New Approaches To Treating Traumatic Optic Neuropathy

Abstract

Purpose : Traumatic optic neuropathy (TON) is an uncommon but devastating cause of permanent visual loss following blunt force trauma to the orbit. For the past decade, optic canal decompression surgery and corticosteroids have been widely suggested for the treatment of TON. However, neither the surgical decompression nor systemic administration of steroids has proved particularly beneficial in the treatment of TON with regard to clinical outcomes. Thus, new approaches for TON therapy are needed. In this study we investigated whether TNFα inhibition and therapeutic hypothermia support survival of retinal ganglion cells (RGCs) in an optic nerve crush (ONC) model and in a novel animal model for TON.

Methods : To investigate the role of TNFα inhibitors and therapeutic hypothermia in RGC survival, optic nerves of mice were unilaterally subjected to crush injury (ONC model). We also developed and used a clinically-relevant animal model for TON using a novel ultrasonic pulse injury modality (sonication-induced TON: SI-TON). To test the role of TNFα in TON, we used selective inhibitors for TNFα administered subcutaneously following trauma. To induce hypothermia, the animals were anesthetized through intraperitoneal injection of a cocktail containing ketamine and xylazine for 3 hours after injury. The control mice were kept on an automatically regulated heating pad to prevent hypothermia, while experimental animals were kept without heating pad. Measured body temperature of control animals was 39 ± 0.5°C, while the temperature of experimental animals was 24 ± 0.5°C (hypothermia model). Whole retina flat-mounts were collected and stained for RGC quantification, and optic nerves were harvested for immunohistochemistry and quantitative RT-PCR.

Results : We found increased TNFα levels in injured compared to control optic nerves of the animals suffering from SI-TON and ONC. High TNFα levels in injured optic nerves were correlated with increased RGC death. Meanwhile, treatment with selective inhibitors of the TNFα significantly reduced retinal damage in animal models of TON. Our data also indicate that hypothermia promotes survival of RGCs after TON. Combinatorial approaches are under evaluation.

Conclusions : Thus, our findings suggest that reduced TNFα activity and therapeutic hypothermia in injured optic nerves are new and promising therapeutic approaches to treating TON.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.