Hypothermia prevents the development of ischemic proliferative retinopathy induced by severe perinatal asphyxia

Rey-Funes, Manuel; Ibarra, Mariano; Dorfman, Verónica Berta; López, Ester Marı́a; López‐Costa, Juan José; Coirini, Héctor; Loidl, César Fabián

doi:10.1016/j.exer.2009.09.019

Cited by 20 publications

(41 citation statements)

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“…These included formation of new vessels, and hypertrophy of Müller cells and perivascular astroglia. 7 We also observed increased enzymatic NO synthase (NOS) activity and age-dependent expression of NOS in hypoxic retinas. 8 Here we describe age-dependent alterations in the inner half layers of the retina produced by PA because of an early formation of vessels and an early expression of AM and GFAP in the hypoxic retinas.…”

Section: Discussionmentioning

confidence: 81%

“…7 Perinatal asphyxia in rats has proved to be a useful model for studying retinopathy, 7,8 as the induction of hypoxiaischemia in the perinatal period produces morphological, biochemical, and molecular changes. The development of the rat CNS at birth is equivalent to the one found in human fetuses at 32 weeks of gestation.…”

Section: Discussionmentioning

confidence: 99%

“…28 The key factor regulating angiogenesis in response to hypoxia is likely to be HIF-1, whose activation stimulates the production of VEGF. 27,29 Considering that PA induces the thickening of the IR and the presence of newly formed vessels in adult hypoxic/ ischemic animals, 7 the aim of the present work was to evaluate the impact of hypoxia-ischemia in a time course study analyzing the changes induced by PA in the retinal structure. We specially focused on the development of retinal damage elicited by vascularization and gliosis, the study of the expression and distribution of pro-angiogenic factors, such as AM and VEGF, and the application of hypothermia as a neuroprotective treatment.…”

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confidence: 99%

“…[10][11][12][13] The changes observed in asphyctic animals include ganglion cell degeneration, neovascularization of the most inner layers of the retina (IR) (including the internal limiting membrane, the retinal nerve fiber layer, and the ganglion cell layer), and Müller cell hypertrophy in the inner half layers of the retina (including the inner nuclear layer, the inner plexiform layer [IPL], the internal limiting membrane, the retinal nerve fiber layer, and the ganglion cell layer), with Copyright 2013 The Association for Research in Vision and Ophthalmology, Inc. www.iovs.org j ISSN: 1552-5783 significant increased expression of glial fibrillary acidic protein (GFAP) in activated Müller cells. 7 Animal studies have shown that a reduction in core temperature protects the nervous system against ischemic damage by a reduction of the metabolism, decreasing reactive oxygen species, and inhibiting the toxic release of nitric oxide (NO). 3,5,8,14,15 Hypothermia during PA prevents central nervous system (CNS) damage when compared with animals kept under normothermic conditions.…”

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confidence: 99%

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Hypothermia Prevents Gliosis and Angiogenesis Development in an Experimental Model of Ischemic Proliferative Retinopathy

Rey-Funes

Dorfman

Ibarra

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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Citation: Rey-Funes M, Dorfman VB, Ibarra ME, et al. Hypothermia prevents gliosis and angiogenesis development in an experimental model of ischemic proliferative retinopathy. Invest Ophthalmol Vis Sci. 2013;54:283654: -284654: . DOI:10.1167 PURPOSE. To develop a time course study of vascularization and glial response to perinatal asphyxia in hypoxic-ischemic animals, and to evaluate hypothermia as possible protective treatment. METHODS.We used retinas of 7-, 15-, 21-, and 30-day-old male Sprague-Dawley rats that were exposed to perinatal asphyxia at either 378C (PA) or 158C (HYP). Born to term animals were used as controls (CTL). We evaluated the thickness of the most inner layers of the retina (IR), including internal limiting membrane, the retinal nerve fiber layer, and the ganglion cell layer; and studied glial development, neovascularization, adrenomedullin (AM), and VEGF by immunohistochemistry, immunofluorescence, and Western blot. RESULTS.A significant increment in IR thickness was observed in the PA group from postnatal day (PND) 15 on. This alteration was concordant with an increased number of new vessels and increased GFAP expression. The immunolocalization of GFAP in the internal limiting membrane and perivascular glia of the IR and in the inner processes of Müller cells was coexpressed with AM, which was also significantly increased from PND7 in PA animals. In addition, VEGF expression was immunolocalized in cells of the ganglion cell layer of the IR and this expression significantly increased in the PA group from PND15 on. The retinas of the HYP group did not show differences when compared with CTL at any age.CONCLUSIONS. This work demonstrates that aberrant angiogenesis and exacerbated gliosis seem to be responsible for the increased thickness of the inner retina as a consequence of perinatal asphyxia, and that hypothermia is able to prevent these alterations.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Hypothermia Prevents Gliosis and Angiogenesis Development in an Experimental Model of Ischemic Proliferative Retinopathy

Rey-Funes

Dorfman

Ibarra

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…The changes observed in asphyctic animals include ganglion cell degeneration, neovascularization of the innermost layers of the retina (the internal limiting membrane, the retinal nerve fiber layer, and the ganglion cell layer), and Müller cell hypertrophy in the inner layers of the retina (including the inner nuclear layer, the inner plexiform layer, the ganglion cell layer, the retinal nerve fiber layer, and the internal limiting membrane) (44). Therefore, in rodents, it makes sense to use the term ischemic proliferative retinopathy to describe these changes.…”

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confidence: 99%

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

Rey-Funes

Larráyoz

Fernández

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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-Perinatal asphyxia induces retinal lesions, generating ischemic proliferative retinopathy, which may result in blindness. Previously, we showed that the nitrergic system was involved in the physiopathology of perinatal asphyxia. Here we analyze the application of methylene blue, a well-known soluble guanylate cyclase inhibitor, as a therapeutic strategy to prevent retinopathy. Male rats (n ϭ 28 per group) were treated in different ways: 1) control group comprised born-to-term animals; 2) methylene blue group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery; 3) perinatal asphyxia (PA) group comprised rats exposed to perinatal asphyxia (20 min at 37°C); and 4) methylene blue-PA group comprised animals born from pregnant rats treated with methylene blue (2 mg/kg) 30 and 5 min before delivery, and then the pups were subjected to PA as above. For molecular studies, mRNA was obtained at different times after asphyxia, and tissue was collected at 30 days for morphological and biochemical analysis. Perinatal asphyxia produced significant gliosis, angiogenesis, and thickening of the inner retina. Methylene blue treatment reduced these parameters. Perinatal asphyxia resulted in a significant elevation of the nitrergic system as shown by NO synthase (NOS) activity assays, Western blotting, and (immuno)histochemistry for the neuronal isoform of NOS and NADPH-diaphorase activity. All these parameters were also normalized by the treatment. In addition, methylene blue induced the upregulation of the anti-angiogenic peptide, pigment epithelium-derived factor. Application of methylene blue reduced morphological and biochemical parameters of retinopathy. This finding suggests the use of methylene blue as a new treatment to prevent or decrease retinal damage in the context of ischemic proliferative retinopathy. retina; nitric oxide; ischemic proliferative retinopathy; methylene blue; angiogenesis PERINATAL ASPHYXIA (PA) is one of the most severe problems in perinatology services across the world (9,15,23,27). PA generates a transient global hypoxia-ischemia status that damages the brain, spinal cord, and retina (14, 17, 39, 52). The degree and the length of perinatal asphyxia are decisive for the development of injury sequelae, such as attention-deficit hyperactivity disorder (1), epilepsy, mental retardation, spasticity, and visual or hearing alterations (61). One third of asphyctic neonates develop serious long-term neurological injuries including several degrees of ischemic proliferative retinopathy (IPR) and even blindness (20).In rats, the retina is particularly sensitive to oxygen alterations (56), and the morphological changes observed in its inner layers are compatible with some alterations observed in human diseases such as retinopathy in diabetes, retinal vein occlusion, and retinopathy of prematurity (ROP), an avoidable cause of visual impairment and blindness in children (20, 61). The changes observed in asphyctic animals include ganglion cell degeneration, n...

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Hypothermia prevents nitric oxide system changes in retina induced by severe perinatal asphyxia

Rey-Funes¹,

Ibarra²,

Dorfman³

et al. 2011

J of Neuroscience Research

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BACKGROUND. Health‐related quality of life (HRQOL) has not been adequately measured in bladder cancer. A recently developed reliable and disease‐specific quality of life instrument (Bladder Cancer Index, BCI) was used to measure urinary, sexual, and bowel function and bother domains in patients with bladder cancer managed with several different interventions, including cystectomy and endoscopic‐based procedures. METHODS. Patients with bladder cancer were identified from a prospective bladder cancer outcomes database and contacted as part of an Institutional Review Board‐approved study to assess treatment impact on HRQOL. HRQOL was measured using the BCI across stratified treatment groups. Bivariate and multivariable analyses adjusted for age, gender, income, education, relationship status, and follow‐up time were performed to compare urinary, bowel, and sexual domains between treatment groups. RESULTS. In all, 315 bladder cancer patients treated at the University of Michigan completed the BCI in 2004. Significant differences were seen in mean BCI function and bother scores between cystectomy and native bladder treatment groups. In addition, urinary function scores were significantly lower among cystectomy patients treated with continent neobladder compared with those treated with ileal conduit (all pairwise P < .05). CONCLUSIONS. The BCI is responsive to functional and bother differences in patients with bladder cancer treated with different surgical approaches. Significant differences between therapy groups in each of the urinary, bowel, and sexual domains exist. Among patients treated with orthotopic continent urinary diversion, functional impairments related to urinary incontinence and lack of urinary control account for the low observed urinary function scores. Cancer 2007. © 2007 American Cancer Society.

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Hypothermia prevents the development of ischemic proliferative retinopathy induced by severe perinatal asphyxia

Cited by 20 publications

References 37 publications

Hypothermia Prevents Gliosis and Angiogenesis Development in an Experimental Model of Ischemic Proliferative Retinopathy

Hypothermia Prevents Gliosis and Angiogenesis Development in an Experimental Model of Ischemic Proliferative Retinopathy

Methylene blue prevents retinal damage in an experimental model of ischemic proliferative retinopathy

Hypothermia prevents nitric oxide system changes in retina induced by severe perinatal asphyxia

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