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Retinal Cell Death (retinal + cell_death)
Selected AbstractsPregnenolone Sulfate, a Naturally Occurring Excitotoxin Involved in Delayed Retinal Cell DeathJOURNAL OF NEUROCHEMISTRY, Issue 6 2000C. Cascio Abstract: The present study was designed to investigate the neurosteroid pregnenolone sulfate (PS), known for its ability to modulate NMDA receptors and interfere with acute excitotoxicity, in delayed retinal cell death. Three hours after exposure of the isolated and intact retina to a 30-min PS pulse, DNA fragmentation as assessed by genomic DNA gel electrophoresis and a modified in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method appeared concurrently with an increase in superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels. At 7 h, the increased amount of DNA laddering was accompanied by a higher number of TUNEL-positive cells in the inner nuclear and ganglion cell layers. Necrotic signs were characterized by DNA smear migration, lactate dehydrogenase (LDH) release, and damage mainly in the inner nuclear layer. PS-induced delayed cell death was markedly reduced by the NMDA receptor antagonists 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid and 3,-hydroxy-5,-pregnan-20-one sulfate but completely blocked after concomitant addition of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Steroids with antioxidant properties (progesterone, dehydroepiandrosterone and its sulfate ester, and 17,-estradiol) differently prevented PS-induced delayed cell death. Cycloheximide treatment protected against DNA fragmentation and LDH release but failed to prevent the rise in SOD activity and TBARS level. We conclude that a brief PS pulse causes delayed cell death in a slowly evolving apoptotic fashion characterized by a cycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset. [source] Zebrafish dou yan mutation causes patterning defects and extensive cell death in the retinaDEVELOPMENTAL DYNAMICS, Issue 5 2007Anne E. Catalano Abstract The size of an organ is largely determined by the number of cells it contains, which in turn is regulated by two opposing processes, cell proliferation and cell death, however, it is generally not clear how cell proliferation and cell death are coordinated during development. Here, we characterize the zebrafish dou yanmi234 mutation that results in a dramatic reduction of retinal size and a disruption of retinal differentiation and lamination. The retinal size reduction is caused by increased retinal cell death in a non,cell-autonomous manner during early development. The phenotypic defect in dou yanmi234 arises coincident with the onset of retinal neurogenesis and differentiation. Interestingly, unlike many other small eye mutations, the mutation does not increase the level of cell death in the brain, suggesting that the brain and retina use different mechanisms to maintain cell survival. Identification and further study of the dou yan gene will enhance our understanding of the molecular mechanisms regulating retinal cellular homeostasis, i.e., the balance between cell proliferation and cell death. Developmental Dynamics 236:1295,1306, 2007. © 2007 Wiley-Liss, Inc. [source] A stress survival response in retinal cells mediated through inhibition of the serine,/,threonine phosphatase PP2AEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2010Sorcha Finnegan Abstract Cell survival signalling involving the PI3K/Akt survival pathway can be negatively regulated by several phosphatases including PP2A. When retinal-derived 661W cells were subjected to trophic factor deprivation this initiated a survival response through inhibition of the activity of PP2A and subsequent upregulation of the Erk and Akt survival pathways. We show this survival response via inhibition of PP2A activity was due in part to increased reactive oxygen species production when retinal cells were deprived of trophic factors. Inhibition of PP2A activity was mediated by a rapid and transient increase in phosphorylation at Tyr307, accompanied by an increase in demethylation and a decrease in the methylated form. Pre-treatment with N -acetyl- l -cysteine, which is involved in scavenging reactive oxygen species, prevented PP2A inhibition and subsequent upregulation of survival pathways. Pre-treatment with the Src family kinase inhibitor PP2 resulted in approximately 50% reduction in cellular levels of phospho-PP2A in trophic factor-deprived 661W cells, suggesting an Src tyrosine kinase had a role to play in this redox regulation of cell survival. We observed similar events in the rd10 mouse retina where there was an increased survival response prior to retinal cell death mediated through an increase in both phospho-PP2A and phospho-Gsk. Together, these results demonstrate that when retinal cells are stressed there is an initial struggle to survive, mediated through inhibition of PP2A and subsequent upregulation of survival pathways, and that these events occur simultaneously with production of reactive oxygen species, thus suggesting an important cell-signalling role for reactive oxygen species. [source] Increased expression of glial cell line-derived neurotrophic factor protects against oxidative damage-induced retinal degenerationJOURNAL OF NEUROCHEMISTRY, Issue 3 2007Aling Dong Abstract Oxidative damage contributes to retinal cell death in patients with age-related macular degeneration or retinitis pigmentosa. One approach to treatment is to identify and eliminate the sources of oxidative damage. Another approach is to identify treatments that protect cells from multiple sources of oxidative damage. In this study, we investigated the effect of increased expression of glial cell line-derived neurotrophic factor (GDNF) in three models of oxidative damage-induced retinal degeneration. Double transgenic mice with doxycycline-inducible expression of GDNF in the retina were exposed to paraquat, FeSO4, or hyperoxia, all sources of oxidative damage and retinal cell death. Compared to controls, mice with increased expression of GDNF in the retina showed significant preservation of retinal function measured by electroretinograms, reduced thinning of retinal cell layers, and fewer TUNEL-positive cells indicating less retinal cell death. Mice over-expressing GDNF also showed less staining for acrolein, nitrotyrosine, and 8-hydroxydeoxyguanosine, indicating less oxidative damage to lipids, proteins, and DNA. This suggests that GDNF did not act solely to allow cells to tolerate higher levels of oxidative damage before initiation of apoptosis, but also reduced damage from oxidative stress to critical macromolecules. These data suggest that gene transfer of Gdnf should be considered as a component of therapy for retinal degenerations in which oxidative damage plays a role. [source] Pregnenolone Sulfate, a Naturally Occurring Excitotoxin Involved in Delayed Retinal Cell DeathJOURNAL OF NEUROCHEMISTRY, Issue 6 2000C. Cascio Abstract: The present study was designed to investigate the neurosteroid pregnenolone sulfate (PS), known for its ability to modulate NMDA receptors and interfere with acute excitotoxicity, in delayed retinal cell death. Three hours after exposure of the isolated and intact retina to a 30-min PS pulse, DNA fragmentation as assessed by genomic DNA gel electrophoresis and a modified in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method appeared concurrently with an increase in superoxide dismutase (SOD) activity and thiobarbituric acid-reactive substances (TBARS) levels. At 7 h, the increased amount of DNA laddering was accompanied by a higher number of TUNEL-positive cells in the inner nuclear and ganglion cell layers. Necrotic signs were characterized by DNA smear migration, lactate dehydrogenase (LDH) release, and damage mainly in the inner nuclear layer. PS-induced delayed cell death was markedly reduced by the NMDA receptor antagonists 4-(3-phosphonopropyl)-2-piperazinecarboxylic acid and 3,-hydroxy-5,-pregnan-20-one sulfate but completely blocked after concomitant addition of the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Steroids with antioxidant properties (progesterone, dehydroepiandrosterone and its sulfate ester, and 17,-estradiol) differently prevented PS-induced delayed cell death. Cycloheximide treatment protected against DNA fragmentation and LDH release but failed to prevent the rise in SOD activity and TBARS level. We conclude that a brief PS pulse causes delayed cell death in a slowly evolving apoptotic fashion characterized by a cycloheximide-sensitive death program downstream of reactive oxygen species generation and lipid peroxidation, turning into secondary necrosis in a retinal cell subset. [source] 2223: Carbon monoxide as a mediator in the retinaACTA OPHTHALMOLOGICA, Issue 2010C BUCOLO Purpose Carbonic monoxide (CO) is organic gas ubiquitously synthesized in mammalian tissues by enzyme that has constitutive and inducible forms. This gas is produced as metabolic end-product in specific cell life phases, and may acts as atypical neuronal messenger. Evidence has recently accumulated suggesting that CO may be cytoprotective because its bioactions, including inhibition of apoptosis, platelet aggregation, complement activation, and inflammatory cytokine production. CO appears to be important to counteract the cytotoxicity caused by excessive production of reactive oxygen (ROS) and nitrogen (RNS) species. Methods In vitro and in vivo models. Results Induction of heme oxygenase (HO)-1 by hemin has been found to prevent retinal cell death after ischemia provoked by ocular hypertension in rats. The LPS-induced expression of pro-inflammatory cytokines, in rat eye, is also inhibited by CO. Interestingly, drugs active as inhibitors of iNOS block CO-induced increases in cGMP in the retina.Drugs inhibiting NO formation by acting on iNOS activity have been found to potently reduce intraocular pressure. Studies from our lab showed that an increase of CO availability by hemin or carbon monoxide-releasing molecules lower the intraocular pressure, suggesting a suppress action of iNOS-derived NO production. Conclusion A better understanding of CO regulation may lead to new therapeutic options that are safer and more efficacious than currently available treatments for various sight-threatening eye diseases, such as retinal degenerations. [source] | ||||||||||