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Retina

Inhibition of Protein Kinase R by C16 Protects the Retinal Ganglion Cells from Hypoxia-induced Oxidative Stress, Inflammation, and Apoptosis

Pages 719-730 | Received 20 Aug 2020, Accepted 16 Sep 2020, Published online: 07 Dec 2020
 

ABSTRACT

Aim/Purpose

Individually, hypoxia and protein kinase R (PKR) induce retinal ganglion cells (RGCs) damage by aggravating reactive oxygen species (ROS), oxidative stress, inflammation, and apoptosis. However, it is still not established in hypoxia mediates such damaging effect by modulating PKR. This study investigated the expression and activation of PKR in hypoxic RGCs and tested if suppression of PKR by C16 is protective.

Materials and Methods

Isolated RGCs were under normoxic or hypoxic conditions for 12 h. In some cases, hypoxic cells were pre-treated with C16, a PKR inhibitor, or n-acetyl cysteine (NAC) a glutathione (GSH) precursor for 1 h and then exposed to hypoxia for the next 12 h.

Results

Hypoxia increased cell death, lactate dehydrogenase (LDH) levels, and levels of single-stranded DNA (ssDNA). It also increased levels of ROS, the activity of the nuclear factor-kappa beta (NF-κB), JNK, and p38 MAPK, expression of Bax, p53, and cleaved caspase-3, levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), and cytoplasmic levels of cytochrome-c. It concomitantly suppressed levels of GSH and Bcl-2. All these events were associated with increased phosphorylation (activation) of PKR and its target eukaryotic initiation factor 2 (eIF2). Pre-incubating the cells with NAC completely prevented all these effects in hypoxic cells. Similar protective effects without affecting levels of ROS and GSH levels were also seen in hypoxic cells pre-treated with C16.

Conclusion

Hypoxia induces oxidative stress, inflammation, and apoptosis in the RGCs mainly by ROS induced activation of PKR, whereas scavenging ROS by NAC or suppressing PKR by C16 is a novel protective mechanism.

Acknowledgments

The authors would like to thanks the technical staff for their help in some measurement of this study and would like to thanks the deanship of the scientific research at King Khalid University for their continuous support.

Conflict of interest

The author declares no conflict of interest.

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