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Selective Over-Expression of Endothelin-1 in Endothelial Cells Exacerbates Inner Retinal Edema and Neuronal Death in Ischemic Retina  [PDF]
Simon S. F. Cheung, Justin W. C. Leung, Amy K. M. Lam, Karen S. L. Lam, Stephen S. M. Chung, Amy C. Y. Lo, Sookja K. Chung
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026184
Abstract: The level of endothelin-1 (ET-1), a potent vasoconstrictor, was associated with retinopathy under ischemia. The effects of endothelial endothelin-1 (ET-1) over-expression in a transgenic mouse model using Tie-1 promoter (TET-1 mice) on pathophysiological changes of retinal ischemia were investigated by intraluminal insertion of a microfilament up to middle cerebral artery (MCA) to transiently block the ophthalmic artery. Two-hour occlusion and twenty-two-hour reperfusion were performed in homozygous (Hm) TET-1 mice and their non-transgenic (NTg) littermates. Presence of pyknotic nuclei in ganglion cell layer (GCL) was investigated in paraffin sections of ipsilateral (ischemic) and contralateral (non-ischemic) retinae, followed by measurement of the thickness of inner retinal layer. Moreover, immunocytochemistry of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS) and aquaporin-4 (AQP4) peptides on retinal sections were performed to study glial cell reactivity, glutamate metabolism and water accumulation, respectively after retinal ischemia. Similar morphology was observed in the contralateral retinae of NTg and Hm TET-1 mice, whereas ipsilateral retina of NTg mice showed slight structural and cellular changes compared with the corresponding contralateral retina. Ipsilateral retinae of Hm TET-1 mice showed more significant changes when compared with ipsilateral retina of NTg mice, including more prominent cell death in GCL characterized by the presence of pyknotic nuclei, elevated GS immunoreactivity in Müller cell bodies and processes, increased AQP-4 immunoreactivity in Müller cell processes, and increased inner retinal thickness. Thus, over-expression of endothelial ET-1 in TET-1 mice may contribute to increased glutamate-induced neurotoxicity on neuronal cells and water accumulation in inner retina leading to edema.
Impairment of Neuronal Glutamate Uptake and Modulation of the Glutamate Transporter GLT-1 Induced by Retinal Ischemia  [PDF]
Rossella Russo, Federica Cavaliere, Giuseppe Pasquale Varano, Marco Milanese, Annagrazia Adornetto, Carlo Nucci, Giambattista Bonanno, Luigi Antonio Morrone, Maria Tiziana Corasaniti, Giacinto Bagetta
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069250
Abstract: Excitotoxicity has been implicated in the retinal neuronal loss in several ocular pathologies including glaucoma. Dysfunction of Excitatory Amino Acid Transporters is often a key component of the cascade leading to excitotoxic cell death. In the retina, glutamate transport is mainly operated by the glial glutamate transporter GLAST and the neuronal transporter GLT-1. In this study we evaluated the expression of GLAST and GLT-1 in a rat model of acute glaucoma based on the transient increase of intraocular pressure (IOP) and characterized by high glutamate levels during the reperfusion that follows the ischemic event associated with raised IOP. No changes were reported in GLAST expression while, at neuronal level, a reduction of glutamate uptake and of transporter reversal-mediated glutamate release was observed in isolated retinal synaptosomes. This was accompanied by modulation of GLT-1 expression leading to the reduction of the canonical 65 kDa form and upregulation of a GLT-1-related 38 kDa protein. These results support a role for neuronal transporters in glutamate accumulation observed in the retina following an ischemic event and suggest the presence of a GLT-1 neuronal new alternative splice variant, induced in response to the detrimental stimulus.
Ischemic Tolerance Protects the Rat Retina from Glaucomatous Damage  [PDF]
Nicolás Belforte, Pablo H. Sande, Nuria de Zavalía, Diego C. Fernandez, Dafne M. Silberman, Mónica S. Chianelli, Ruth E. Rosenstein
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023763
Abstract: Glaucoma is a leading cause of acquired blindness which may involve an ischemic-like insult to retinal ganglion cells and optic nerve head. We investigated the effect of a weekly application of brief ischemia pulses (ischemic conditioning) on the rat retinal damage induced by experimental glaucoma. Glaucoma was induced by weekly injections of chondroitin sulfate (CS) in the rat eye anterior chamber. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 min; this maneuver started after 6 weekly injections of vehicle or CS and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. Glaucoma was evaluated in terms of: i) intraocular pressure (IOP), ii) retinal function (electroretinogram (ERG)), iii) visual pathway function (visual evoked potentials, (VEPs)) iv) histology of the retina and optic nerve head. Retinal thiobarbituric acid substances levels were assessed as an index of lipid peroxidation. Ischemic conditioning significantly preserved ERG, VEPs, as well as retinal and optic nerve head structure from glaucomatous damage, without changes in IOP. Moreover, ischemia pulses abrogated the increase in lipid peroxidation induced by experimental glaucoma. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies in glaucoma treatment.
In vivo characterization of ischemic retina in diabetic retinopathy  [cached]
Lukas Reznicek,Marcus Kernt,Christos Haritoglou,et al
Clinical Ophthalmology , 2010,
Abstract: Lukas Reznicek, Marcus Kernt, Christos Haritoglou, Anselm Kampik, Michael Ulbig, Aljoscha S NeubauerDepartment of Ophthalmology, Ludwig Maximilian University, Munich, GermanyObjective: The aim of this article is to characterize pathomorphologic changes within particular layers of fluorescein angiographically 'ischemic' compared to 'nonischemic' retina in patients with diabetic retinopathy.Methods: Cross-sectional images of ischemic retinal areas were obtained using Heidelberg Spectralis optical coherence tomography (OCT). Presumed retinal ischemia was defined as focal hypofluorescence in early or early and late phase fluorescein angiography. Pathomorphologic changes on OCT were evaluated and the thickness of retinal layers measured and compared with nonischemic retina at corresponding topographic locations in a matched-pairs design based on 22 eyes (mean age 64 ± 14).Results: In all eyes, based on spectral domain-OCT cross-section images, the retina layers in ischemic retinal areas could be segmented. Total retinal thickness was significantly increased in ischemic compared to nonischemic areas (381 ± 94 μm versus 323 ± 89 μm, P = 0.005). Middle retinal layers (inner nuclear layer, outer plexiform layer, and outer nuclear layer) were significantly thickened in retinal ischemic areas (215 ± 82 μm versus 168 ± 62 μm, P = 0.002). The inner retinal layers (retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer) showed a nonsignificant change (117 ± 53 μm versus 98 ± 30 μm), while the outer layers were slightly thinned (photoreceptors plus retinal pigment epithelium layer; 51 ± 9 μm versus 57 ± 8 μm, P = 0.02) in ischemic versus nonischemic retina.Conclusions: Ischemic diabetic retina seems to be thickened due to thickening of, in particular, middle retinal layers, which can be measured with high-resolution OCT.Keywords: OCT, Spectralis OCT, fluorescein angiography, diabetic retinopathy, ischemic retina, retinal thickness, retinal layers
In vivo characterization of ischemic retina in diabetic retinopathy
Lukas Reznicek, Marcus Kernt, Christos Haritoglou, et al
Clinical Ophthalmology , 2011, DOI: http://dx.doi.org/10.2147/OPTH.S13850
Abstract: vivo characterization of ischemic retina in diabetic retinopathy Original Research (5173) Total Article Views Authors: Lukas Reznicek, Marcus Kernt, Christos Haritoglou, et al Published Date December 2010 Volume 2011:5 Pages 31 - 35 DOI: http://dx.doi.org/10.2147/OPTH.S13850 Lukas Reznicek, Marcus Kernt, Christos Haritoglou, Anselm Kampik, Michael Ulbig, Aljoscha S Neubauer Department of Ophthalmology, Ludwig Maximilian University, Munich, Germany Objective: The aim of this article is to characterize pathomorphologic changes within particular layers of fluorescein angiographically 'ischemic' compared to 'nonischemic' retina in patients with diabetic retinopathy. Methods: Cross-sectional images of ischemic retinal areas were obtained using Heidelberg Spectralis optical coherence tomography (OCT). Presumed retinal ischemia was defined as focal hypofluorescence in early or early and late phase fluorescein angiography. Pathomorphologic changes on OCT were evaluated and the thickness of retinal layers measured and compared with nonischemic retina at corresponding topographic locations in a matched-pairs design based on 22 eyes (mean age 64 ± 14). Results: In all eyes, based on spectral domain-OCT cross-section images, the retina layers in ischemic retinal areas could be segmented. Total retinal thickness was significantly increased in ischemic compared to nonischemic areas (381 ± 94 μm versus 323 ± 89 μm, P = 0.005). Middle retinal layers (inner nuclear layer, outer plexiform layer, and outer nuclear layer) were significantly thickened in retinal ischemic areas (215 ± 82 μm versus 168 ± 62 μm, P = 0.002). The inner retinal layers (retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer) showed a nonsignificant change (117 ± 53 μm versus 98 ± 30 μm), while the outer layers were slightly thinned (photoreceptors plus retinal pigment epithelium layer; 51 ± 9 μm versus 57 ± 8 μm, P = 0.02) in ischemic versus nonischemic retina. Conclusions: Ischemic diabetic retina seems to be thickened due to thickening of, in particular, middle retinal layers, which can be measured with high-resolution OCT.
Global and Ocular Hypothermic Preconditioning Protect the Rat Retina from Ischemic Damage  [PDF]
Ezequiel M. Salido, Damián Dorfman, Melina Bordone, Mónica Chianelli, María Florencia González Fleitas, Ruth E. Rosenstein
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061656
Abstract: Retinal ischemia could provoke blindness. At present, there is no effective treatment against retinal ischemic damage. Strong evidence supports that glutamate is implicated in retinal ischemic damage. We investigated whether a brief period of global or ocular hypothermia applied 24 h before ischemia (i.e. hypothermic preconditioning, HPC) protects the retina from ischemia/reperfusion damage, and the involvement of glutamate in the retinal protection induced by HPC. For this purpose, ischemia was induced by increasing intraocular pressure to 120 mm Hg for 40 min. One day before ischemia, animals were submitted to global or ocular hypothermia (33°C and 32°C for 20 min, respectively) and fourteen days after ischemia, animals were subjected to electroretinography and histological analysis. Global or ocular HPC afforded significant functional (electroretinographic) protection in eyes exposed to ischemia/reperfusion injury. A marked alteration of the retinal structure and a decrease in retinal ganglion cell number were observed in ischemic retinas, whereas global or ocular HPC significantly preserved retinal structure and ganglion cell count. Three days after ischemia, a significant decrease in retinal glutamate uptake and glutamine synthetase activity was observed, whereas ocular HPC prevented the effect of ischemia on these parameters. The intravitreal injection of supraphysiological levels of glutamate induced alterations in retinal function and histology which were significantly prevented by ocular HPC. These results support that global or ocular HPC significantly protected retinal function and histology from ischemia/reperfusion injury, probably through a glutamate-dependent mechanism.
Neonatal Hyperglycemia Inhibits Angiogenesis and Induces Inflammation and Neuronal Degeneration in the Retina  [PDF]
Elsa Kermorvant-Duchemin, Alexis Christophe Pinel, Sophie Lavalette, Delphine Lenne, William Raoul, Bertrand Calippe, Francine Behar-Cohen, José-Alain Sahel, Xavier Guillonneau, Florian Sennlaub
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0079545
Abstract: Recent evidence suggests that transient hyperglycemia in extremely low birth weight infants is strongly associated with the occurrence of retinopathy of prematurity (ROP). We propose a new model of Neonatal Hyperglycemia-induced Retinopathy (NHIR) that mimics many aspects of retinopathy of prematurity. Hyperglycemia was induced in newborn rat pups by injection of streptozocine (STZ) at post natal day one (P1). At various time points, animals were assessed for vascular abnormalities, neuronal cell death and accumulation and activation of microglial cells. We here report that streptozotocin induced a rapid and sustained increase of glycemia from P2/3 to P6 without affecting rat pups gain weight or necessitating insulin treatment. Retinal vascular area was significantly reduced in P6 hyperglycemic animals compared to control animals. Hyperglycemia was associated with (i) CCL2 chemokine induction at P6, (ii) a significant recruitment of inflammatory macrophages and an increase in total number of Iba+ macrophages/microglia cells in the inner nuclear layer (INL), and (iii) excessive apoptosis in the INL. NHIR thereby reproduces several aspects of ischemic retinopathies, including ROP and diabetic retinopathies, and might be a useful model to decipher hyperglycemia-induced cellular and molecular mechanisms in the small rodent.
Postconditioning with Inhaled Carbon Monoxide Counteracts Apoptosis and Neuroinflammation in the Ischemic Rat Retina  [PDF]
Nils Schallner, Matthias Fuchs, Christian I. Schwer, Torsten Loop, Hartmut Buerkle, Wolf Alexander Lagrèze, Christian van Oterendorp, Julia Biermann, Ulrich Goebel
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0046479
Abstract: Purpose Ischemia and reperfusion injury (I/R) of neuronal structures and organs is associated with increased morbidity and mortality due to neuronal cell death. We hypothesized that inhalation of carbon monoxide (CO) after I/R injury (‘postconditioning’) would protect retinal ganglion cells (RGC). Methods Retinal I/R injury was performed in Sprague-Dawley rats (n = 8) by increasing ocular pressure (120 mmHg, 1 h). Rats inhaled room air or CO (250 ppm) for 1 h immediately following ischemia or with 1.5 and 3 h latency. Retinal tissue was harvested to analyze Bcl-2, Bax, Caspase-3, HO-1 expression and phosphorylation of the nuclear transcription factor (NF)-κB, p38 and ERK-1/2 MAPK. NF-κB activation was determined and inhibition of ERK-1/2 was performed using PD98059 (2 mg/kg). Densities of fluorogold prelabeled RGC were analyzed 7 days after injury. Microglia, macrophage and Müller cell activation and proliferation were evaluated by Iba-1, GFAP and Ki-67 staining. Results Inhalation of CO after I/R inhibited Bax and Caspase-3 expression (Bax: 1.9±0.3 vs. 1.4±0.2, p = 0.028; caspase-3: 2.0±0.2 vs. 1.5±0.1, p = 0.007; mean±S.D., fold induction at 12 h), while expression of Bcl-2 was induced (1.2±0.2 vs. 1.6±0.2, p = 0.001; mean±S.D., fold induction at 12 h). CO postconditioning suppressed retinal p38 phosphorylation (p = 0.023 at 24 h) and induced the phosphorylation of ERK-1/2 (p<0.001 at 24 h). CO postconditioning inhibited the expression of HO-1. The activation of NF-κB, microglia and Müller cells was potently inhibited by CO as well as immigration of proliferative microglia and macrophages into the retina. CO protected I/R-injured RGC with a therapeutic window at least up to 3 h (n = 8; RGC/mm2; mean±S.D.: 1255±327 I/R only vs. 1956±157 immediate CO treatment, vs. 1830±109 1.5 h time lag and vs. 1626±122 3 h time lag; p<0.001). Inhibition of ERK-1/2 did not counteract the CO effects (RGC/mm2: 1956±157 vs. 1931±124, mean±S.D., p = 0.799). Conclusion Inhaled CO, administered after retinal ischemic injury, protects RGC through its strong anti-apoptotic and anti-inflammatory effects.
Ischemic Postconditioning Alleviates Neuronal Injury Caused by Relief of Carotid Stenosis in a Rat Model of Cerebral Hypoperfusion  [PDF]
Chunsheng Feng,Tianfei Luo,Li Qi,Boyu Wang,Yinan Luo,Pengfei Ge
International Journal of Molecular Sciences , 2012, DOI: 10.3390/ijms131013338
Abstract: The effects of early relief of heavy bilateral carotid stenosis and ischemic postconditioning on hippocampus CA1 neurons are still unclear. In this study, we used a rat model to imitate severe bilateral carotid stenosis in humans. The rats were divided into sham group, carotid stenosis group, stenosis relief group and ischemic postconditioning group. Ischemic postconditioning consisted of three cycles of 30 s ischemia and 30 s reperfusion. The cerebral blood flow was measured with a laser Doppler flowmeter. Neuronal death in the CA1 region was observed by hematoxylin-eosin staining, and the number of live neurons was assessed by cell counting under a light microscope. The levels of oxidative products MDA and 8- iso-PGF2α, inflammatory factors IL-1β and TNF-α, and the activities of anti-oxidative enzymes SOD and CAT were assayed by specific enzyme-linked immunosorbent assay (ELISA) kits, respectively. We found that relief of carotid stenosis and ischemic postconditioning could increase cerebral blood flow. When stenosis was relieved, the percentage of live neurons was 66.6% ± 6.2% on day 3 and 62.3% ± 9.8% on day 27, which was significantly higher than 55.5% ± 4.8% in stenosis group. Ischemic postconditioning markedly improved the live neurons to 92.5% ± 6.7% on day 3 and 88.6% ± 9.1% on day 27. Further study showed that, neuronal death caused by relief of stenosis is associated with increased oxidative stress and enhanced inflammatory response, and the protection of ischemic postconditioning is related to inhibition of oxidative stress and suppression of inflammatory response.
Tracing neuronal tracts in the olfactory pathway of rat and detecting ischemic core in a rat model of focal ischemia using manganese enhanced magnetic resonance imaging
Ke Fang,Yingxia Li,Hua Liu,Weijing Liao,Hao Lei
Chinese Science Bulletin , 2004, DOI: 10.1007/BF03183410
Abstract: Manganese enhanced magnetic resonance imaging (MRI) is a novel neuroimaging technique that can be usedin vivo to trace neuronal tract and to study brain functions dynamically. In this study, manganese enhanced MRI was used to trace the neuronal tracts between the laminar structures of the olfactory bulb (OB) in rat and to study the so-called “calcium overload” phenomenon in a rat model of cerebral ischemia. High spatial resolution images of the OB were obtained and used to measure the transportation rate of Mn2+ among the laminar structures of the OB, which was shown to be approximately 0.2 mm/h under resting condition. In the rat focal ischemia study, it was found that the total area of brain regions with Mn2+ accumulation (representing brain regions with calcium overload) was only 55%±15% of the area of the ischemic brain regions shown by diffusion-weighted imaging (DWI). Manganese enhanced MRI might be more accurate than DWI in detecting the ischemic core at the early stage of experimental cerebral ischemia.
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