO-/-, 0.59 ± 0.02; IDO-/- and l-kynurenine, 0.47 ± 0.08; P = 0.007, n = 6).
Conclusions:
The kynurenine pathway represents a novel target to prevent post-cardiac arrest brain injury. The neuroprotective effects of indoleamine 2,3-dioxygenase deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema.
Insights
Deleting indoleamine 2,3-dioxygenase (IDO) improved survival and neurologic function after cardiac arrest in mice. This genetic modification protected brain white matter and reduced swelling, suggesting IDO is a therapeutic target for cardiac arrest brain injury.
Area of Science:
- Neuroscience
- Biochemistry
- Cardiology
Background:
- Tryptophan catabolism via the kynurenine pathway is implicated in post-cardiac arrest brain injury.
- Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting enzyme in this pathway.
Purpose of the Study:
- To investigate the therapeutic potential of modulating the kynurenine pathway in cardiac arrest outcomes.
- To evaluate the effects of genetic IDO deletion on brain injury following cardiac arrest.
Main Methods:
- Wild-type and IDO-deleted (IDO-/-) mice underwent 8-minute cardiac arrest.
- Evaluated survival, neurologic function, and locomotor activity post-resuscitation.
- Utilized brain MRI (diffusion tensor and diffusion-weighted imaging), assessed microglia/macrophage activation, and measured neurofilament light chain levels.
Main Results:
- IDO-/- mice exhibited significantly higher survival rates (11/16 vs. 6/16) and improved neurologic function compared to wild-type mice.
- IDO deletion preserved locomotor activity and circadian rhythms, and protected white matter integrity (increased fractional anisotropy in corpus callosum and external capsule).
- IDO-/- mice showed reduced neurofilament light chain release and prevented water diffusion abnormalities in the brain, indicating less cytotoxic edema.
Conclusions:
- The kynurenine pathway, specifically IDO, is a promising therapeutic target for mitigating post-cardiac arrest brain injury.
- IDO deletion confers neuroprotection by preserving white matter microintegrity and reducing cerebral cytotoxic edema.
