Avenues for Acute Neuroprotection in Traumatic Optic Neuropathy

Abstract

Purpose : Traumatic optic neuropathy (TON) is a devastating cause of permanent visual loss (due to retinal ganglion cell (RGC) death) following blunt injury to the head. Although TON has been the subject of substantial basic and clinical research, insights into its basic pathophysiologic and molecular mechanisms remain limited. While RGC loss from the primary injury is irreversible, the secondary injury from pro-inflammatory cytokine release and oxidative stress may be prevented. In this study, we investigated whether reduced cytokine activity and reactive oxygen species (ROS) production promote survival of RGCs in two animal models of TON.

Methods : To test neuroprotective effect of reduced cytokine levels and ROS production in TON, we used selective inhibitors for TNFα (etanercept) and ROS (MTP 131) administered subcutaneously alone or together. To this end, we used optic nerve crush (ONC) and a novel ultrasonic pulse injury modality (sonication-induced TON: SI-TON) as our mouse models. Pattern electroretinogram (PERG) was used as a measure of visual function. Using Red Mitochondrial Superoxide Indicator (MitoSox, a dye for ROS), activation of ROS following injury was evaluated using a Heidelberg Spectralis scanning laser ophthalmoscope. Whole retinae were collected, stained, and flat-mounted for RGC quantification two weeks after injury. Optic nerves were harvested for immunohistochemistry and quantitative RT-PCR.

Results : We found increased TNFα levels and ROS production in injured eyes compared to control eyes. High TNFα and ROS levels were correlated with increased RGC death: after injury, the number of RGCs in the retina as well as visual function measured by PERG steadily decreased over a two-week period. At the same time, treatment with inhibitors for TNFα (etanercept) and ROS (MTP 131) significantly reduced retinal damage and improved visual function in both animal models of TON. Surprisingly, treatment with both inhibitors (etanercept and MTP 131) together did not result in an additive effect observed for animals, when compared to treatment with the single agent treatment groups.

Conclusions : Our findings suggest that reduced TNFα levels and ROS production after injury are promising therapeutic approaches to treating TON. However, additional combinatorial strategies for etanercept and MTP 131 should be evaluated for treatment of TON.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.