Inhibition of Retinal Ganglion Cell Loss By a Novel ROCK Inhibitor (E212) in Ischemic Optic Nerve Injury Via Antioxidative and Anti-Inflammatory Actions

Abstract

This study investigated the neuroprotective effects of administration of ROCK inhibitor E212 on ischemic optic neuropathy. METHODS.Rats received an intravitreal injection of either E212 or PBS immediately after optic nerve infarct. The oxidative stress in the retina was detected by performing superoxide dismutase activity and CellROX assays. The integrity of retinal pigment epithelium was determined by staining of zona occludens 1. The visual function, retinal ganglion cell (RGC) density, and RGC apoptosis were determined by using flash visual-evoked potential analysis, retrograde FluoroGold labeling, and TdT-dUTP nick end-labeling assay. Macrophage infiltration was detected by staining for ED1. The protein levels of TNF-α, p-CRMP, p-AKT1, p-STAT3, and CD206 were evaluated using Western blotting. RESULTS.Administration of E212 resulted in a 1.23-fold increase in the superoxide dismutase activity of the retina and 2.28-fold decrease in RGC-produced reactive oxygen species as compared to the levels observed upon treatment with PBS (P < 0.05). Moreover, E212 prevented the disruption of the blood-retinal barrier (BRB) in contrast to PBS. The P1-N2 amplitude and RGC density in the E212-treated group were 1.75-and 2.05-fold higher, respectively, than those in the PBS-treated group (P < 0.05). The numbers of apoptotic RGCs and macrophages were reduced by 2.93-and 2.54-fold, respectively, in the E212treated group compared with those in the PBS-treated group (P < 0.05). The levels of p-AKT1, p-STAT3, and CD206 were increased, whereas those of p-PTEN, p-CRMP2, and TNF-α were decreased after treatment with E212 (P < 0.05). CONCLUSIONS.Treatment with E212 suppresses oxidative stress, BRB disruption, and neuroinflammation to protect the visual function in ischemic optic neuropathy.

Intravitreal Injection of Long-Acting Pegylated Granulocyte Colony-Stimulating Factor Provides Neuroprotective Effects via Antioxidant Response in a Rat Model of Traumatic Optic Neuropathy

“…The procedure has been described in detail in our previously published reports [ 7 , 21 , 22 , 23 , 30 , 31 ]. Briefly speaking, after ONC, fVEPs were recorded 14 days later by a visual electrodiagnostic system (Espion, Diagnosys LLC, Gaithersburg, MA, USA).…”

“…The detailed steps have been described in our previous reports [ 7 , 21 , 22 , 23 , 30 , 31 ]. Briefly, the retrograde labeling of the RGCs was performed 7 days before the rats were euthanized on day 14.…”

Role of Oxidative Stress in Ocular Diseases Associated with Retinal Ganglion Cells Degeneration

“…Although the experimental studies are limited to investigating the pathophysiology of oxidative stress in NAION, some studies using antioxidants to treat NAION showed prolonged RGC survival [ 175 , 237 , 238 ]. In addition to glaucoma, brimonidine and Rho kinase inhibitors demonstrated antioxidative function and neuroprotective properties in ischemic optic neuropathy [ 237 , 238 ], and fasudil, one specific Rho kinase inhibitor, has been investigated in human subjects [ 239 ].…”

The Protective Effects of n-Butylidenephthalide on Retinal Ganglion Cells during Ischemic Injury

“…At the same time, disc swelling and compartment syndrome further induce oxidative stress [4,[9][10][11][12]. Oxidative stress promotes the development of neuroinflammation and the loss of RGCs [12][13][14][15]. However, the complete mechanism constituting the cause of this chain reaction is still unknown.…”