Pregabalin Mediates Retinal Ganglion Cell Survival From Retinal Ischemia/Reperfusion Injury Via the Akt/GSK3β/β-Catenin Signaling Pathway

Abstract

Purpose Progressive retinal ganglion cell (RGC) loss induced by retinal ischemia/reperfusion (RIR) injury leads to irreversible visual impairment. Pregabalin (PGB) is a promising drug for neurodegenerative diseases. However, with regard to RGC survival, its specific role and exact mechanism after RIR injury remain unclear. In this study, we sought to investigate whether PGB could protect RGCs from mitochondria-related apoptosis induced by RIR and explore the possible mechanisms. Methods C57BL/6J mice and primary RGCs were pretreated with PGB prior to ischemia/reperfusion modeling. The retinal structure and cell morphology were assessed by immunochemical assays and optical coherence tomography. CCK8 was used to assay cell viability, and an electroretinogram was performed to detect RGC function. Mitochondrial damage was assessed by a reactive oxygen species (ROS) assay kit and transmission electron microscopy. Western blot and immunofluorescence assays quantified the expression of proteins associated with the Akt/GSK3β/β-catenin pathway. Results Treatment with PGB increased the viability of RGCs in vitro. Consistently, PGB preserved the normal thickness of the retina, upregulated Bcl-2, reduced the ratio of cleaved caspase-3/caspase-3 and the expression of Bax in vivo. Meanwhile, PGB improved mitochondrial structure and prevented excessive ROS production. Moreover, PGB restored the amplitudes of oscillatory potentials and photopic negative responses following RIR. The mechanisms underlying its neuroprotective effects were attributed to upregulation of the Akt/GSK3β/β-catenin pathway. However, PGB-mediated neuroprotection was suppressed when using MK2206 (an Akt inhibitor), whereas it was preserved when treated with TWS119 (a GSK3β inhibitor). Conclusions PGB exerts a protective effect against RGC apoptosis induced by RIR injury, mediated by the Akt/GSK3β/β-catenin pathway.

Retinal Microenvironment‐Protected Rhein‐GFFYE Nanofibers Attenuate Retinal Ischemia‐Reperfusion Injury via Inhibiting Oxidative Stress and Regulating Microglial/Macrophage M1/M2 Polarization

“…In addition, we found that Rh‐GFFYE can stabilize the mitochondrial membrane potential, which can reflect the function of mitochondria as the site of ROS production. [ 22,44 ] Thus, these results suggest that Rh‐GFFYE nanofibers suppress oxidative stress, which is an early event in RIR injury.…”

“…As previously reported, intracellular ROS production is dramatically elevated under OGD conditions. [ 22 ] Thus, we also evaluated the effects of Rh‐GFFYE and the control compounds on the intracellular ROS level. The cellular ROS levels in R28 cells were assessed by 2′,7′‐dichlorofluorescin diacetate (H 2 DCF‐DA) assay using confocal laser scanning microscope (CLSM) observation (Figure 2E ).…”

Silicone Wire Embolization-induced Acute Retinal Artery Ischemia and Reperfusion Model in Mouse: Gene Expression Provides Insight into Pathological Processes

“…S1). Additionally, OPs have also been used to sensitively monitor retinal ischemic effects by detecting changes before any alterations in b-waves occur [25][26][27]. The amplitudes of OPs in the experimental eyes, particularly in the 60-minute ischemia and 7-days reperfusion group, significantly decreased to less than 50% of those in the sham eyes (Fig.…”