Functional and Structural Evaluation of Sildenafil in a Rat Model of Acute Retinal Ischemia/Reperfusion Injury

Ezra-Elia, Raaya; Silva, Germana Alegro da; Zanoni, Diogo Sousa; Laufer-Amorim, Renée; Amaral, Andréia Vitor Couto do; Laus, José Luiz; Ofri, Ron

doi:10.1080/02713683.2016.1193615

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…Ezra‐Elia et al . () revealed a tendency of less necrosis in retinas of sildenafil‐treated animals, suggesting that SC prevents apoptosis in treated animals. Thus, there is a trend towards a positive effect of SC that could implicate the possible anti‐apoptotic effect, demonstrated by decreased apoptosis and increased anti‐apoptosis expression.…”

Section: Discussionmentioning

confidence: 88%

Histological, morphometric, protein and gene expression analyses of rat retinas with ischaemia–reperfusion injury model treated with sildenafil citrate

Zanoni

Silva

Ezra-Elia

et al. 2017

Int J Experimental Path

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The aim of this study was to better understand the role of apoptosis in a retinal ischaemia-reperfusion injury model and to determine whether sildenafil citrate treatment can prevent retinal cell apoptosis. Thirty-six rats were divided into a control group (n = 6) and two experimentally induced ischaemia-reperfusion groups (7 and 21 days; n = 15 per group). The induced ischaemia-reperfusion groups were treated with sildenafil for 7 and 21 days (n = 10 per group), and 10 animals were treated with a placebo for the same period (n = 5 per group). Paracentesis of the anterior chamber was performed with a 30-G needle attached to a saline solution (0.9%) bag positioned at a height of 150 cm above the eye for 60 min. Intraocular pressure was measured by rebound tonometer (TonoVet ). The eyes were analysed by histology and morphometry, and by immunohistochemistry and qRT-PCR for expression of Caspase-7, Caspase-6, Caspase-9, Tnf-r2, Fas-l, Bcl-2 and Bax. Sildenafil-treated animals showed lower levels of histopathological changes (inflammatory, cellular and tissue) than their placebo-treated counterparts at both 7 and 21 days. The retinal ganglion cell layer (RGC) was preserved in the sildenafil groups (SG), with a cell count closer to control than in the placebo groups (PG). Caspase-7 expression was significantly higher in both treated groups at 7 days compared to controls. Gene expression levels in both treatment groups differed from the controls, but in SG Bax and Caspase-6 expression levels were similar to control animals. These results suggest that the main mechanism of retinal cell death in this model is apoptosis, as there is an increase in pro-apoptotic factors and decrease in the anti-apoptotic ones. Also, sildenafil seems to protect the retinal ganglion cell layer from apoptosis. Cell survival was evident in the histological and morphometric analyses, and sildenafil treatment had a protective effect in the apoptosis pathways, with gene expression levels in SG similar to the controls.

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Section: Discussionmentioning

confidence: 88%

Histological, morphometric, protein and gene expression analyses of rat retinas with ischaemia–reperfusion injury model treated with sildenafil citrate

Zanoni

Silva

Ezra-Elia

et al. 2017

Int J Experimental Path

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“…Caspase-8 and caspase-9 are initiators, while caspase-3 is an executioner. In the intrinsic apoptotic pathway, during cellular stress, active capase-9 will cleave and activate caspase-3, then lead to degradation of cellular components for apoptosis (38–40). In the extrinsic apoptotic pathway, activated caspase-8 can lead to either downstream activation of the intrinsic pathway by inducing mitochondrial stress, or direct activation of caspase-3 activation and apoptosis (41–43).…”

Section: Discussionmentioning

confidence: 99%

CD47 blockade reduces ischemia/reperfusion injury in donation after cardiac death rat kidney transplantation

Wang

Jia

et al. 2018

American Journal of Transplantation

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Modulation of nitric oxide activity through blockade of CD47 signaling has been shown to reduce ischemia-reperfusion injury (IRI) in various models of tissue ischemia. Here, we evaluate the potential effect of an antibody-mediated CD47 blockade in a syngeneic and an allogeneic DCD rat kidney transplant model. The donor organ was subjected to 1 hour of warm ischemia time after circulatory cessation, then flushed with a CD47 monoclonal antibody (CD47mAb) in the treatment group, or an isotype-matched immunoglobulin in the control group. We found that CD47mAb treatment improved survival rates in both models. Serum markers of renal injury were significantly decreased in the CD47mAb-treated group compared with the control group. Histologically the CD47mAb-treated group had significantly reduced scores of acute tubular injury and acute tubular necrosis. The expression of biomarkers related to mitochondrial stress and apoptosis also were significantly lower in the CD47mAb-treated groups. Overall, the protective effects of CD47 blockade were greater in the syngeneic model. Our data show that CD47mAb blockade decreased the IRI of DCD kidneys in rat transplant models. This therapy has the potential to improve DCD kidney transplant outcomes in the human setting.

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“…[4][5][6][7][8] Rodent models of temporarily elevated IOP-induced retinal I/R injury have been widely used for understanding the pathological mechanisms of ischemic retinopathy. 4,7,9 Acute ischemia followed by natural reperfusion can cause retinal inflammatory and neurodegenerative responses. 10,11 However, the precise pathological mechanisms underlying the development of ischemic retinopathy have not been comprehensively established.…”

Section: Introductionmentioning

confidence: 99%

“…I/R injury can be experimentally induced by transient occlusion of cardiovascular/ocular vessels or high intraocular pressure (IOP) 4–8 . Rodent models of temporarily elevated IOP‐induced retinal I/R injury have been widely used for understanding the pathological mechanisms of ischemic retinopathy 4,7,9 . Acute ischemia followed by natural reperfusion can cause retinal inflammatory and neurodegenerative responses 10,11 .…”

Section: Introductionmentioning

confidence: 99%

Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

et al. 2022

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Retinal ischemia-reperfusion (I/R) injury is a common cause of visual impairment. To date, no effective treatment is available for retinal I/R injury. In addition, the precise pathological mechanisms still need to be established. Recently, pemafibrate, a peroxisome proliferator-activated receptor α (PPARα) modulator, was shown to be a promising drug for retinal ischemia. However, the role of pemafibrate in preventing retinal I/R injury has not been documented. Here, we investigated how retinal degeneration occurs in a mouse model of retinal I/R injury by elevation of intraocular pressure and examined whether pemafibrate could be beneficial against retinal degeneration. Adult mice were orally administered pemafibrate (0.5 mg/kg/day) for 4 days, followed by retinal I/R injury.The mice were continuously administered pemafibrate once every day until the end of the experiments. Retinal functional changes were measured using electroretinography. Retina, liver, and serum samples were used for western blotting, quantitative PCR, immunohistochemistry, or enzyme linked immunosorbent assay. Retinal degeneration induced by retinal inflammation was prevented by pemafibrate administration. Pemafibrate administration increased the hepatic PPARα target gene expression and serum levels of fibroblast growth factor 21, a neuroprotective molecule in the eye. The expression of hypoxia-response and pro-and anti-apoptotic/inflammatory genes increased in the retina following retinal I/R injury; however, these changes were modulated by pemafibrate administration. In conclusion, pemafibrate is a promising preventive drug for ischemic retinopathies.

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Functional and Structural Evaluation of Sildenafil in a Rat Model of Acute Retinal Ischemia/Reperfusion Injury

Abstract: Electroretinography, RGC counts, and retinal morphometry failed to show any neuroprotective effect of sildenafil in acute retinal I/R injury in rats. A slight positive effect of sildenafil was qualitatively indicated by histopathology and IHC.

Cited by 7 publications

References 49 publications

Histological, morphometric, protein and gene expression analyses of rat retinas with ischaemia–reperfusion injury model treated with sildenafil citrate

Histological, morphometric, protein and gene expression analyses of rat retinas with ischaemia–reperfusion injury model treated with sildenafil citrate

CD47 blockade reduces ischemia/reperfusion injury in donation after cardiac death rat kidney transplantation

Retinal degeneration induced in a mouse model of ischemia–reperfusion injury and its management by pemafibrate treatment

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