Edaravone prevents high glucose-induced injury in retinal Müller cells through thioredoxin1 and the PGC-1α/NRF1/TFAM pathway

Abstract

Context Oxidative injury in a high-glucose (HG) environment may be a mechanism of diabetic retinopathy (DR) and edaravone can protect retinal ganglion cells by scavenging ROS. Objective To explore the effect of edaravone on HG-induced injury. Materials and methods First, Müller cells were cultured by different concentrations of glucose for different durations to obtain a suitable culture concentrations and duration. Müller cells were then divided into Control, HG + Vehicle, HG + Eda-5 μM, HG + Eda-10 μM, HG + Eda-20 μM, and HG + Eda-40 μM groups. Cells were cultured by 20 mM glucose and different concentrations of edaravone for 72 h. Results The IC 50 of glucose at 12–72 h is 489.3, 103.5, 27.92 and 20.71 mM, respectively. When Müller cells were cultured in 20 mM glucose for 72 h, the cell viability was 52.3%. Edaravone significantly increased cell viability compared to Vehicle (68.4% vs 53.3%; 78.6% vs 53.3%). The EC 50 of edaravone is 34.38 μM. HG induced high apoptosis rate (25.5%), while edaravone (20 and 40 μM) reduced it to 12.5% and 6.89%. HG increased the DCF fluorescence signal (189% of Control) and decreased the mitochondrial membrane potential by 57%. Edaravone significantly decreased the DCF fluorescence signal (144% and 132% of Control) and recovered the mitochondrial membrane potential to 68% and 89% of Control. Furthermore, HG decreased the expression of TRX1, PGC-1α, NRF1 and TFAM, which were restored by edaravone. Discussion and conclusion These findings provide a new potential approach for the treatment of DR and indicated new molecular targets in the prevention of DR.

Suppression of cAMP/PKA/CREB signaling ameliorates retinal injury in diabetic retinopathy

“…18,21,22 These changes are the main pathological features in the early stage of DR. Long-term exposure of Müller cells to early and HG would cause accumulation of intracellular ROS, resulting in oxidative stress and mitochondrial dysfunction, thereby inducing the death of Müller cells, 11 as the disease progresses.…”

“…Shanghai SLAC Laboratory Animal Co., Ltd. (Shanghai, China) provided newborn Sprague–Dawley (SD) rats (10 days old). The isolation of primary Müller cells was performed according to the previous work 11 . In short, the eye sample was collected under an aseptic condition.…”

“…The isolation of primary Müller cells was performed according to the previous work. 11 In short, the eye sample was collected under an aseptic condition.…”

“…Previous studies have shown that high‐glucose (HG) stimulation degrades Cx43 gap junctions, inhibits cell‐to‐cell communication within Müller cells, and affects Müller cell's survival 9 . Further, Müller cell loss and programmed death are observed in vivo DR rodent and in vitro HG‐induced models 10,11 . However, the mechanism underlying HG‐mediated Müller cell death remains unknown.…”

“…9 Further, Müller cell loss and programmed death are observed in vivo DR rodent and in vitro HG-induced models. 10,11 However, the mechanism underlying HG-mediated Müller cell death remains unknown.…”