Redox homeostasis in optic nerve injury response and functional recovery

Abstract

Purpose : Trauma to the optic nerve, whether direct or indirect, initiates a cascading sequence of metabolic and inflammatory processes which lead to traumatic optic neuropathy (TON), a devastating cause of permanent visual loss for which no effective treatment exists. Our lab has shown that redox homeostasis is disrupted early in the onset of TON in our animal model of indirect optic nerve injury. Accumulation of reactive oxygen species (ROS) in the retina prior to the loss of retinal neurons and function, and dysfunctional mitochondrial lipidomic profiles are evidenced early in the disease process. This study further characterizes the observed redox dysregulation after indirect optic nerve trauma and assesses whether modulation and rapid reestablishment of redox homeostasis can improve functional recovery and outcomes.

Methods : We used our published sonication-induced traumatic optic neuropathy (SI-TON) animal model to assess optic nerve and retinal transcriptomic (RNA-seq) and mitochondrial morphological (TEM) profiles in early (48hr), and ongoing (1-week) TON. We further used retinal Muller glia cell lines established in our laboratory from non-regenerative mammals (human and mouse), and regenerative-competent xenopus to assess species-dependent differences in the response to increasing oxidative stress and redox homeostatic maintenance.

Results : Transcriptomic signatures associated with ‘oxidative stress’ and ‘protein folding’ are significantly dysregulated at the onset of TON, showing disruption in both the ROS scavenging and oxidized product handling (reductive) balance of the redox pathway. We show that mitochondria within the optic nerve undergo severe aberrant morphological changes even as the RGC somas in the retina continue to function normally. In-vitro, cells from regenerative competent xenopus demonstrate a remarkable resilience to high levels of oxidative stress when compared to their mammalian counterparts. Overexpression of thioredoxin and/or supplementation with thioredoxin and/or glutathione precursor compounds leads to a shift in the oxidative stress tolerance of mammalian retinal cells.

Conclusions : Our results indicate that redox balance disruption plays a role in the pathophysiology of TON and that retinal cell loss begins after the tissue’s ability to maintain redox homeostasis is overwhelmed. Rapid reestablishment of redox homeostasis via pharmacological agents may provide therapeutic benefit in TON.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.