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Caspase-3 inhibitor Z-DEVD-FMK enhances retinal ganglion cell survival and vision restoration after rabbit traumatic optic nerve injury

Article type: Research Article

Authors: Liu, Yuanyuan | Yan, Hua | Chen, Song | Sabel, Bernhard A.

Affiliations: Department of Ophthalmology, Tianjin Medical University General Hospital, Tianjin, China | Institute of Medical Psychology, Medical Faculty, Otto.-v.-Guericke University of Magdeburg, Magdeburg, Germany

Note: [] Corresponding author: Dr. Hua Yan, Department of Ophthalmology, Tianjin Medical University General Hospital, No. 154, Anshan Road, Tianjin 300052, China. Tel.: +86 22 60362465; Fax: +86 22 27813550; E-mail: phuayan2000@163.com

Note: [] Song CHEN is co-first author.

Keywords: Caspase-3 inhibitor, optic nerve injury, apoptosis, neuroprotection, vision restoration

DOI: 10.3233/RNN-159001

Journal: Restorative Neurology and Neuroscience, vol. 33, no. 2, pp. 205-220, 2015

Published: 2015
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Abstract

Purpose: Vision loss after traumatic optic nerve injury is considered irreversible because of the retrograde loss of retinal ganglion cells (RGCs) which undergo apoptosis. Because the second messenger caspase-3 plays a major role in apoptosis, we now evaluated the efficacy of the specific caspase-3 inhibitor, Z-DEVD-FMK, in a rabbit model of fluid percussion injury (FPI) which mimics traumatic optic nerve injury in humans to enhance cell survival and improve vision. Methods: Survival of RGCs and recovery of vision were studied using retinal morphological markers and visual evoked potentials (VEP), respectively. The FPI traumatized animals were treated in their right eye with a single intravitreal or peribulbar injection of Z-DEVD-FMK 30 min post-injury compared to 2% DMSO control injections in their left eye. Results: Intravitreal Z-DEVD-FMK, but not control injections, led to down-regulation of capase-3 and reduced, in a dose-dependent manner, RGCs apoptosis from 7 to 21 days post-injury. These morphological improvements were accompanied by vision restoration as documented by VEP. The neuroprotection after intravitreal injection of Z-DEVD-FMK was more effective than the peribulbar application. Conclusions: The caspase-3 inhibitor Z-DEVD-FMK is neuroprotective by inhibiting RGCs apoptosis when injected 30 min after optic nerve damage and significantly promotes restoration of vision. A controlled clinical trial is now needed to evaluate the efficacy and safety of Z-DEVD-FMK in humans.

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