Effects of Experimental Drugs on Traumatic Optic Neuropathy in Mice

Abstract

Project ID: 134

Awards: Excellence in Research Communication

Program Affliation: Volunteer Research 

Project Advisor: Nathan Evanson

Abstract: In the United States, traumatic brain injuries (TBI) are a major cause of disability, affecting 2.8 million Americans annually. TBI is an immediate source of visual deficits and impairments via direct or indirect trauma to the eyes, optic nerve, and/or visual processing areas of the brain. Traumatic injury to the optic nerve is called traumatic optic neuropathy (TON), and usually occurs in the setting of TBI. Recent research has suggested that the cellular stress response known as Endoplasmic Reticulum (ER) Stress, with the associated Unfolding Protein Response (UPR) is involved in apoptosis of retinal ganglion cells as a result of TON. Pharmacological manipulations of the PERK (PKR-like ER Kinase) pathway (such as with salubrinal or ISRIB) have displayed promising neuroprotective effects, mediated by the signaling molecule eIF2ɑ (eukaryotic initiation factor-2 alpha). Salubrinal is a selective phosphatase inhibitor of eIF2ɑ. Conversely, ISRIB inhibits phosphorylation of eIF2ɑ (p-eIF2ɑ). eIF2ɑ, and its state of phosphorylation, dictates its important interactions with other signaling molecules such as ATF4 and CHOP that can either be adaptive or apoptotic. In this study, we used a closed-head weight drop model of TBI and TON in C57Bl/6 male mice. Mice were injected intraperitoneally once daily for seven days post injury with Salubrinal, ISRIB, or vehicle. Retinas were used for Western Blotting. We hypothesize that Salubrinal or ISRIB treatment following TBI will improve neuroprotection compared to vehicle.