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Diabetic Retinopathy: Mechanisms Underlying Pathophysiology and Therapies 2.0
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Diabetic Retinopathy: Mechanisms Underlying Pathophysiology and Therapies 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 6888

Special Issue Editor

Prof. Dr. Peter Koulen

E-Mail Website
Guest Editor
1. Department of Ophthalmology, School of Medicine, University of Missouri, Kansas City, MO 64108, USA
2. Department of Biomedical Sciences, School of Medicine, University of Missouri, Kansas City, MO 64108, USA
Interests: drug target discovery and drug development for disorders of the CNS and retina; calcium signaling; neuroprotection; neurodegeneration; synaptic signaling; neurophysiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The identification of mechanisms underlying the pathophysiology and therapies of diabetic retinopathy continues to be an area of significant research efforts, attracting scientists from a diverse range of fields, including neuroscience, pharmacology, and medicinal chemistry, among several others. With the ultimate goal to generate intervention strategies that slow or even reverse structural and functional degeneration of the retina and that attenuate or eliminate vascular complications input from numerous fields, such as neurology, ophthalmology, and endocrinology, appears critically needed, as effective therapies for diabetic retinopathy are lacking.

Research efforts towards treating or curing diabetic retinopathy are characteristic for how clinical practice and basic and translational research inform each other and how such interactions can result in novel therapeutic strategies of high clinical relevance. Recent methodological advances in synthetic and medicinal chemistry, mass spectrometry, proteomics, drug target discovery, and drug development have generated significant developments in this field. Therefore, this Special Issue invites manuscript submissions, namely, research and review papers, targeting the gamut of methodological and scientific innovation in this field. Of specific interest to this Special Issue are papers focused on the discovery and mechanistic characterization of novel drug targets, signaling pathways, and mechanisms of action as they are relevant for diabetic retinopathy. These contributions can be general and broad in their basic science and translational-research-focused or highly focused on specific research models related to structural and functional degeneration of the retina and vascular complications.

Dr. Peter Koulen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neuroprotection
  • retina
  • diabetic macular edema
  • proliferative and non-proliferative diabetic retinopathy therapy development
  • pathophysiology

Published Papers (2 papers)

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Research

17 pages, 3703 KiB  
Article
Novel Short-Chain Quinones to Treat Vision Loss in a Rat Model of Diabetic Retinopathy
by Abraham Daniel, Dino Premilovac, Lisa Foa, Zikai Feng, Krupali Shah, Qianyi Zhang, Krystel L. Woolley, Nicole Bye, Jason A. Smith and Nuri Gueven
Int. J. Mol. Sci. 2021, 22(3), 1016; https://doi.org/10.3390/ijms22031016 - 20 Jan 2021
Cited by 8 | Viewed by 2133
Abstract
Diabetic retinopathy (DR), one of the leading causes of blindness, is mainly diagnosed based on the vascular pathology of the disease. Current treatment options largely focus on this aspect with mostly insufficient therapeutic long-term efficacy. Mounting evidence implicates mitochondrial dysfunction and oxidative stress [...] Read more.
Diabetic retinopathy (DR), one of the leading causes of blindness, is mainly diagnosed based on the vascular pathology of the disease. Current treatment options largely focus on this aspect with mostly insufficient therapeutic long-term efficacy. Mounting evidence implicates mitochondrial dysfunction and oxidative stress in the central etiology of DR. Consequently, drug candidates that aim at normalizing mitochondrial function could be an attractive therapeutic approach. This study compared the mitoprotective compounds, idebenone and elamipretide, side-by-side against two novel short-chain quinones (SCQs) in a rat model of DR. The model effectively mimicked type 2 diabetes over 21 weeks. During this period, visual acuity was monitored by measuring optokinetic response (OKR). Vision loss occurred 5–8 weeks after the onset of hyperglycemia. After 10 weeks of hyperglycemia, visual function was reduced by 65%. From this point, the right eyes of the animals were topically treated once daily with the test compounds. The left, untreated eye served as an internal control. Only three weeks of topical treatment significantly restored vision from 35% to 58–80%, while visual acuity of the non-treated eyes continued to deteriorate. Interestingly, the two novel SCQs restored visual acuity better than idebenone or elamipretide. This was also reflected by protection of retinal pathology against oxidative damage, retinal ganglion cell loss, reactive gliosis, vascular leakage, and retinal thinning. Overall, mitoprotective and, in particular, SCQ-based compounds have the potential to be developed into effective and fast-acting drug candidates against DR. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms Underlying Pathophysiology and Therapies 2.0)
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16 pages, 2285 KiB  
Article
Mitochondrial Ceramide Effects on the Retinal Pigment Epithelium in Diabetes
by Yan Levitsky, Sandra S. Hammer, Kiera P. Fisher, Chao Huang, Travan L. Gentles, David J. Pegouske, Caimin Xi, Todd A. Lydic, Julia V. Busik and Denis A. Proshlyakov
Int. J. Mol. Sci. 2020, 21(11), 3830; https://doi.org/10.3390/ijms21113830 - 28 May 2020
Cited by 13 | Viewed by 4104
Abstract
Mitochondrial damage in the cells comprising inner (retinal endothelial cells) and outer (retinal pigment epithelium (RPE)) blood–retinal barriers (BRB) is known to precede the initial BRB breakdown and further histopathological abnormalities in diabetic retinopathy (DR). We previously demonstrated that activation of acid sphingomyelinase [...] Read more.
Mitochondrial damage in the cells comprising inner (retinal endothelial cells) and outer (retinal pigment epithelium (RPE)) blood–retinal barriers (BRB) is known to precede the initial BRB breakdown and further histopathological abnormalities in diabetic retinopathy (DR). We previously demonstrated that activation of acid sphingomyelinase (ASM) is an important early event in the pathogenesis of DR, and recent studies have demonstrated that there is an intricate connection between ceramide and mitochondrial function. This study aimed to determine the role of ASM-dependent mitochondrial ceramide accumulation in diabetes-induced RPE cell damage. Mitochondria isolated from streptozotocin (STZ)-induced diabetic rat retinas (7 weeks duration) showed a 1.64 ± 0.29-fold increase in the ceramide-to-sphingomyelin ratio compared to controls. Conversely, the ceramide-to-sphingomyelin ratio was decreased in the mitochondria isolated from ASM-knockout mouse retinas compared to wild-type littermates, confirming the role of ASM in mitochondrial ceramide production. Cellular ceramide was elevated 2.67 ± 1.07-fold in RPE cells derived from diabetic donors compared to control donors, and these changes correlated with increased gene expression of IL-1β, IL-6, and ASM. Treatment of RPE cells derived from control donors with high glucose resulted in elevated ASM, vascular endothelial growth factor (VEGF), and intercellular adhesion molecule 1 (ICAM-1) mRNA. RPE from diabetic donors showed fragmented mitochondria and a 2.68 ± 0.66-fold decreased respiratory control ratio (RCR). Treatment of immortalized cell in vision research (ARPE-19) cells with high glucose resulted in a 25% ± 1.6% decrease in citrate synthase activity at 72 h. Inhibition of ASM with desipramine (15 μM, 1 h daily) abolished the decreases in metabolic functional parameters. Our results are consistent with diabetes-induced increase in mitochondrial ceramide through an ASM-dependent pathway leading to impaired mitochondrial function in the RPE cells of the retina. Full article
(This article belongs to the Special Issue Diabetic Retinopathy: Mechanisms Underlying Pathophysiology and Therapies 2.0)
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