Retinylamine Benefits Early Diabetic Retinopathy in Mice

Liu, Haitao; Tang, Jie; Du, Yunpeng; Lee, Chieh Allen; Golczak, Marcin; Muthusamy, Arivalagan; Antonetti, David A.; Veenstra, Alexander A.; Amengual, Jaume; Lintig, Johannes von; Palczewski, Krzysztof; Kern, Tim S

doi:10.1074/jbc.m115.655555

Cited by 46 publications

(58 citation statements)

References 79 publications

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“…For patients with Stargardt disease wherein A2E is thought to be a primary contributor to macular degeneration (Sparrow and Boulton, 2005;Moiseyev et al, 2010;Charbel Issa et al, 2015;Saad and Washington, 2016), direct RPE65 inhibition by emixustat-like molecules could be therapeutically advantageous, as it was previously reported that both emixustat and its predecessor retinylamine lower A2E formation in mouse models of Stargardt disease (Maeda et al, 2011;Bavik et al, 2015). These compounds also exert beneficial effects in mouse models of diabetic retinopathy thought to be related to their ability to inhibit RPE65 (Liu et al, 2015). Improving visual cycle modulator potency could lessen any off-target side effects.…”

Section: Rdh8mentioning

confidence: 91%

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Kiser

Zhang

Badiee

et al. 2017

J Pharmacol Exp Ther

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Modulators of the visual cycle have been developed for treatment of various retinal disorders. These agents were designed to inhibit retinoid isomerase [retinal pigment epithelium-specific 65 kDa protein (RPE65)], the rate-limiting enzyme of the visual cycle, based on the idea that attenuation of visual pigment regeneration could reduce formation of toxic retinal conjugates. Of these agents, certain ones that contain primary amine groups can also reversibly form retinaldehyde Schiff base adducts, which contributes to their retinal protective activity. Direct inhibition of RPE65 as a therapeutic strategy is complicated by adverse effects resulting from slowed chromophore regeneration, whereas effective retinal sequestration can require high drug doses with potential off-target effects. We hypothesized that the RPE65-emixustat crystal structure could help guide the design of retinaldehydesequestering agents with varying degrees of RPE65 inhibitory activity. We found that addition of an isopropyl group to the central phenyl ring of emixustat and related compounds resulted in agents effectively lacking in vitro retinoid isomerase inhibitory activity, whereas substitution of the terminal 6-membered ring with branched moieties capable of stronger RPE65 interaction potentiated inhibition. The isopropyl derivative series produced discernible visual cycle suppression in vivo, albeit much less potently than compounds with a high affinity for the RPE65 active site. These agents were distributed into the retina and formed Schiff base adducts with retinaldehyde. Except for one compound [3-amino-1-(3-isopropyl-5-((2,6,6-trimethylcyclohex-1-en-1-yl)methoxy)phenyl)propan-1-ol (MB-007)], these agents conferred protection against retinal phototoxicity, suggesting that both direct RPE65 inhibition and retinal sequestration are mechanisms of potential therapeutic relevance.

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Section: Rdh8mentioning

confidence: 91%

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Kiser

Zhang

Badiee

et al. 2017

J Pharmacol Exp Ther

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“…73 However, in a separate study, we did not find that diabetes altered all-transretinaldehyde levels compared to that in age-matched nondiabetic mice. 75 Also little or no photoreceptor death has been reported in the diabetic mouse model. 6 Diabetes does, however, result in activation of retinal NADPH oxidase because apocynin can correct the diabetes-induced lesions.…”

Section: Discussionmentioning

confidence: 99%

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Berkowitz

Kern

Bissig

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Diabetes appears to induce a visual cycle defect because rod dysfunction is correctable with systemic treatment of the visual cycle chromophore 11-cis-retinaldehyde. However, later studies have found no evidence for visual cycle impairment. Here, we further examined whether photoreceptor dysfunction is corrected with 11-cis-retinaldehyde. Because antioxidants correct photoreceptor dysfunction in diabetes, the hypothesis that exogenous visual chromophores have antioxidant activity in the retina of diabetic mice in vivo was tested.METHODS. Rod function in 2-month-old diabetic mice was evaluated using transretinal electrophysiology in excised retinas and apparent diffusion coefficient (ADC) MRI to measure light-evoked expansion of subretinal space (SRS) in vivo. Optokinetic tracking was used to evaluate cone-based visual performance. Retinal production of superoxide free radicals, generated mostly in rod cells, was biochemically measured with lucigenin. Diabetic mice were systemically treated with a single injection of either 11-cis-retinaldehyde, 9-cisretinaldehyde (a chromophore surrogate), or all-trans-retinaldehyde (the photoisomerization product of 11-cis-retinaldehyde).RESULTS. Consistent with previous reports, diabetes significantly reduced (1) dark-adapted rod photo responses (transretinal recording) by~18%, (2) rod-dominated light-stimulated SRS expansion (ADC MRI) by~21%, and (3) cone-dominated contrast sensitivity (using optokinetic tracking [OKT]) by~30%. Both 11-cis-retinaldehyde and 9-cis-retinaldehyde largely corrected these metrics of photoreceptor dysfunction. Higher-than-normal retinal superoxide production in diabetes by~55% was also significantly corrected following treatment with 11-cis-retinaldehyde, 9-cis-retinaldehyde, or all-trans-retinaldehyde.CONCLUSIONS. Collectively, data suggest that retinaldehydes improve photoreceptor dysfunction in diabetic mice, independent of the visual cycle, via an antioxidant mechanism.

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“…More important, this therapy, which acts in the RPE, also inhibited retinal lesions that are clinically relevant in DR (degeneration of retinal capillaries and increased permeability). 59 The available data suggest that RPE cells and possibly also the visual cycle contribute to the development of DR. Neither the RPE nor enzymes of the visual cycle have previously been identified as potential contributors to the pathogenesis of DR or as potential targets for therapeutic inhibition of DR.…”

Section: Rpe Datamentioning

confidence: 99%

“…59 Retinylamine is an analog of vitamin A that is selectively retained by only two tissues in the body, RPE and liver. It is an effective trap for reactive aldehydes, and is known to inhibit the RPE-specific protein 65 kDa, 85,86 an enzyme of the visual cycle that converts alltrans-retinol esters back to 11-cis-retinal.…”

Section: Rpe Datamentioning

confidence: 99%

Mechanistic Insights into Pathological Changes in the Diabetic Retina

Roy

Kern

Song

et al. 2017

The American Journal of Pathology

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147

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Increasing evidence points to inflammation as one of the key players in diabetes-mediating adverse effects to the neuronal and vascular components of the retina. Sustained inflammation induces biochemical and molecular changes, ultimately contributing to retinal complications and vision loss in diabetic retinopathy. In this review, we describe changes involving metabolic abnormalities secondary to hyperglycemia, oxidative stress, and activation of transcription factors, together with neuroglial alterations in the diabetic retina. Changes in biochemical pathways and how they promote pathophysiologic developments involving proinflammatory cytokines, chemokines, and adhesion molecules are discussed. Inflammation-mediated leukostasis, retinal ischemia, and neovascularization and their contribution to pathological and clinical stages leading to vision loss in diabetic retinopathy (DR) are highlighted. In addition, potential treatment strategies involving fibrates, connexins, neuroprotectants, photobiomodulation, and anti-inflammatory agents against the development and progression of DR lesions are reviewed. The importance of appropriate animal models for testing novel strategies against DR lesions is discussed; in particular, a novel nonhuman primate model of DR and the suitability of rodent models are weighed. The purpose of this review is to highlight our current understanding of the pathogenesis of DR and to summarize recent advances using novel approaches or targets to investigate and inhibit the retinopathy. (Am J Pathol 2017, 187: 9e19; http://dx

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Retinylamine Benefits Early Diabetic Retinopathy in Mice

Cited by 46 publications

References 79 publications

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice

Mechanistic Insights into Pathological Changes in the Diabetic Retina

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