Kynurenine-mediated redox regulation provides neuroprotection in central retinal artery occlusion.

BACKGROUND

Central retinal artery occlusion (CRAO) causes irreversible vision loss through ischemia-reperfusion (I/R) injury, characterized by oxidative stress and retinal ganglion cell (RGC) death. Current therapies are inadequate. This study investigates kynurenine (Kyn)—a tryptophan metabolite—as a novel therapeutic agent targeting dual pathways to combat retinal I/R injury.

METHODS

The unilateral pterygopalatine ophthalmic artery occlusion (UPOAO) model was established by inserting a silicone filament embolus into the pterygopalatine artery. The detection of tryptophan metabolites in serum and retinal tissues was carried out using metabolomics. In the UPOAO mouse model, kynurenine (Kyn) was administered via intravitreal injection. Simultaneously, R28 retinal cells were treated with Kyn during oxygen-glucose deprivation (OGD) induction to model ischemic injury in vitro. Electroretinography (ERG) was performed to examine the visual function of the mice. Western blot analysis and immunofluorescence were used to detect the apoptosis level of retinal ganglion cells (RGCs). The role of Kyn in activating the aryl hydrocarbon receptor (AhR) to reduce oxidative stress in RGCs was demonstrated by using an AhR inhibitor.

RESULTS

The neuroprotective effects of Kyn are mediated by a dual pathway: activation of the AhR-Nrf2 signaling axis, which transcriptionally upregulates antioxidant genes to mitigate oxidative stress, and modulation of downstream kynurenine pathway (KP) metabolites. While AhR-Nrf2 signaling provides transcriptional support for redox homeostasis, KP metabolites directly scavenge reactive oxygen species, synergistically counteracting oxidative damage and energy deficits in RIR injury.

CONCLUSIONS

Our findings highlight Kyn as a pathway-specific therapeutic candidate for CRAO, with potential for receptor-targeted and metabolic modulation strategies in treating retinal ischemia-reperfusion injuries.