VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy

Amato, Rosario; Biagioni, Martina; Cammalleri, Maurizio; Monte, Massimo Dal; Casini, G.

doi:10.1167/iovs.16-19285

Cited by 43 publications

(60 citation statements)

References 55 publications

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“…In retinal ischemia, VEGF decreases in a gradient from the RGC to the outer plexiform layer. With rapid damage to the RGCs, neuronal cell damage precedes capillary degeneration, Endothelial cell survival factors, including VEGF, are released by retinal neuronal cells, including RGCs [42, 43]. Thus another potential mechanism for enhanced survival of the retina in our study is the stimulation of VEGF production by retinal neurons.…”

Section: Discussionmentioning

confidence: 83%

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

Mathew

Poston

Dreixler

et al. 2017

Graefes Arch Clin Exp Ophthalmol

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Purpose Ischemia-associated retinal degeneration is one of the leading causes of vision loss and to date, there are no effective treatment options. We hypothesized that delayed injection of bone marrow stem cells (BMSCs) 24 h after the onset of ischemia could effectively rescue ischemic retina from its consequences, including apoptosis, inflammation, and increased vascular permeability, thereby preventing retinal cell loss. Methods Retinal ischemia was induced in adult Wistar rats by increasing intraocular pressure (IOP) to 130–135 mm Hg for 55 min. BMSCs harvested from rat femur were injected into the vitreous 24 h post-ischemia. Functional recovery was assessed 7 days later using electroretinography (ERG) measurements of the a-wave, b-wave, P2, scotopic threshold response (STR), and oscillatory potentials (OP). The retinal injury and anti-ischemic effects of BMSCs were quantitated by measuring apoptosis, autophagy, inflammatory markers, and retinal-blood barrier permeability. The distribution and fate of BMSC were qualitatively examined using real-time fundus imaging, and retinal flat mounts. Results Intravitreal delivery of BMSCs significantly improved recovery of the ERG a- and b-waves, OP, negative STR, and P2, and attenuated apoptosis as evidenced by decreased TUNEL and caspase-3 protein levels. BMSCs significantly increased autophagy, decreased inflammatory mediators (TNF-α, IL-1β, IL-6), and diminished retinal vascular permeability. BMSCs persisted in the vitreous and were also found within ischemic retina. Conclusions Taken together, our results indicate that intravitreal injection of BMSCs rescued the retina from ischemic damage in a rat model. The mechanisms include suppression of apoptosis, attenuation of inflammation and vascular permeability, and preservation of autophagy.

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Section: Discussionmentioning

confidence: 83%

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

Mathew

Poston

Dreixler

et al. 2017

Graefes Arch Clin Exp Ophthalmol

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“…On the other hand, a recent study in retinal explants of mice demonstrated that VEGF prevents neuronal apoptosis shortly after exposure to various harmful stimuli frequent in diabetics including hyperglycaemia, AGEs and oxygen peroxide. However, this neuroprotective effect was eliminated when the ex vivo retinas were preincubated with a VEGF trapping protein or after many days of stimuli (Amato, Biagioni, Cammalleri, Dal Monte, & Casini, ). Thus, the following dilemma arises: How to correctly modulate VEGF levels in each patient in order to produce regression of neovascularization without inducing neuronal demise?…”

Section: Trophic Factorsmentioning

confidence: 99%

A journey into the retina: Müller glia commanding survival and death

Subirada

Paz

Ridano

et al. 2018

Eur J of Neuroscience

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Müller glial cells (MGCs) are known to participate actively in retinal development and to contribute to homoeostasis through many intracellular mechanisms. As there are no homologous cells in other neuronal tissues, it is certain that retinal health depends on MGCs. These macroglial cells are located at the centre of the columnar subunit and have a great ability to interact with neurons, astrocytes, microglia and endothelial cells in order to modulate different events. Several investigations have focused their attention on the role of MGCs in diabetic retinopathy, a progressive pathology where several insults coexist. As expected, data suggest that MGCs display different responses according to the severity of the stimulus, and therefore trigger distinct events throughout the course of the disease. Here, we describe physiological functions of MGCs and their participation in inflammation, gliosis, synthesis and secretion of trophic and antioxidant factors in the diabetic retina. We invite the reader to consider the protective/deleterious role of MGCs in the early and late stages of the disease. In the light of the results, we open up the discussion around and ask the question: Is it possible that the modulation of a single cell type could improve or even re-establish retinal function after an injury?

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“…As previously reported, 1 µM OCT protects from apoptosis retinal explants exposed to OS (Amato et al, 2016). Similar to the dose-response experiment in HRECs, we performed an experiment in OS-treated retinal explants to assess the efficacy of decreasing concentrations of OCT and of MNP-OCT.…”

Section: Os-induced Apoptotic Cell Death In Retinal Explants Is Reducmentioning

confidence: 95%

“…Ex vivo cultures were prepared according to published protocols (Amato et al, 2016). Briefly, retinas were dissected, cut into four fragments and transferred onto Millicell-CM culture inserts (Merck Millipore, Burlington, MA, United States) with ganglion cells up.…”

Section: Retinal Explantsmentioning

confidence: 99%

“…The endogenous neuropeptide somatostatin has been widely studied for its powerful neuroprotective properties that may be exploited for DR treatment, and these studies have been extensively reviewed (Gabriel, 2013;Hernandez et al, 2014;Szabadfi et al, 2014;Simo-Servat et al, 2018;Cervia et al, 2019). In particular, the treatment with the somatostatin analog octreotide (OCT) has been found to inhibit apoptotic cell death and avoid vascular endothelial growth factor (VEGF) overexpression in retinal explants exposed to typical diabetic stressors such as hyperglycemia, oxidative stress (OS) or advanced glycation end-products (Amato et al, 2016). OCT has been shown also to maintain the apoptosis-autophagy equilibrium in high glucose conditions by promoting the restoration of the autophagic flux in bipolar, amacrine, and ganglion cells (Amato et al, 2018a).…”

Section: Introductionmentioning

confidence: 99%

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Association of the Somatostatin Analog Octreotide With Magnetic Nanoparticles for Intraocular Delivery: A Possible Approach for the Treatment of Diabetic Retinopathy

Amato

Giannaccini

Monte

et al. 2020

Front. Bioeng. Biotechnol.

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The somatostatin analog octreotide (OCT) displays important neuroprotective and antiangiogenic properties that could make it an interesting candidate to treat diabetic retinopathy (DR). Unfortunately, systemic drug administration is hindered by severe side effects, therefore topical administration routes are preferable. However, drug delivery through eye drops may be difficult due to ocular barriers and, in the long term, could induce ocular damage. On the other hand, intraocular injections must be repeated to maintain drug concentration, and this may cause severe damage to the eye. To decrease injection frequency, long-term release and reduced biodegradation could be obtained by binding the drug to biodegradable polymeric nanoparticles. In the present study, we made a preparation of OCT bound to magnetic nanoparticles (MNP-OCT) and tested its possible use as an OCT delivery system to treat retinal pathologies such as DR. In particular, in vitro, ex vivo, and in vivo experimental models of the mammalian retina were used to investigate the possible toxicity of MNPs, possible effects of the binding to MNPs on OCT bioactivity, and the localization of MNP-OCT in the retina after intraocular injection. The results showed that, both in human retinal endothelial cells (HRECs) and in mouse retinal explants, MNPs were not toxic and the binding with MNPs did not influence OCT antiangiogenic or antiapoptotic activity. Rather, effects of MNP-OCT were observed at concentrations up to 100-fold (in HRECs) or 10-fold (in mouse retinal explants) lower compared to OCT, indicating that OCT bioactivity was enhanced in MNP-OCT. MNP-OCT in mouse retinas in vivo after intraocular delivery were initially localized mainly to the outer retina, at the level of the retinal pigment epithelium, while after 5 days they were observed throughout the retinal thickness. These observations demonstrate that MNP-OCT may be used as an OCT intraocular delivery system that may ensure OCT localization to the retina and enhanced OCT bioactivity. Further studies will be necessary to determine the OCT release rate in the retina and the persistence of drug effects in the long period.

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VEGF as a Survival Factor in Ex Vivo Models of Early Diabetic Retinopathy

Cited by 43 publications

References 55 publications

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

Bone-marrow mesenchymal stem-cell administration significantly improves outcome after retinal ischemia in rats

A journey into the retina: Müller glia commanding survival and death

Association of the Somatostatin Analog Octreotide With Magnetic Nanoparticles for Intraocular Delivery: A Possible Approach for the Treatment of Diabetic Retinopathy

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