Therapeutic Potential of Targeting Lipid Aldehydes and Lipoxidation End-Products in the Treatment of Ocular Disease

McDowell, Rosemary E; McGeown, JG; Stitt, Alan W.; Curtis, Tim M.

doi:10.4155/fmc.12.202

Cited by 9 publications

(22 citation statements)

References 190 publications

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“…However, this is unlikely to occur exclusively through elevated oxidative stress and lipoxidation since other lipid aldehydes and ALEs fail to accumulate in Müller cells during diabetes. 10,22 Therefore, we were interested in exploring whether the accumulation of FDP-lysine adducts in retinal Müller glia might be associated with the downregulation of specific ACR detoxifying ALDH and AKR enzymes in these cells. Of the ALDH and AKR genes found to be expressed in the retina (Fig.…”

Section: Diabetes Downregulates Müller Glia Aldh1a1 Protein Expressionmentioning

confidence: 99%

“…8 Although ROS may directly affect cell function, in recent years increasing evidence has suggested that many of the detrimental effects of oxidative stress result from ROS-induced lipid peroxidation reactions. [9][10][11] Lipid peroxidation causes the formation of a number of lipid aldehyde byproducts, including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and acrolein (ACR). These aldehydes are toxic, at least in part, due to their ability to react with cellular and tissue proteins leading to the formation of advanced lipoxidation end products (ALEs) which induce protein dysfunction and alter cellular responses.…”

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confidence: 99%

“…These aldehydes are toxic, at least in part, due to their ability to react with cellular and tissue proteins leading to the formation of advanced lipoxidation end products (ALEs) which induce protein dysfunction and alter cellular responses. [9][10][11] They also are more stable than ROS, allowing them to propagate oxidative injury by diffusing far from their site of origin. 12 Several studies have suggested that lipid aldehydes and ALEs contribute to the development of diabetic retinopathy.…”

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confidence: 99%

“…20 More recently, we demonstrated that FDP-lysine preferentially accumulates in retinal Müller glia during diabetes and, when modelled in vitro, this accumulation induces dysfunction of these cells consistent with that observed in the diabetic retina. 21,22 Although it generally has been assumed that the raised levels of lipid aldehydes and ALEs observed in the retina during diabetes result from increased lipid peroxidation, 10 the possibility that impairment of lipid aldehyde defense mechanisms also may contribute has yet to be determined.…”

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confidence: 99%

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Diabetes Impairs the Aldehyde Detoxifying Capacity of the Retina

McDowell

McGahon

Augustine

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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Section: Diabetes Downregulates Müller Glia Aldh1a1 Protein Expressionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Diabetes Impairs the Aldehyde Detoxifying Capacity of the Retina

McDowell

McGahon

Augustine

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…In terms of the reported ALDH2-induced protection against aldehyde-related diseases, we speculated that ALDH2 might also be able to alleviate retinal diseases [18]. Alda-1 (N-[1,3-benzodioxol-5-ylmethyl]-2,6-dichlorobenzamide) is a ALDH2 activator, which specifically increases the expression of ALDH2 and its enzymatic activity [6].…”

Section: Introductionmentioning

confidence: 99%

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Yan

Long²,

Wei

et al. 2020

BMC Ophthalmol

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Background: Retinitis pigmentosa (RP) is a kind of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. RP has been a conundrum without satisfactory countermeasures in clinic until now. Acetaldehyde dehydrogenase 2 (ALDH2), a major enzyme involved in aldehyde detoxification, has been demonstrated to be beneficial for a growing number of human diseases, such as cardiovascular dysfunction, diabetes mellitus and neurodegeneration. However, its protective effect against RP remains unknown. Our study explored the impact of ALDH2 on retinal function and structure in N-methyl-N-nitrosourea (MNU)-induced RP rats. Methods: Rats were gavaged with 5 mg/kg Alda-1, an ALDH2 agonist, 5 days before and 3 days after MNU administration. Assessments of retinal function and morphology as well as measurement of specific proteins expression level were conducted. Results: Electroretinogram recordings showed that Alda-1 administration alleviated the decrease in amplitude caused by MNU, rendering protection of retinal function. Mitigation of photoreceptor degeneration in MNU-treated retinas was observed by optical coherence tomography and retinal histological examination. In addition, Western blotting results revealed that ALDH2 protein expression level was upregulatedwith increased expression of SIRT1 protein after the Alda-1 intervention. Besides, endoplasmic reticulum stress (ERS) was reduced according to the significant downregulation of GRP78 protein, while apoptosis was ameliorated as shown by the decreased expression of PARP1 protein.Conclusions: Together, our data demonstrated that ALDH2 could provide preservation of retinal function and morphology against MNU-induced RP, with the underlying mechanism at least partly related to the modulation of SIRT1, ERS and apoptosis.

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Müller glial dysfunction during diabetic retinopathy in rats is reduced by the acrolein-scavenging drug, 2-hydrazino-4,6-dimethylpyrimidine

et al. 2018

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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.

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Therapeutic Potential of Targeting Lipid Aldehydes and Lipoxidation End-Products in the Treatment of Ocular Disease

Cited by 9 publications

References 190 publications

Diabetes Impairs the Aldehyde Detoxifying Capacity of the Retina

Diabetes Impairs the Aldehyde Detoxifying Capacity of the Retina

Protection of retinal function and morphology in MNU-induced retinitis pigmentosa rats by ALDH2: an in-vivo study

Müller glial dysfunction during diabetic retinopathy in rats is reduced by the acrolein-scavenging drug, 2-hydrazino-4,6-dimethylpyrimidine

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