Histologic Characterization of Retina Neuroglia Modifications in Diabetic Zucker Diabetic Fatty Rats

Fernandez-Bueno, Iván; Jones, Robert B.; Soriano-Romaní, Laura; López-García, Antonio; Galvin, Orla; Cheetham, Sharon C.; Diebold, Yolanda

doi:10.1167/iovs.17-21742

Cited by 14 publications

(3 citation statements)

References 37 publications

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“…Glial activation is considered as an indicator of injury to the retina during disease or stress conditions including ischemia/reperfusion (Yokota et al, 2011; Shosha et al, 2016; Renner et al, 2017), oxygen-induced retinopathy (Narayanan et al, 2011), diabetes (Fernandez-Bueno et al, 2017; Chaurasia et al, 2018) and neurotoxicity by NMDA (Casson et al, 2004; Sakamoto et al, 2017). Although a direct relationship between macroglial activation and ganglion cell death is not well defined, it can be said that Muller cell activation is a feature of retinal neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

et al. 2019

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Dysfunction of retinal neurons is a major cause of vision impairment in blinding diseases that affect children and adults worldwide. Cellular damage resulting from polyamine catabolism has been demonstrated to be a major player in many neurodegenerative conditions. We have previously shown that inhibition of polyamine oxidase (PAO) using MDL 72527 significantly reduced retinal neurodegeneration and cell death signaling pathways in hyperoxia-mediated retinopathy. In the present study, we investigated the impact of PAO inhibition in limiting retinal neurodegeneration in a model of NMDA (N-Methyl-D-aspartate)-induced excitotoxicity. Adult mice (8–10 weeks old) were given intravitreal injections (20 nmoles) of NMDA or NMLA (N-Methyl-L-aspartate, control). Intraperitoneal injection of MDL 72527 (40 mg/kg body weight/day) or vehicle (normal saline) was given 24 h before NMDA or NMLA treatment and continued until the animals were sacrificed (varied from 1 to 7 days). Analyses of retinal ganglion cell (RGC) layer cell survival was performed on retinal flatmounts. Retinal cryostat sections were prepared for immunostaining, TUNEL assay and retinal thickness measurements. Fresh frozen retinal samples were used for Western blotting analysis. A marked decrease in the neuronal survival in the RGC layer was observed in NMDA treated retinas compared to their NMLA treated controls, as studied by NeuN immunostaining of retinal flatmounts. Treatment with MDL 72527 significantly improved survival of NeuN positive cells in the NMDA treated retinas. Excitotoxicity induced neurodegeneration was also demonstrated by reduced levels of synaptophysin and degeneration of inner retinal neurons in NMDA treated retinas compared to controls. TUNEL labeling studies showed increased cell death in the NMDA treated retinas. However, treatment with MDL 72527 markedly reduced these changes. Analysis of signaling pathways during excitotoxic injury revealed the downregulation of pro-survival signaling molecules p-ERK and p-Akt, and the upregulation of a pro-apoptotic molecule BID, which were normalized with PAO inhibition. Our data demonstrate that inhibition of polyamine oxidase blocks NMDA-induced retinal neurodegeneration and promotes cell survival, thus offering a new therapeutic target for retinal neurodegenerative disease conditions.

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Section: Discussionmentioning

confidence: 99%

Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

et al. 2019

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“…A remarkable and unexpected finding from this study was the long-lived persistence of GFAP upregulation in blast-exposed retinas, even 8 months after a single exposure to ABO. GFAP upregulation is typically a signature that accompanies any insult to the retina, including neuronal degeneration and cell death in retinal degenerative diseases, 23,24 hyperglycemia insult in diabetic retinopathy, 50,51 and ischemic insult in ocular stroke. 52 The persistence of a gliotic response suggests that the local microenvironment of the retina was perturbed by blast exposure, belying the apparent ''normalcy'' of retinal layer thickness.…”

Section: Persistence Of Gliotic Response Several Months After Blast Ementioning

confidence: 99%

Long-Term Functional and Structural Consequences of Primary Blast Overpressure to the Eye

Allen

Motz

Feola

et al. 2018

Journal of Neurotrauma

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Acoustic blast overpressure (ABO) injury in military personnel and civilians is often accompanied by delayed visual deficits. However, most animal model studies dealing with blast-induced visual defects have focused on short-term (≤1 month) changes. Here, we evaluated long-term (≤8 months) retinal structure and function deficits in rats with ABO injury. Adult male Long-Evans rats were subjected to ABO from a single blast (approximately 190 dB SPL, ∼63 kPa, @80 psi), generated by a shock tube device. Retinal function (electroretinography; ERG), visual function (optomotor response), retinal thickness (spectral domain-optical coherence tomography; SD-OCT), and spatial cognition/exploratory motor behavior (Y-maze) were measured at 2, 4, 6, and 8 months post-blast. Immunohistochemical analysis of glial fibrillary acidic protein (GFAP) in retinal sections was performed at 8 months post-blast. Electroretinogram a- and b-waves, oscillatory potentials, and flicker responses showed greater amplitudes with delayed implicit times in both eyes of blast-exposed animals, relative to controls. Contrast sensitivity (CS) was reduced in both eyes of blast-exposed animals, whereas spatial frequency (SF) was decreased only in ipsilateral eyes, relative to controls. Total retinal thickness was greater in both eyes of blast-exposed animals, relative to controls, due to increased thickness of several retinal layers. Age, but not blast exposure, altered Y-maze outcomes. GFAP was greatly increased in blast-exposed retinas. ABO exposure resulted in visual and retinal changes that persisted up to 8 months post-blast, mimicking some of the visual deficits observed in human blast-exposed patients, thereby making this a useful model to study mechanisms of injury and potential treatments.

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“…The highest retinal thickness was obtained with PhC 3 with NIC+VIP, but relevant degenerative changes in the NR morphology and glial cell activation were observed. This degeneration may be related to an increase in the retinal thickness [ 20 , 73 , 74 ], which could explain the results observed. NR cultured with PhC 3 with NIC also showed suitable preservation of the NR layers, although in this case, outer segments were not identifiable.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases

Alonso-Alonso

Srivastava

Usategui-Martín

et al. 2020

Stem Cells International

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Mesenchymal stem cells (MSC) secrete neuroprotective molecules that may be useful as an alternative to cell transplantation itself. Our purpose was to develop different pharmaceutical compositions based on conditioned medium (CM) of adipose MSC (aMSC) stimulated by and/or combined with nicotinamide (NIC), vasoactive intestinal peptide (VIP), or both factors; and to evaluate in vitro their proliferative and neuroprotective potential. Nine pharmaceutical compositions were developed from 3 experimental approaches: (1) unstimulated aMSC-CM collected and combined with NIC, VIP, or both factors (NIC+VIP), referred to as the aMSC-CM combined composition; (2) aMSC-CM collected just after stimulation with the mentioned factors and containing them, referred to as the aMSC-CM stimulated-combined composition; and (3) aMSC-CM previously stimulated with the factors, referred to as the aMSC stimulated composition. The potential of the pharmaceutical compositions to increase cell proliferation under oxidative stress and neuroprotection were evaluated in vitro by using a subacute oxidative stress model of retinal pigment epithelium cells (line ARPE-19) and spontaneous degenerative neuroretina model. Results showed that oxidatively stressed ARPE-19 cells exposed to aMSC-CM stimulated and stimulated-combined with NIC or NIC+VIP tended to have better recovery from the oxidative stress status. Neuroretinal explants cultured with aMSC-CM stimulated-combined with NIC+VIP had better preservation of the neuroretinal morphology, mainly photoreceptors, and a lower degree of glial cell activation. In conclusion, aMSC-CM stimulated-combined with NIC+VIP contributed to improving the proliferative and neuroprotective properties of the aMSC secretome. Further studies are necessary to evaluate higher concentrations of the drugs and to characterize specifically the aMSC-secreted factors related to neuroprotection. However, this study supports the possibility of improving the potential of new effective pharmaceutical compositions based on the secretome of MSC plus exogenous factors or drugs without the need to inject cells into the eye, which can be very useful in retinal pathologies.

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Histologic Characterization of Retina Neuroglia Modifications in Diabetic Zucker Diabetic Fatty Rats

Cited by 14 publications

References 37 publications

Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

Targeting Polyamine Oxidase to Prevent Excitotoxicity-Induced Retinal Neurodegeneration

Long-Term Functional and Structural Consequences of Primary Blast Overpressure to the Eye

Mesenchymal Stem Cell Secretome Enhancement by Nicotinamide and Vasoactive Intestinal Peptide: A New Therapeutic Approach for Retinal Degenerative Diseases

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