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PubMed1998

Expression of the protective proteins hemopexin and haptoglobin by cells of the neural retina.

The blood-retinal barrier, consisting of retinal pigment epithelial cells and retinal endothelial cells, prevents hemopexin and haptoglobin, anti-oxidant protective plasma proteins normally synthesized by the liver, from entering the neural retina. If present, these proteins must, therefore, be made locally. The cell types within the retina in which hemopexin and haptoglobin mRNAs are made have been investigated. RNA was extracted from both the neural retina and pigment epithelium obtained by dissection of human donor eyes as well as from cultured pigment epithelial and photoreceptor cells. The mRNAs for both haptoglobin and hemopexin were detected, using reverse-transcriptase polymerase chain reaction, in the neural retina and cultured photoreceptors but not in pigment epithelial cells. The cellular location of these mRNAs was determined using in situ hybridization of sections of human retina which revealed that haptoglobin mRNA was located principally in the photoreceptor cells, cells of the inner nuclear layer and some cells of the ganglion cell layer. Hemopexin mRNA, previously shown to be made in the human neural retina (Hunt et al., 1996. Journal of Cellular Physiology 168: 71-80), is expressed by most of the cells of neural retina including the photoreceptors and, notably, the ganglion cells.

Antioxidants↗

PubMed2000

N -methyl- D -aspartate (NMDA) induced apoptosis in adult rabbit retinas.

Previously we showed that apoptosis is involved in N -methyl- D -aspartate (NMDA) induced excitotoxicity in adult rat retinas. Since rabbits have a higher endogenous level of glutamate in the retina and very different retinal structures, it is not clear if apoptosis is similarly involved in adult rabbit retinas after intravitreal injection of NMDA. In this study, we used ultrastructural features, TdT-mediated biotin-dUTP nick end labeling (TUNEL) and two caspase inhibitors to examine whether apoptosis is involved in NMDA-induced excitotoxicity in adult rabbit retinas. At 18 hr after an intravitreal injection of 400 nmoles NMDA, typical apoptotic features in degenerative cells in the retinal ganglion cell layer (RGCL) and the inner nuclear layer (INL) were noted by electron microscopy. TUNEL positive nuclei were detected in these layers as early as 4 hr showing maximal numbers at 18 hr. At 7 days, significant loss of nuclei from the RGCL was noted at the visual streak, the superior and the inferior retinas. These losses were abolished by simultaneous administration of MK-801 and ameliorated by YVAD, a caspase-1 inhibitor, but not by IETD, a caspase-8 inhibitor. These results indicated that, similar to adult rat retinas, apoptosis is involved in NMDA receptor-mediated excitotoxicity in rabbit retinas and that specific caspases may play important roles.

Animals↗

PubMed2001

Expression of angiotensin-converting enzyme (ACE) in the developing chicken retina.

Angiotensin-converting enzyme (ACE) performs two contrasting enzymatic effects: as part of the renin-angiotensin system it converts angiotensin I into physiologically active angiotensin II, and it inactivates a number of peptides, e.g. substance P. These peptides are well known neurotransmitters in the retina and recently angiotensin II was described in retinal neurons. We therefore investigated a possible involvement of ACE in retinal metabolism by determining the mRNA and protein expression of ACE in the developing and mature chicken retina. ACE-mRNA expression was investigated by RT-PCR in the iris/ciliary body, the choroid, the optic nerve head, pecten, and the retina. Levels of ACE-mRNA were quantified by competitive PCR with heterologous competitor fragments in the retina at different developmental stages. To localize protein expression of ACE in the mature chicken retina an antibody directed against ACE was used. ACE-mRNA was present in all ocular tissues examined. Quantification of ACE-mRNA in avascular retinas of developing chickens revealed small amounts (0.13 attomol microl(-1)) at embryonic day 7 and values of about 0.6 attomol microl(-1)during embryonic days 7-17. ACE-mRNA expression transiently increased ten-fold (7.3 attomol microl(-1)) on postnatal day 1, decreased again to about 1.4 attomol microl(-1)on postnatal day 6, and remained constant thereafter. ACE-immunohistochemistry revealed labeling of photoreceptors, bipolar cells, amacrine cells, and cells in the ganglion cell layer as well as of Müller glia. Our data show that ACE-mRNA is an intrinsic component of the retina and that ACE itself has a widespread but distinct cellular distribution. The transient high expression of ACE-mRNA directly after hatching indicate, that ACE may be involved in fine tuning the neuropeptidergic equipment of the retinal network during the initial phase of visual experience.

Animals↗

PubMed2001

Voltage-dependent calcium channels in the rat retina: involvement in NMDA-stimulated influx of calcium.

Rises in intracellular Ca2+ induced by activation of glutamate receptors are of ultimate importance for neuronal excitability and pathophysiological processes. In the present study, we aimed to elucidate the types of voltage-dependent Ca2+ channels involved in the NMDA-stimulated influx of Ca2+ into the isolated rat retina by using selective blockers. Additionally, the number of binding sites for radioligands labelling L- ([3H]nitrendipine), N- ([125I]omega-conotoxin MVIIA) and P/Q-type ([125I]omega-conotoxin MVIIC) Ca2+ channels was assessed in the rat retina and, for further comparison, in the rat cortex. Incubation of isolated rat retinas with 100 microM NMDA produced a three-fold increase in the influx of 45Ca2+ that was completely blunted by MK-801, a NMDA receptor antagonist, and partially attenuated (approximately 20%) by tetrodotoxin, a Na+ channel blocker. The L-type Ca2+ channel blocker nifedipine reduced NMDA-stimulated Ca2+ influx in a dose-related fashion, with a maximum reduction of approximately 50%. Similar effects were observed with verapamil and diltiazem. Blockers of N- and P/Q-type Ca2+ channels had no significant effect on the influx of Ca2+ evoked by NMDA. Co2+, a non-specific Ca2+ channel blocker, caused an inhibition of NMDA-stimulated Ca2+ influx similar to that of nifedipine. Therefore, of all voltage-dependent Ca2+ channels, L-type channels appear to make the greatest contribution (up to 50%) to the NMDA-stimulated influx of Ca2+ into the isolated rat retina. This finding contrasts with evidence obtained in brain neurones supporting a role for L-, N- and P/Q-type channels in NMDA-evoked Ca2+ signals. A comparison of the number of radioligand binding sites associated with L-, N- or P/Q-type Ca2+ channels in the rat cortex and retina revealed that such a difference cannot be ascribed to a distinct expression pattern of these channels in both tissues, although some variations were found. Interestingly, a different affinity of [3H]nitrendipine for L-type Ca2+ channels in the rat retina and cortex was observed which may reflect the expression of different classes of L-type channels in these tissues. The ability of L-type Ca2+ channel blockers to attenuate NMDA-stimulated Ca2+ influx may underlie their neuroprotective effects in the retina.

Analysis of Variance↗

PubMed2001

Immunohistochemical studies of the retina following long-term implantation with subretinal microphotodiode arrays.

This study evaluates the feline retina following surgical placement of a semiconductor-based microphotodiode array (MPA) into the subretinal space. Post-operative evaluations of implant durability and clinical biocompatibility have been carried out in these animals. Here, we examine the integrity of the implanted retina using anatomical techniques and immunocytochemical metabolic indicators. After appropriate fixation, the retina was divided into strips to compare areas directly over the implant versus those adjacent to the implant or in the opposite, unimplanted eye. In addition to histological analyses, the distribution of glial fibrillary acidic protein (GFAP), Na, K-ATPase, and the neurotransmitters (glutamate, glycine, and GABA) was examined using immunohistochemistry. Directly above the implant there was a near-complete loss of photoreceptor outer and inner segments and the outer nuclear layer. In comparison, the retina immediately adjacent to the implant appeared normal. In the inner nuclear layer overlying the implant, some cellular disorganization was present, however, the content was not significantly reduced. Also GFAP was up-regulated in the Müller cells directly overlying the MPA, but the retina adjacent to the implant showed a normal distribution of GFAP in the astrocytes located in the ganglion cell layer. The distributions of Na, K-ATPase adjacent to and overlying the implant were not different. Glutamate showed a decrease in overall labeling, but no change in the inner retinal layers. Glycine was found to be up-regulated in the inner nuclear layer immediately overlying the implant, while GABA showed decreased labeling over the MPA. Since photoreceptors overlying the implant degenerate, we compared the changes observed in the implanted retina to those in the Abyssinian cat model of photoreceptor degeneration. Generally, the retinal changes observed over the implant were similar to those seen in the Abyssinian cat, indicating that they may be associated with photoreceptor degeneration. Future studies will concentrate on MPAs designed to improve circulation to the outer retina which may decrease cell loss.

Animals↗

PubMed2002

Up-regulation of cytochrome oxidase in the retina following optic nerve injury.

The purpose of this study is to investigate the cytochrome oxidase (COX) activity in the retina and optic nerve following an optic nerve injury. The optic nerve crush of one eye was carried out in Balb/c mice. A semi-quantitative RT-PCR method was then adopted to evaluate the mRNA expression of cytochrome oxidase subunit 1 (COX1) in the retina after surgery. Up-regulation of COX1 mRNA in the retina was detected by RT-PCR at 24 hr following the optic nerve injury. Total retinal mitochondrial mass measured by fluorescent intensity of MitoTracker green was not altered following the injury. COX histochemistry performed on cryostat sections showed an elevated enzyme activity of COX in the retina and in the optic nerve. In the retina, elevation of the COX activity was observed in the retinal ganglion cell layer and the overlying nerve fibre layer. The increase of COX activity began from 24 hr after injury, peaked around day 3, and maintained up to 1 week after the operation. In the optic nerve, increase of COX activity was observed in regions distal to the crush line and distributed either randomly or in a cone shape. In conclusion, both the expression of COX1 mRNA in retina and the activity of COX in inner plexiform layer and retinal ganglion cell layer were elevated following optic nerve injury without affecting total retinal mitochondrial mass. These findings suggested that one of early responses in the retina and in the optic nerve after the optic nerve injury is to scale up the energy production.

Animals↗

PubMed1999

Connexin alpha1 and cell proliferation in the developing chick retina.

During the formation of the eye, high levels of connexin alpha1 (connexin 43) are expressed within the tissues of the cornea, lens, and neural retina. In order to determine whether connexin alpha1 plays a role in the regulation of cell proliferation we have used a novel antisense technique to reduce its expression early in development (embryonic days 2-4). Application of Pluronic gel, containing antisense oligodeoxynucleotides (ODNs) to connexin alpha1, to one eye of early chick embryos results in a rapid and significant reduction of alpha1 protein which lasts for 24-48 h. Embryos grown for 48 h, after ODN application to one eye, showed a marked reduction in the diameter of the treated, compared to that of the contralateral untreated, eye. Sections cut from the treated eyes showed that the retina was also reduced in size. TUNEL labeling and staining with propidium iodide showed that apoptosis within the retinae of both treated and untreated eyes was rare and thus that the reduction in the area of the retina brought about by antisense ODNs directed at connexin alpha1 was unlikely to be the result of increased cell death. However, the number of mitotic figures in the ventricular zone of the antisense-treated retinae revealed by propidium iodide staining was significantly reduced (P < 0.0001) to 53 +/- 3.5% (n = 5) of that in the contralateral untreated control eyes. Embryos in which one eye was sham operated, treated with pluronic gel, or treated with sense ODN showed no significant changes in eye size or in the number of mitotic figures within the neural retina. These results point to a role for connexin alpha1-mediated gap-junctional communication in controlling the early wave of neurogenesis in the chick retina.

Animals↗

PubMed1996

Folate and 10-formyltetrahydrofolate dehydrogenase in human and rat retina: relation to methanol toxicity.

Ocular toxicity, a well-recognized outcome of methanol poisoning in humans, correlates with formate accumulation in blood following the ingestion of methanol. Rodents, however, are a species known to be resistant to the toxicity of formate. The present study was designed to determine whether components of folate-dependent formate oxidation, e.g., folate and 10-CHO-H4-folate dehydrogenase (10-FDH), exist in retina and whether differences in these components might explain species-determined susceptibility to methanol intoxication. Total folate levels were determined in human and rat retinal tissues and were found to be much lower than the levels in liver. However, folate levels in human retina were only 14% of those determined in rat retina. Western blot analysis was used to quantify the amount of cytosolic and mitochondrial 10-FDH in retinal tissues. Results of these studies showed that comparable amounts of this enzyme were present in both cellular compartments in each species. However, the amount of 10-FDH in human retina was approximately three times the amount found in rat retina. In order to determine the cell type(s) within the retina that contained 10-FDH, immunohistochemical staining for 10-FDH was carried out. Confocal microscopic image analysis of human and rat retinae showed colocalization of 10-FDH primarily with Muller cell protein markers [glial fibrillary acidic protein (GFAP), vimentin, and carbonic anhydrase]. Therefore, 10-FDH was found to be preferentially localized in this cell type. Since Müller cells appear to represent the target for formate-induced ocular toxicity, our data suggest that formate oxidation reactions might serve two roles, first a protective role and then a role in methanol-induced toxicity in Müller cells.

Adenosine Triphosphate↗

PubMed1989

Analysis of cat retina for dopamine, dihydroxyphenylacetic acid, 3-methoxytyramine and homovanillic acid.

Twenty retinas from 10 cats were evaluated for dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT) and homovanillic acid (HVA) by high pressure liquid chromatography and electrochemical detection. Dopamine was present in all 20 retinas at a mean concentration of 3.00 +/- 0.54 ng/mg protein. Dihydroxyphenylacetic acid, 3-MT and HVA were detected in 16, 14 and 9 retinas respectively. In retinas in which these metabolites were detectable, they were present in the following mean concentrations: DOPAC, 1.07 +/- 0.21 ng/mg protein; 3-MT, 3.44 +/- 0.97 ng/mg protein and HVA, 4.54 +/- 1.05 ng/mg protein. Significantly higher concentrations of 3-MT (p = 0.0108, paired t test) and HVA (p = 0.0166, paired t test) than DOPAC were present in cat retina. Linear correlation analysis between DA and its metabolites indicated that the 3-MT and DOPAC concentrations correlated well with each other and with the amount of DA in cat retina. The concentrations of the end product metabolite, HVA, had poor correlations with the concentrations of 3-MT, DOPAC or DA. These data indicated that once DA is released in cat retina it can be metabolized to 3-MT, DOPAC and HVA.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Evidence of chronic inflammation in retina excised after relaxing retinotomy for anterior proliferative vitreoretinopathy.

BACKGROUND: Epiretinal membranes from eyes with proliferative vitreoretinopathy (PVR) frequently express molecules associated with chronic inflammation. To investigate the extent to which inflammation may compromise the detached retina, we determined the expression of inflammatory molecules in anterior retina removed after relaxing retinotomy for retinal detachment complicated by anterior PVR. METHODS: Surgical retinal specimens were studied immunohistochemically for the distribution of the vascular cell adhesion molecules VCAM, E-selectin, P-selectin, ICAM and PECAM and for the presence of the cytokine TNF alpha and of T lymphocytes (CD3-positive cells), macrophages (CD68-positive cells) and HLA-DR molecules. The findings were compared with those in control cadaveric retina. RESULTS: Aberrant expression of ICAM-1 was observed in four of nine retinal specimens from eyes with PVR, whereas its expression in control retinas was confined to the external limiting membrane and ganglion cell layers. PECAM was observed in seven of nine surgical retinal specimens and in four of five controls. E-selectin and P-selectin were expressed within the luminal aspects of four of nine retinal specimens from eyes with PVR, and VCAM was present in three of nine surgical specimens investigated. All cadaveric control retinas were negative for E-selectin and VCAM, whilst one was positive for P-selectin. Staining for TNF alpha was observed within luminal aspects and walls of retinal vessels from eight of nine surgical specimens, but was not seen in any of the cadaveric controls. T lymphocytes and cells expressing the macrophage marker CD68 were identified in two and seven of nine diseased retinas respectively, but not in any of the controls. Cells staining for HLA-DR were observed in eight of nine surgical retinal specimens and in three of five controls. CONCLUSION: The present findings indicate that retina from eyes with advanced PVR may itself be subject to inflammatory changes, and indicate that the PVR process is not limited to retinal membranes, but involves a more widespread distribution of inflammation than is generally appreciated.

Chronic Disease↗

PubMed1991

Adenosine in vertebrate retina: localization, receptor characterization, and function.

1. The uptake of [3H] adenosine into specific populations of cells in the inner retina has been demonstrated. In mammalian retina, the exogenous adenosine that is transported into cells is phosphorylated, thereby maintaining a gradient for transport of the purine into the cell. 2. Endogenous stores of adenosine have been demonstrated by localization of cells that are labeled for adenosine-like immunoreactivity. In the rabbit retina, certain of these cells, the displaced cholinergic, GABAergic amacrine cells, are also labeled for adenosine. 3. Purines are tonically released from dark-adapted rabbit retinas and cultured embryonic chick retinal neurons. Release is significantly increased with K+ and neurotransmitters. The evoked release consists of adenosine, ATP, and purine metabolites, and while a portion of this release is Ca2+ dependent, one other component may occur via the bidirectional purine nucleoside transporter. 4. Differential distributions of certain enzymes involved in purine metabolism have also been localized to the inner retina. 5. Heterogeneous distributions of the two subtypes of adenosine receptors, A1 and A2, have been demonstrated in the mammalian retina. Coupling of receptors to adenylate cyclase has also been demonstrated. 6. Adenosine A1 receptor agonists significantly inhibit the K(+)-stimulated release of [3H]-acetylcholine from the rabbit retina, suggesting that endogenous adenosine may modulate the light-evoked or tonic release of ACh.

Acetylcholine↗

PubMed1984

Ornithine delta-aminotransferase activity in retina and other tissues.

Ornithine delta-aminotransferase (OAT) activity was determined in liver, kidney, brain, retina and ciliary body-iris of rat, rabbit, calf and human. OAT activities (nanomoles delta 1-pyrroline-5-carboxylate/mg protein/hr) in retina were (mean +/- SE) 324 +/- 43, 240 +/- 24, 234 +/- 26 and 218 +/- 22 respectively in rat, rabbit, calf and human. The OAT activities in retina were three times higher than in brain and 80% of that of liver. 2-oxoglutarate was the preferred amino acceptor substrate for OAT activity. In rat retina the activities of OAT with glyoxalate, beta-hydroxypyruvate, pyruvate, and oxaloacetate were 51, 44, 30, and 30% of that of 2-oxoglutarate respectively. A lack of substrate OAT specificity indicates OAT deficiency such as occur in gyrate atrophy of the choroid and retina could impair metabolism of ketoacids. A candidate for possible toxicity to the retina in OAT deficiency is glyoxalate. Arginine glycine transamidinase activity was not detectable in human retina, thus a previously postulated creatine phosphate deprivation in OAT deficiency may not be applicable to the pathogenesis of the disease.

Animals↗

PubMed1980

Certain aspects of acetylcholine metabolism in teleost retina.

Acetylcholine (ACh) synthesis and release from isolated superfused retina of the teleost Eugerres plumieri has been studied under different physiological conditions. The retinas were superfused with Krebs-Ringer solutions containing [14C]choline and the extracellular space of 32% was determined by [3H]inulin. The retina accumulates choline (Ch) from the superfusion medium and this process is mediated by a high affinity transport system with a Km of 1.82 microM. The incorporated Ch is mainly utilized for the synthesis of ACh. The ACh content of the light-adapted retina is not significantly different from that of a dark-adapted one. However, the release of [14C]ACh from the light-adapted retina was 52% higher as compared to the release from the dark-adapted retina. Flicker stimulation induced a larger increase in ACh release, than from either light or dark adapted retina, proportional to flicker frequency. The results suggest that changes in ACh utilization were related to the function of cellular units responsible for light changes transduction rather than light detection.

Acetylcholine↗

PubMed1988

The development of astrocytes and blood vessels in the postnatal rabbit retina.

Antibodies to glial fibrillary acidic protein (GFAP) have been used to study the shape and location of astrocytes in whole mount preparations of developing postnatal rabbit retina. At all developmental stages GFAP-positive astrocytes were detectable. At birth, they were few in number and only weakly labelled. With further development, their number as well as their labelling intensity increased. Following Nissl counterstaining it was observed that GFAP-positive astrocytes, always situated in the nerve fibre layer, are capable of cell division during about the first 4 postnatal weeks. GFAP-positive astrocytes were always confined to a wing-shaped area extending horizontally from both sides of the optic nerve head. It is suggested that astrocytes are not generated in the entire rabbit retina, which is in clear contrast to the second glial cell type of the rabbit retina, the Müller cell; and it has been concluded that the confinement of astrocytes to the medullary rays region in the adult rabbit is established during ontogenesis, and is not due to a secondary restriction of astrocytes to this region. Horizontal sections cut through entire rabbit retinae at various postnatal stages revealed that the first intraretinal blood vessels are not found before postnatal day 9. This is more than 1 week later than the first astrocytes are detectable. It is suggested that, at least in the rabbit, retinal astrocytes do not co-migrate with blood vessel endothelial cells from the optic disc into the retina, a hypothesis considered recently for the cat retina. It was, however, not possible to decide unequivocally if, in this material, astroglial progenitors are derived from retinal neuroepithelial cells or invade the retina from the optic nerve head.

Animals↗

PubMed1992

Analysis of opsin mRNA and protein expression in adult and regenerating newt retina by immunology and hybridization.

Rod photoreceptor cells were analysed in adult and regenerating Notophthalmus viridescens retinae using a combination of immunochemical and molecular biological approaches. Monoclonal anti-rhodopsin antibody (Rho-4D2) labelled rod but not cone photoreceptors in adult newt retinae. The antibody bound to the entire cell body, from the synaptic ending through to the outer segment, as examined by light and electron immunocytochemistry. The antibody labelled two bands of 35 and 56 kDa in Western blots of urodele retinal preparations separated by gel electrophoresis. In situ hybridization with radiolabelled anti-sense riboprobes specific for bovine opsin revealed intense patches of silver grains overlying approximately 50% of photoreceptor inner segment myoid regions; no signal above background was detected elsewhere in the retina, or with radiolabelled sense riboprobe controls. Northern blot analysis using the probe on poly A(+) mRNA of adult newt retinae indicated a single band of 1.5 kb, corresponding to the opsin transcript. Following surgical removal of the original retina in test animals, retinal regeneration was studied by sampling tissue from 0-50 days post-surgery. The reappearance of opsin immunoreactivity was examined by light microscopical techniques. No opsin expression was detected in regenerating tissue prior to 16 days. Subsequent to this time, rho-4D2 bound to cells in central areas in which substantial lamination of the new retina had already occurred, and was limited to the scleral border. At no time was any immunoreactivity observed in more peripheral undifferentiated tissue. Thus the reformation of a functional retina seems to follow the same control mechanisms as during development, photoreceptor redifferentiation being at least partly governed by positional or environmental cues.

Animals↗

PubMed1990

Differential effect of aging on 3H-SCH 23390 binding sites in the retina and in distinct areas of the rat brain.

The effects of age on the binding parameters of the selective D-1 dopamine (DA) receptor antagonist 3H-SCH 23390 were studied in membrane preparations from rat striatum, substantia nigra, olfactory tubercle, prefrontal cortex and retina. When compared with 3-month-old animals, there was a significant decrease in the density of 3H-SCH 23390 binding sites in the striatum (-25%), substantia nigra (-24%), and olfactory tubercle (-23%), but not in the prefrontal cortex of senescent (23-month-old) rats. The affinity of 3H-SCH 23390 for D-1 DA receptors did not change with age in any of the brain areas analyzed. In contrast, the density of 3H-SCH 23390 binding sites was higher (+53%) in the retina of aged rats that in 3-month-old controls. Confirming previous studies, we observed that light deprivation induced a significant increment in the density of 3H-SCH 23390 binding sites in the retina of adult rats (+31%) but not in the retina of aged animals. The ability of light exposure to activate DAergic neurons in the rat retina was not altered by normal aging. In fact, a similar increase in the concentration of DOPAC was observed in the retina of light-adapted adult and senescent rats when compared to their respective dark-adapted controls (+94% and +95%, respectively). The results indicate that aging has a differential effect on D-1 DA receptors in the retina and different areas of the rat brain. Finally, the age-related increment in the density of retinal D-1 DA receptors does not appear to depend on presynaptic mechanisms, since DA metabolism is increased by light to the same extent in young and aged rats.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2001

Ischemia increases prostaglandin H synthase-2 levels in retina and visual cortex in piglets.

BACKGROUND: Ischemia increases levels of prostaglandin H synthase-2 (PGHS-2) in neonatal brain and cerebral vasculature, but effects on the developing visual system are unknown. We examined the effects of ischemia on PGHS-2 mRNA and protein levels in the retina and visual cortex in anesthetized piglets. METHODS: Ten minutes of complete retinal and brain ischemia was induced by increasing intracranial pressure. After 2-12 h of reperfusion, samples of retina and visual cortex were collected for determinations of levels of PGHS-2 mRNA (RNase protection assay) or protein (immunohistochemistry and western blotting). Tissues also were obtained from control animals. RESULTS: Levels of PGHS-2 mRNA were undetectable in control animals but showed a dramatic increase at 2-4 h in the cortex and retina in animals exposed to ischemia. Detectable but limited PGHS-2 immunoreactivity (IR) was present in the retina and visual cortex from control animals. In piglets not subjected to ischemia, PGHS-2 IR was localized mainly to the outer limiting membrane and to the Muller cells. Ischemia induced a marked increase in PGHS-2 IR in the neural retina, with the greatest increase in the photoreceptor layer. PGHS-2 levels in whole retina also increased at 8 h after ischemia. In the intact visual cortex PGHS-2 IR was evident in layers II and V. Ischemia increased the intensity of IR in layers II/III as well as layer V. CONCLUSIONS: Detectable amounts of PGHS-2 protein are present in the piglet retina and visual cortex under normal conditions, but levels are markedly increased 8-12 h after ischemic stress. Enhanced PGHS-2 levels after ischemic stress may contribute to delayed pathological changes of the visual system in the neonate.

Animals↗

PubMed1997

The relationship between accumulation of advanced glycation end products and expression of vascular endothelial growth factor in human diabetic retinas.

Both advanced glycation end products and vascular endothelial growth factor are believed to play a role in the pathogenesis of diabetic retinopathy. It is known that vascular endothelial growth factor causes retinal neovascularization and a breakdown of the blood-retinal barrier; how advanced glycation end products affect the retina, however, remains largely unclear. The substance-Ne-(carboxymethyl)lysine is a major immunologic epitope, i.e. a dominant advanced glycation end products antigen. We generated an anti-Ne-(carboxymethyl)lysine antibody to investigate the relationship between the localization of advanced glycation end products and that of vascular endothelial growth factor in 27 human diabetic retinas by immunohistochemistry. Nine control retinas were also examined. In all 27 diabetic retinas, Ne-(carboxymethyl)lysine was located in the thickened vascular wall. In 19 of the 27 retinas, strand-shaped Ne-(carboxymethyl)lysine immunoreactivity was also observed around the vessels. In all 27 diabetic retinas, vascular endothelial growth factor revealed a distribution pattern similar to that of Ne-(carboxymethyl)lysine. Vascular endothelial growth factor was also located in the vascular wall and in the perivascular area. Neither Ne-(carboxymethyl)lysine nor vascular endothelial growth factor immunoreactivity was detected in the 9 control retinas. Vessels with positive immunoreactivity for Ne-(carboxymethyl)lysine and/or vascular endothelial growth factor were counted. A general association was noted between accumulation of Ne-(carboxymethyl)lysine and expression of vascular endothelial growth factor in the eyes with non-proliferative diabetic retinopathy (p < 0.01) and proliferative diabetic retinopathy (p < 0.05).

Aged↗