Aims/hypothesisRecent studies suggest that abnormal function in Müller glial cells plays an important role in the pathogenesis of diabetic retinopathy. This is associated with the selective accumulation of the acrolein-derived advanced lipoxidation end-product, Nε-(3-formyl-3,4-dehydropiperidino)lysine (FDP-lysine), on Müller cell proteins. The aim of the current study was to identify more efficacious acrolein-scavenging drugs and determine the effects of the most potent on Müller cell FDP-lysine accumulation and neuroretinal dysfunction during diabetes.MethodsAn ELISA-based in vitro assay was optimised to compare the acrolein-scavenging abilities of a range of drugs. This identified 2-hydrazino-4,6-dimethylpyrimidine (2-HDP) as a new and potent acrolein scavenger. The ability of this agent to modify the development of diabetic retinopathy was tested in vivo. Male Sprague Dawley rats were divided into three groups: (1) non-diabetic; (2) streptozotocin-induced diabetic; and (3) diabetic treated with 2-HDP in their drinking water for the duration of diabetes. Liquid chromatography high-resolution mass spectrometry was used to detect 2-HDP reaction products in the retina. Immunohistochemistry, real-time quantitative (q)RT-PCR and electroretinography were used to assess retinal changes 3 months after diabetes induction.Results2-HDP was the most potent of six acrolein-scavenging agents tested in vitro (p < 0.05). In vivo, administration of 2-HDP reduced Müller cell accumulation of FDP-lysine at 3 months in rats rendered diabetic with streptozotocin (p < 0.001). A 2-HDP adduct was identified in the retinas of diabetic animals treated with this compound. 2-HDP supplementation was associated with reduced Müller cell gliosis (p < 0.05), reduced expression of the oxidative stress marker haem oxygenase-1 (p < 0.001) and partial normalisation of inwardly rectifying K+ channel 4.1 (Kir4.1) expression (p < 0.001 for staining in perivascular regions and the innermost region of the ganglion cell layer). Diabetes-induced retinal expression of inflammatory markers, inflammatory signalling compounds and activation of retinal microglial cells were all reduced in 2-HDP-treated animals. Retinal neurophysiological defects in diabetic animals, as indicated by changes in the electroretinogram 7 weeks after induction of diabetes, were also reduced by 2-HDP (p < 0.05–0.01 for b-wave amplitudes at flash intensities from −10 to +10 dB; p < 0.01 for time to peak of summed oscillatory potentials at +10 dB).Conclusions/interpretationThese findings support the hypothesis that Müller cell accumulation of FDP-lysine plays an important role in the development of diabetic retinopathy. Our results also suggest that 2-HDP may have therapeutic potential for delaying or treating this sight-threatening complication.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4707-y) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

These findings suggest that downregulation of ALDH and AKR enzymes, particularly ALDH1a1, may contribute ALE accumulation in the diabetic retina.

Lipoxidation reactions and the subsequent accumulation of advanced lipoxidation end products (ALEs) have been implicated in the pathogenesis of many of the leading causes of visual impairment. Here, we begin by outlining some of the major lipid aldehydes produced through lipoxidation reactions, the ALEs formed upon their reaction with proteins, and the endogenous aldehyde metabolizing enzymes involved in protecting cells against lipoxidation mediated damage. Discussions are subsequently focused on the clinical and experimental evidence supporting the contribution of lipid aldehydes and ALEs in the development of ocular diseases. From these discussions, it is clear that inhibition of lipoxidation reactions and ALE formation could represent a new therapeutic avenue for the treatment of a broad range of ocular disorders. Current and emerging pharmacological strategies to prevent or neutralize the effects of lipid aldehydes and ALEs are therefore considered, with particular emphasis on the potential of these drugs for treatment of diseases of the eye.