Oxidative stress plays an important role in the development of diabetic retinopathy. Here, we examined whether alpha-lipoic acid (alpha-LA), a natural antioxidant, attenuated retinal injury in diabetic mice. The a-LA was orally administered to control mice or mice with streptozotocin-induced diabetes. We found that alpha-LA reduced oxidative stress, decreased and increased retinal 4-hydroxy-2-nonenal and glutathione peroxidase, respectively, and inhibited retinal cell death. Concomitantly, alpha-LA reversed the decreased activation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase, and increased the levels of peroxisome proliferator-activated receptor delta and sirtuin3 in diabetic mouse retinas, similar to results shown after metformin treatment of retinal pigment epithelial cells (RPE) exposed to high glucose. Moreover, alpha-LA lowered the levels of O-linked beta-N-acetylglucosamine transferase (OGT) and thioredoxin-interacting protein (TXNIP) in diabetic retinas that were more pronounced after metformin treatment of RPE cells. Importantly, alpha-LA lowered interactions between AMPK and OGT as shown by co-immunoprecipitation analyses, and this was accompanied by less cell death as measured by double immunofluorescence staining by terminal deoxynucleotide transferase-mediated dUTP nick-end labelling and OGT or TXNIP in retinal ganglion cells. Consistently, alpha-LA lowered the levels of cleaved poly(ADP-ribose) polymerase and pro-apoptotic marker cleaved caspase-3 in diabetic retinas. Our results indicated that alpha-LA reduced retinal cell death partly through AMPK activation or OGT inhibition in diabetic mice. (C) 2018 Elsevier Inc. All rights reserved.