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Pereira-Figueiredo D, Nascimento AA, Cunha-Rodrigues MC, Brito R, Calaza KC. Caffeine and Its Neuroprotective Role in Ischemic Events: A Mechanism Dependent on Adenosine Receptors. Cell Mol Neurobiol 2022; 42:1693-1725. [PMID: 33730305 PMCID: PMC11421760 DOI: 10.1007/s10571-021-01077-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/05/2021] [Indexed: 02/07/2023]
Abstract
Ischemia is characterized by a transient, insufficient, or permanent interruption of blood flow to a tissue, which leads to an inadequate glucose and oxygen supply. The nervous tissue is highly active, and it closely depends on glucose and oxygen to satisfy its metabolic demand. Therefore, ischemic conditions promote cell death and lead to a secondary wave of cell damage that progressively spreads to the neighborhood areas, called penumbra. Brain ischemia is one of the main causes of deaths and summed with retinal ischemia comprises one of the principal reasons of disability. Although several studies have been performed to investigate the mechanisms of damage to find protective/preventive interventions, an effective treatment does not exist yet. Adenosine is a well-described neuromodulator in the central nervous system (CNS), and acts through four subtypes of G-protein-coupled receptors. Adenosine receptors, especially A1 and A2A receptors, are the main targets of caffeine in daily consumption doses. Accordingly, caffeine has been greatly studied in the context of CNS pathologies. In fact, adenosine system, as well as caffeine, is involved in neuroprotection effects in different pathological situations. Therefore, the present review focuses on the role of adenosine/caffeine in CNS, brain and retina, ischemic events.
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Affiliation(s)
- D Pereira-Figueiredo
- Neurobiology of the Retina Laboratory, Biomedical Sciences Program, Biomedical Institute, Fluminense Federal University, Niterói, RJ, Brazil
| | - A A Nascimento
- Neurobiology of the Retina Laboratory, Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, RJ, Brazil
| | - M C Cunha-Rodrigues
- Neurobiology of the Retina Laboratory, Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, RJ, Brazil
| | - R Brito
- Laboratory of Neuronal Physiology and Pathology, Cellular and Molecular Biology Department, Institute of Biology, Fluminense Federal University, Niterói, RJ, Brazil
| | - K C Calaza
- Neurobiology of the Retina Laboratory, Biomedical Sciences Program, Biomedical Institute, Fluminense Federal University, Niterói, RJ, Brazil.
- Neurobiology of the Retina Laboratory, Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, RJ, Brazil.
- Neurobiology Department, Biology Institute of Fluminense Federal University, Niteroi, RJ, Brazil.
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Influence of Trace Elements on Neurodegenerative Diseases of The Eye-The Glaucoma Model. Int J Mol Sci 2021; 22:ijms22094323. [PMID: 33919241 PMCID: PMC8122456 DOI: 10.3390/ijms22094323] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/16/2021] [Accepted: 04/18/2021] [Indexed: 02/07/2023] Open
Abstract
Glaucoma is a heterogeneous group of chronic neurodegenerative disorders characterized by a relatively selective, progressive damage to the retinal ganglion cells (RGCs) and their axons, which leads to axon loss and visual field alterations. To date, many studies have shown the role of various elements, mainly metals, in maintaining the balance of prooxidative and antioxidative processes, regulation of fluid and ion flow through cell membranes of the ocular tissues. Based on the earlier and current research results, their relationship with the development and progression of glaucoma seems obvious and is increasingly appreciated. In this review, we aimed to summarize the current evidence on the role of trace elements in the pathogenesis and prevention of glaucomatous diseases. Special attention is also paid to the genetic background associated with glaucoma-related abnormalities of physiological processes that regulate or involve the ions of elements considered as trace elements necessary for the functioning of the cells.
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Nivison-Smith L, Khoo P, Acosta ML, Kalloniatis M. Pre-treatment with vinpocetine protects against retinal ischemia. Exp Eye Res 2016; 154:126-138. [PMID: 27899287 DOI: 10.1016/j.exer.2016.11.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 10/17/2016] [Accepted: 11/22/2016] [Indexed: 01/15/2023]
Abstract
Vinpocetine has been shown to have beneficial effects for tissues of the central nervous system subjected to ischemia and other related metabolic insults. We recently showed vinpocetine promotes glucose availability, prevents unregulated cation channel permeability and regulates glial reactivity when present during retinal ischemia. Less is known however about the ability of vinpocetine to protect against future ischemic insults. This study explores the effect of vinpocetine when used as a pre-treatment in an ex vivo model for retinal ischemia using cation channel permeability of agmatine (AGB) combined with immunohistochemistry as a measure for cell functionality. We found that vinpocetine pre-treatment reduced cation channel permeability and apoptotic marker immunoreactivity in the GCL and increased parvalbumin immunoreactivity of inner retinal neurons in the inner nuclear layer following ischemic insult. Vinpocetine pre-treatment also reduced Müller cell reactivity following ischemic insults of up to 120 min compared to untreated controls. Many of vinpocetine's effects however were transient in nature suggesting the drug can protect retinal neurons against future ischemic damage but may have limited long-term applications.
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Affiliation(s)
- Lisa Nivison-Smith
- Centre for Eye Health, University of New South Wales, Sydney, 2052, Australia; School of Optometry and Vision Science, University of New South Wales, Sydney, 2052, Australia.
| | - Pauline Khoo
- School of Optometry and Vision Science, University of New South Wales, Sydney, 2052, Australia
| | - Monica L Acosta
- School of Optometry and Vision Science, University of Auckland, New Zealand; New Zealand National Eye Centre, University of Auckland, New Zealand
| | - Michael Kalloniatis
- Centre for Eye Health, University of New South Wales, Sydney, 2052, Australia; School of Optometry and Vision Science, University of New South Wales, Sydney, 2052, Australia; School of Optometry and Vision Science, University of Auckland, New Zealand; New Zealand National Eye Centre, University of Auckland, New Zealand
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Shukry M, Kamal T, Ali R, Farrag F, Almadaly E, Saleh AA, Abu El-Magd M. Pinacidil and levamisole prevent glutamate-induced death of hippocampal neuronal cells through reducing ROS production. Neurol Res 2015; 37:916-23. [DOI: 10.1179/1743132815y.0000000077] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Sakamoto K, Suzuki Y, Kurauchi Y, Mori A, Nakahara T, Ishii K. Hydrogen sulfide attenuates NMDA-induced neuronal injury via its anti-oxidative activity in the rat retina. Exp Eye Res 2014; 120:90-6. [DOI: 10.1016/j.exer.2014.01.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 01/06/2014] [Accepted: 01/10/2014] [Indexed: 12/29/2022]
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Vinpocetine regulates cation channel permeability of inner retinal neurons in the ischaemic retina. Neurochem Int 2014; 66:1-14. [DOI: 10.1016/j.neuint.2014.01.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Revised: 12/09/2013] [Accepted: 01/04/2014] [Indexed: 11/23/2022]
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8
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Zhong YS, Wang J, Liu WM, Zhu YH. Potassium ion channels in retinal ganglion cells (review). Mol Med Rep 2013; 8:311-9. [PMID: 23732984 DOI: 10.3892/mmr.2013.1508] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 05/22/2013] [Indexed: 11/06/2022] Open
Abstract
Retinal ganglion cells (RGCs) consolidate visual processing and constitute the last step prior to the transmission of signals to higher brain centers. RGC death is a major cause of visual impairment in optic neuropathies, including glaucoma, age‑related macular degeneration, diabetic retinopathy, uveoretinitis and vitreoretinopathy. Discharge patterns of RGCs are primarily determined by the presence of ion channels. As the most diverse group of ion channels, potassium (K+) channels play key roles in modulating the electrical properties of RGCs. Biochemical, molecular and pharmacological studies have identified a number of K+ channels in RGCs, including inwardly rectifying K+ (Kir), ATP‑sensitive K+ (KATP), tandem‑pore domain K+ (TASK), voltage‑gated K+ (Kv), ether‑à‑go‑go (Eag) and Ca2+‑activated K+ (KCa) channels. Kir channels are important in the maintenance of the resting membrane potential and controlling RGC excitability. KATP channels are involved in RGC survival and neuroprotection. TASK channels are hypothesized to contribute to the regulation of resting membrane potentials and firing patterns of RGCs. Kv channels are important regulators of cellular excitability, functioning to modulate the amplitude, duration and frequency of action potentials and subthreshold depolarizations, and are also important in RGC development and protection. Eag channels may contribute to dendritic repolarization during excitatory postsynaptic potentials and to the attenuation of the back propagation of action potentials. KCa channels have been observed to contribute to repetitive firing in RGCs. Considering these important roles of K+ channels in RGCs, the study of K+ channels may be beneficial in elucidating the pathophysiology of RGCs and exploring novel RGC protection strategies.
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Affiliation(s)
- Yi-Sheng Zhong
- Department of Ophthalmology, Ruijin Hospital Affiliated Medical School, Shanghai Jiaotong University, Shanghai 200025, P.R. China
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Salido EM, Dorfman D, Bordone M, Chianelli M, González Fleitas MF, Rosenstein RE. Global and ocular hypothermic preconditioning protect the rat retina from ischemic damage. PLoS One 2013; 8:e61656. [PMID: 23626711 PMCID: PMC3633982 DOI: 10.1371/journal.pone.0061656] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 03/12/2013] [Indexed: 11/18/2022] Open
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.
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Affiliation(s)
- Ezequiel M Salido
- Laboratory of Retinal Neurochemistry and Experimental Ophthalmology, Department of Human Biochemistry, School of Medicine, University of Buenos Aires/CEFyBO, CONICET, Buenos Aires, Argentina
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10
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Reichenbach A, Bringmann A. New functions of Müller cells. Glia 2013; 61:651-78. [PMID: 23440929 DOI: 10.1002/glia.22477] [Citation(s) in RCA: 478] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 01/10/2012] [Indexed: 12/12/2022]
Abstract
Müller cells, the major type of glial cells in the retina, are responsible for the homeostatic and metabolic support of retinal neurons. By mediating transcellular ion, water, and bicarbonate transport, Müller cells control the composition of the extracellular space fluid. Müller cells provide trophic and anti-oxidative support of photoreceptors and neurons and regulate the tightness of the blood-retinal barrier. By the uptake of glutamate, Müller cells are more directly involved in the regulation of the synaptic activity in the inner retina. This review gives a survey of recently discoved new functions of Müller cells. Müller cells are living optical fibers that guide light through the inner retinal tissue. Thereby they enhance the signal/noise ratio by minimizing intraretinal light scattering and conserve the spatial distribution of light patterns in the propagating image. Müller cells act as soft, compliant embedding for neurons, protecting them in case of mechanical trauma, and also as soft substrate required for neurite growth and neuronal plasticity. Müller cells release neuroactive signaling molecules which modulate neuronal activity, are implicated in the mediation of neurovascular coupling, and mediate the homeostasis of the extracellular space volume under hypoosmotic conditions which are a characteristic of intense neuronal activity. Under pathological conditions, a subset of Müller cells may differentiate to neural progenitor/stem cells which regenerate lost photoreceptors and neurons. Increasing knowledge of Müller cell function and responses in the normal and diseased retina will have great impact for the development of new therapeutic approaches for retinal diseases.
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Affiliation(s)
- Andreas Reichenbach
- Paul Flechsig Institute of Brain Research, University of Leipzig, Leipzig, Germany.
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11
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Abstract
Retinal ischemia is a common clinical entity and, due to relatively ineffective treatment, remains a common cause of visual impairment and blindness. Generally, ischemic syndromes are initially characterized by low homeostatic responses which, with time, induce injury to the tissue due to cell loss by apoptosis. In this respect, retinal ischemia is a primary cause of neuronal death. It can be considered as a sort of final common pathway in retinal diseases and results in irreversible morphological and functional changes. This review summarizes the recent knowledge on the effects of ischemia in retinal tissue and points out experimental strategies/models performed to gain better comprehension of retinal ischemia diseases. In particular, the nature of the mechanisms leading to neuronal damage (i.e., excess of glutamate release, oxidative stress and inflammation) will be outlined as well as the potential and most intriguing retinoprotective approaches and the possible therapeutic use of naturally occurring molecules such as neuropeptides. There is a general agreement that a better understanding of the fundamental pathophysiology of retinal ischemia will lead to better management and improved clinical outcome. In this respect, to contrast this pathological state, specific pharmacological strategies need to be developed aimed at the many putative cascades generated during ischemia.
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12
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Caprara C, Grimm C. From oxygen to erythropoietin: relevance of hypoxia for retinal development, health and disease. Prog Retin Eye Res 2011; 31:89-119. [PMID: 22108059 DOI: 10.1016/j.preteyeres.2011.11.003] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2011] [Revised: 11/01/2011] [Accepted: 11/07/2011] [Indexed: 12/20/2022]
Abstract
Photoreceptors and other cells of the retina consume large quantities of energy to efficiently convert light information into a neuronal signal understandable by the brain. The necessary energy is mainly provided by the oxygen-dependent generation of ATP in the numerous mitochondria of retinal cells. To secure the availability of sufficient oxygen for this process, the retina requires constant blood flow through the vasculature of the retina and the choroid. Inefficient supply of oxygen and nutrients, as it may occur in conditions of disturbed hemodynamics or vascular defects, results in tissue ischemia or hypoxia. This has profound consequences on retinal function and cell survival, requiring an adaptational response by cells to cope with the reduced oxygen tension. Central to this response are hypoxia inducible factors, transcription factors that accumulate under hypoxic conditions and drive the expression of a large variety of target genes involved in angiogenesis, cell survival and metabolism. Prominent among these factors are vascular endothelial growth factor and erythropoietin, which may contribute to normal angiogenesis during development, but may also cause neovascularization and vascular leakage under pathologically reduced oxygen levels. Since ischemia and hypoxia may have a role in various retinal diseases such as diabetic retinopathy and retinopathy of prematurity, studying the cellular and molecular response to reduced tissue oxygenation is of high relevance. In addition, the concept of preconditioning with ischemia or hypoxia demonstrates the capacity of the retina to activate endogenous survival mechanisms, which may protect cells against a following noxious insult. Part of these mechanisms is the local production of protective factors such as erythropoietin. Due to its plethora of effects in the retina including neuro- and vaso-protective activities, erythropoietin has gained strong interest as potential therapeutic factor for retinal degenerative diseases.
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Affiliation(s)
- Christian Caprara
- Lab for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Zurich, Switzerland
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13
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Sakamoto K, Ohki K, Saito M, Nakahara T, Ishii K. Small Molecule Cyclin-Dependent Kinase Inhibitors Protect Against Neuronal Cell Death in the Ischemic-Reperfused Rat Retina. J Ocul Pharmacol Ther 2011; 27:419-25. [DOI: 10.1089/jop.2010.0141] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Kenji Sakamoto
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Kayo Ohki
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Maki Saito
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Tsutomu Nakahara
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Kunio Ishii
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
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14
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Bringmann A, Wiedemann P. Müller glial cells in retinal disease. ACTA ACUST UNITED AC 2011; 227:1-19. [PMID: 21921569 DOI: 10.1159/000328979] [Citation(s) in RCA: 306] [Impact Index Per Article: 21.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2011] [Accepted: 04/27/2011] [Indexed: 11/19/2022]
Abstract
Virtually all pathogenic stimuli activate Müller cells. Reactive Müller cells exert protective and toxic effects on photoreceptors and neurons. They contribute to oxidative stress and glutamate toxicity due to malfunctions of glutamate uptake and glutathione synthesis. Downregulation of potassium conductance disrupts transcellular potassium and water transport, resulting in neuronal hyperexcitability and edema. Protective effects of reactive Müller cells include upregulation of adenosine 5'-triphosphate (ATP)-degrading ectoenzymes, which enhances the extracellular availability of the neuroprotectant adenosine, abrogation of the osmotic release of ATP, which might protect retinal ganglion cells from apoptosis, and the release of antioxidants and neurotrophic factors. The dedifferentiation of reactive Müller cells to progenitor-like cells might have an impact on future therapeutic approaches. A better understanding of the gliotic mechanisms will be helpful in developing efficient therapeutic strategies aiming at increased protective and regenerative properties and decreased toxicity of reactive Müller cells.
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Affiliation(s)
- Andreas Bringmann
- Department of Ophthalmology and Eye Hospital, University of Leipzig, Leipzig, Germany
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Wurm A, Pannicke T, Iandiev I, Francke M, Hollborn M, Wiedemann P, Reichenbach A, Osborne NN, Bringmann A. Purinergic signaling involved in Müller cell function in the mammalian retina. Prog Retin Eye Res 2011; 30:324-42. [DOI: 10.1016/j.preteyeres.2011.06.001] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2011] [Revised: 06/06/2011] [Accepted: 06/06/2011] [Indexed: 10/18/2022]
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Sakamoto K, Ohki K, Saito M, Nakahara T, Ishii K. Histological protection by donepezil against neurodegeneration induced by ischemia-reperfusion in the rat retina. J Pharmacol Sci 2010; 112:327-35. [PMID: 20197638 DOI: 10.1254/jphs.09302fp] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Although a blockade of acetylcholine esterase has been reported to suppress neuronal cell death induced by exogenous glutamate and beta-amyloid, information is still limited regarding the neuroprotective effects of the acetylcholine esterase inhibitor donepezil. We histologically examined the effects of donepezil on neuronal injury induced by ischemia-reperfusion. Intravenous and intravitreous treatment with donepezil 15 min prior to ischemia dramatically reduced the retinal damage. The protective effect of donepezil in the ganglion cell layer was not affected by mecamylamine, a nicotinic acetylcholine-receptor antagonist, nor scopolamine, a muscarinic acetylcholine-receptor antagonist. The protective effect of donepezil in the inner plexiform layer was reduced not by mecamylamine, but by scopolamine. Neostigmine, a choline-esterase inhibitor, and pilocarpine, a muscarinic acetylcholine-receptor agonist, have protective effects in the inner plexiform layer and the inner nuclear layer. These results suggest that not only the activation of acetylcholine receptors but also a mechanism unrelated to acetylcholine-esterase inhibition contribute to the protective effect of donepezil on the ganglion cells in the ischemic-reperfused rat retina. Donepezil may be useful as a therapeutic drug against retinal diseases that cause neuronal cell death such as glaucoma with high intraocular pressure.
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Affiliation(s)
- Kenji Sakamoto
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.
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Szabadfi K, Mester L, Reglodi D, Kiss P, Babai N, Racz B, Kovacs K, Szabo A, Tamas A, Gabriel R, Atlasz T. Novel neuroprotective strategies in ischemic retinal lesions. Int J Mol Sci 2010; 11:544-561. [PMID: 20386654 PMCID: PMC2852854 DOI: 10.3390/ijms11020544] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Revised: 01/27/2010] [Accepted: 01/27/2010] [Indexed: 02/04/2023] Open
Abstract
Retinal ischemia can be effectively modeled by permanent bilateral common carotid artery occlusion, which leads to chronic hypoperfusion-induced degeneration in the entire rat retina. The complex pathways leading to retinal cell death offer a complex approach of neuroprotective strategies. In the present review we summarize recent findings with different neuroprotective candidate molecules. We describe the protective effects of intravitreal treatment with: (i) urocortin 2; (ii) a mitochondrial ATP-sensitive K+ channel opener, diazoxide; (iii) a neurotrophic factor, pituitary adenylate cyclase activating polypeptide; and (iv) a novel poly(ADP-ribose) polymerase inhibitor (HO3089). The retinoprotective effects are demonstrated with morphological description and effects on apoptotic pathways using molecular biological techniques.
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Affiliation(s)
- Krisztina Szabadfi
- Department of Experimental Zoology and Neurobiology, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(K.S.);
(N.B.);
(R.G.)
| | - Laszlo Mester
- Department of Biochemistry and Medical Chemistry, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(L.M.);
(B.R.);
(K.K.);
(A.S.)
| | - Dora Reglodi
- Department of Anatomy, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(D.R.);
(P.K.);
(A.T.)
| | - Peter Kiss
- Department of Anatomy, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(D.R.);
(P.K.);
(A.T.)
| | - Norbert Babai
- Department of Experimental Zoology and Neurobiology, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(K.S.);
(N.B.);
(R.G.)
| | - Boglarka Racz
- Department of Biochemistry and Medical Chemistry, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(L.M.);
(B.R.);
(K.K.);
(A.S.)
| | - Krisztina Kovacs
- Department of Biochemistry and Medical Chemistry, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(L.M.);
(B.R.);
(K.K.);
(A.S.)
| | - Aliz Szabo
- Department of Biochemistry and Medical Chemistry, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(L.M.);
(B.R.);
(K.K.);
(A.S.)
| | - Andrea Tamas
- Department of Anatomy, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(D.R.);
(P.K.);
(A.T.)
| | - Robert Gabriel
- Department of Experimental Zoology and Neurobiology, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(K.S.);
(N.B.);
(R.G.)
| | - Tamas Atlasz
- Department of Experimental Zoology and Neurobiology, University of Pecs, H-7624 Pecs, Hungary; E-Mails:
(K.S.);
(N.B.);
(R.G.)
- Department of Sportbiology, University of Pecs, H-7624 Pecs, Hungary
- Author to whom correspondence should be addressed; E-Mail:
; Tel.: +36-72-503-600/4613; Fax: +36-72-501-517
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Ogawa N, Mori A, Hasebe M, Hoshino M, Saito M, Sakamoto K, Nakahara T, Ishii K. Nitric oxide dilates rat retinal blood vessels by cyclooxygenase-dependent mechanisms. Am J Physiol Regul Integr Comp Physiol 2009; 297:R968-77. [DOI: 10.1152/ajpregu.91005.2008] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
It has been suggested that nitric oxide (NO) stimulates the cyclooxygenase (COX)-dependent mechanisms in the ocular vasculature; however, the importance of the pathway in regulating retinal circulation in vivo remains to be elucidated. Therefore, we investigated the role of COX-dependent mechanisms in NO-induced vasodilation of retinal blood vessels in thiobutabarbital-anesthetized rats with and without neuronal blockade (tetrodotoxin treatment). Fundus images were captured with a digital camera that was equipped with a special objective lens. The retinal vascular response was assessed by measuring changes in diameter of the retinal blood vessel. The localization of COX and soluble guanylyl cyclase in rat retina was examined using immunohistochemistry. The NO donors (sodium nitroprusside and NOR3) increased the diameter of the retinal blood vessels but decreased systemic blood pressure in a dose-dependent manner. Treatment of rats with indomethacin, a nonselective COX inhibitor, or SC-560, a selective COX-1 inhibitor, markedly attenuated the vasodilation of retinal arterioles, but not the depressor response, to the NO donors. However, both the vascular responses to NO donors were unaffected by the selective COX-2 inhibitors NS-398 and nimesulide. Indomethacin did not change the retinal vascular and depressor responses to hydralazine, 8-(4-chlorophenylthio)-guanosine-3′, 5′-cyclic monophosphate (a membrane-permeable cGMP analog) and 8-(4-chlorophenylthio)-adenosine-3′, 5′-cyclic monophosphate (a membrane-permeable cAMP analog). Treatment with SQ 22536, an adenylyl cyclase inhibitor, but not ODQ, a soluble guanylyl cyclase inhibitor, significantly attenuated the NOR3-induced vasodilation of retinal arterioles. The COX-1 immunoreactivity was found in retinal blood vessels. The retinal blood vessel was faintly stained for soluble guanylyl cyclase, although the apparent immunoreactivities on mesenteric and choroidal blood vessels were observed. These results suggest that NO exerts a substantial part of its dilatory effect via a mechanism that involves COX-1-dependent pathway in rat retinal vasculature.
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Affiliation(s)
- Naoto Ogawa
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Asami Mori
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Masami Hasebe
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Maya Hoshino
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Maki Saito
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Kenji Sakamoto
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Tsutomu Nakahara
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
| | - Kunio Ishii
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan
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Choi A, Choi JS, Yoon YJ, Kim KA, Joo CK. KR-31378, a potassium-channel opener, induces the protection of retinal ganglion cells in rat retinal ischemic models. J Pharmacol Sci 2009; 109:511-7. [PMID: 19372634 DOI: 10.1254/jphs.fp0072067] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
KR-31378 is a newly developed K(ATP)-channel opener. To investigate the ability of KR-31378 to protect retinal ganglion cells (RGC), experiments were conducted using two retinal ischemia models. Retinal ischemia was induced by transient high intraocular pressure (IOP) for acute ischemia and by three episcleral vein occlusion for chronic retinal ischemia. KR-31378 was injected intraperitoneally and administered orally in the acute and chronic ischemia models, respectively. Under the condition of chronic ischemia, RGC density in the KR-31378-treated group was statistically higher than that in the non-treated group, and IOP was reduced. In the acute retinal ischemia model, 90% of RGC were degenerated after one week in non-treated retina, but, RGC in KR-31378-treated retina were protected from ischemic damage in a dose-dependent manner and showed inhibited glial fibrillary acidic protein (GFAP) expression. Furthermore, the KR-31378 protective effect was inhibited by glibenclamide treatment in acute ischemia. These findings indicate that systemic KR-31378 treatment may protect against ischemic injury-induced ganglion cell loss in glaucoma.
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Affiliation(s)
- Anho Choi
- Department of Ophthalmology and Visual Science, College of Medicine and Korean Eye and Gene Bank Related to Blindness, The Catholic University of Korea, Seoul, Korea
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20
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Housley GD, Bringmann A, Reichenbach A. Purinergic signaling in special senses. Trends Neurosci 2009; 32:128-41. [DOI: 10.1016/j.tins.2009.01.001] [Citation(s) in RCA: 135] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2008] [Revised: 12/22/2008] [Accepted: 01/05/2009] [Indexed: 02/06/2023]
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EMRE S, GUL M, ATES B, ESREFOGLU M, KOC B, ERDOGAN A, YESILADA E. Comparison of the Protective Effects of Prostaglandin Analogues in the Ischemia and Reperfusion Model of Rabbit Eyes. Exp Anim 2009; 58:505-13. [DOI: 10.1538/expanim.58.505] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022] Open
Affiliation(s)
- Sinan EMRE
- Department of Ophthalmology, Faculty of Medicine, Inonu University
- Department of Ophthalmology, Faculty of Medicine, Celal Bayar University
| | - Mehmet GUL
- Department of Histology and Embryology, Faculty of Medicine, Inonu University
| | - Burhan ATES
- Department of Chemistry, Faculty of Science and Art, Inonu University
| | - Mukaddes ESREFOGLU
- Department of Histology and Embryology, Faculty of Medicine, Inonu University
| | - Bekir KOC
- Department of Ophthalmology, Faculty of Medicine, Inonu University
| | - Ali ERDOGAN
- Department of Chemistry, Faculty of Science and Art, Inonu University
| | - Elif YESILADA
- Department of Medical Biology and Genetics, Faculty of Medicine, Inonu University
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22
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Dan C, Jian-Bin T, Hui W, Le-Ping Z, Jin Z, Ju-Fang H, Xue-Gang L. Synaptophysin expression in rat retina following acute high intraocular pressure. Acta Histochem Cytochem 2008; 41:173-8. [PMID: 19180202 PMCID: PMC2629489 DOI: 10.1267/ahc.08034] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2008] [Accepted: 11/11/2008] [Indexed: 11/22/2022] Open
Abstract
In response to injury, synapse alteration may occur earlier than the changes in the cell body of neurons. Although retinal ganglion cell death and thinning of the inner part of retina were found after acute high intraocular pressure (HIOP), the structural and functional changes of synapses in the retina remain unknown. In the present study, we investigated the protein and mRNA expression of synaptophysin (SYN), an important molecule closely related to synaptic activities, synaptogenesis and synaptic plasticity. In addition, we also studied the ultrastructural changes of the retinal synapses. We found that (1) synaptophysin was upregulated transiently at both protein and mRNA level following HIOP; (2) broadened distribution of synaptophysin protein was present within the outer nuclear layer at the early stage following HIOP; (3) in the outer nuclear layer bouton-like vesicle-containing structures were observed by electron microscopy. This data suggested that, besides degeneration, synapses in rat retina may undergo regenerative events following HIOP.
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Affiliation(s)
- Chen Dan
- Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University
| | - Tong Jian-Bin
- Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University
| | - Wang Hui
- Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University
| | - Zeng Le-Ping
- Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University
| | - Zhou Jin
- Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University
| | - Huang Ju-Fang
- Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University
| | - Luo Xue-Gang
- Department of Anatomy & Neurobiology, Xiangya School of Medicine, Central South University
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Ding J, Ding N, Wang N, Lu Q, Lu N, Yang D, Bu X, Han S, Li J. Determination of conventional protein kinase C isoforms involved in high intraocular pressure-induced retinal ischemic preconditioning of rats. Vision Res 2008; 49:315-21. [PMID: 19013479 DOI: 10.1016/j.visres.2008.10.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2008] [Revised: 10/13/2008] [Accepted: 10/13/2008] [Indexed: 01/26/2023]
Abstract
Evidence indicates that conventional protein kinase C (cPKC) plays a pivotal role in the development of retinal ischemic preconditioning (IPC). In this study, the effect of high intraocular pressure (IOP)-induced retinal IPC on cPKC isoform-specific membrane translocation and protein expression were observed. We found that cPKCgamma membrane translocation increased significantly at the early stage (20min-1h), while the protein expression levels of cPKCalpha and gamma were markedly elevated in the delayed retinal IPC (12-168h) of rats. The increased protein expressions of cPKCalpha at 72h and cPKCgamma at 24h after IPC were further confirmed by immunofluorescence staining. In addition, we found that cPKCgamma co-localized with retinal ganglion cell (RGC)-specific marker, neurofilaments heavy chain (NF-H) by using double immunofluorescence labeling. These results suggest that increased cPKCgamma membrane translocation and up-regulated protein expressions of cPKCalpha and gamma are involved in the development of high IOP-induced rat retinal IPC.
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Affiliation(s)
- Jingwen Ding
- Beijing Tongren Eye Center, Capital Medical University Affiliated Beijing Tongren Hospital, Vision Science Laboratory, School of Ophthalmology, Beijing, China
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Morphine pretreatment provides histologic protection against ischemia-reperfusion injury in rabbit retina. Retina 2008; 28:511-7. [PMID: 18327147 DOI: 10.1097/iae.0b013e31815960c3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
PURPOSE Pharmacologic preconditioning with morphine has been shown to protect several kinds of tissues against ischemia-reperfusion injury. The aim of the present study was to investigate whether intravitreal administration of morphine induces structural protection against ischemic damage in a rabbit model of ischemic retinopathy. METHODS Twenty-eight male white New Zealand rabbits were used. Animals in saline control group received 0.1 mL of phosphate-buffered saline (PBS) intravitreally with no postinjection ischemia. In the saline-control ischemia group, 15 minutes after injection of PBS, retinal ischemia was induced by raising intraocular pressure to 150 mmHg for 60 minutes. In three treatment-ischemia groups, morphine (1, 5, and 10 micromol/L) was administered intravitreally 15 minutes before induction of ischemia. In another experiment, naloxone (40 micromol/L) was administered 5 minutes before intravitreal administration of morphine (10 micromol/L) followed by 60 minutes of ischemia to investigate the role of opioid receptors in mediating the possible protective effect of morphine. Toxicity controls were performed with morphine (10 micromol/L) and naloxone (40 micromol/L) without ischemia. Histologic evaluation was performed for all groups on the seventh postoperative day. RESULTS Sixty minutes of ischemia led to severe cell loss in ganglion cell layer and thinning of the inner nuclear layer in saline-control ischemia compared to that of the nonischemia control group (P < 0.001). Thickness of the inner plexiform layer to the inner limiting membrane was significantly increased due to edema (P < 0.001). Administration of morphine in higher doses (5 and 10 micromol/L) significantly improved all of the above mentioned indices (P < 0.05). Administration of naloxone 15 minutes before morphine reversed most of the morphine protective effects. CONCLUSIONS Morphine pretreatment provides significant histologic protection against ischemic injury in rabbit retina. Pharmacologic evidence suggests that this protective phenomenon may be mediated in part by opiate receptors.
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Na KD, Kang SY, Seong GJ, Hong S, Chun MJ, Kim CY. Ischemic Preconditioning and the Role of Protein Kinase C in Cultured Retinal Ganglion Cell Line. JOURNAL OF THE KOREAN OPHTHALMOLOGICAL SOCIETY 2008. [DOI: 10.3341/jkos.2008.49.6.979] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Kyoung Doo Na
- Department of Ophthalmology, Yonsei University College of Medicine, The Institute of Vision Research, Seoul, Korea
| | - Sung Yong Kang
- Department of Ophthalmology, Yonsei University College of Medicine, The Institute of Vision Research, Seoul, Korea
| | - Gong Je Seong
- Department of Ophthalmology, Yonsei University College of Medicine, The Institute of Vision Research, Seoul, Korea
| | - Samin Hong
- Department of Ophthalmology, Yonsei University College of Medicine, The Institute of Vision Research, Seoul, Korea
| | - Mi-Jin Chun
- Department of Ophthalmology, Yonsei University College of Medicine, The Institute of Vision Research, Seoul, Korea
| | - Chan Yun Kim
- Department of Ophthalmology, Yonsei University College of Medicine, The Institute of Vision Research, Seoul, Korea
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Lönngren U, Näpänkangas U, Lafuente M, Mayor S, Lindqvist N, Vidal-Sanz M, Hallböök F. The growth factor response in ischemic rat retina and superior colliculus after brimonidine pre-treatment. Brain Res Bull 2006; 71:208-18. [PMID: 17113948 DOI: 10.1016/j.brainresbull.2006.09.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2006] [Revised: 08/08/2006] [Accepted: 09/06/2006] [Indexed: 10/24/2022]
Abstract
The alpha-2-adrenergic receptor agonist brimonidine has been shown to increase survival of retinal ganglion cells following ischemic injury to the rat retina. Increased expression of growth factors has been suggested to be involved in this action. We investigated expressional changes of growth factors and their receptors following transient retinal ischemia induced by selective ligature of ophthalmic vessels in rats pre-treated with vehicle or 0.5% brimonidine. In addition, analysis of expression in retinal samples following unilateral administration of brimonidine to normal tissue was performed. Tissue samples of retina and superior colliculus were collected at time points between 6h and 14 days of retinal reperfusion. Analysis of mRNA levels of the ligands BDNF, NT3, CNTF, FGF1, FGF2, FGF9 and HGF; as well as the receptors TrkB, TrkC, p75(NTR), CNTFRalpha, FGFR1, FGFR3, FGFR4 and HGFR were performed using qRT-PCR. The cell specific markers Thy1 and GFAP were analysed. We report transiently increased retinal levels of BDNF, NT3, p75(NTR), FGFR1 and HGFR and decreased levels of FGF9, HGF, TrkB, TrkC, FGFR4 and Thy1 following ischemia. The decreases were counteracted by brimonidine. Brimonidine treatment gave an increase in BDNF, NT3 and CNTF levels compared to the vehicle treated group. In superior colliculus increased levels of growth factor mRNA were found. In conclusion, transient ischemia has a profound effect on gene expression in rat retina. Alterations can also be seen in the superior colliculus but are smaller. Brimonidine pre-treatment attenuates an acute injury-induced response by decreasing the expression of several genes, among them p75(NTR). Brimonidine also causes a prolonged increase of several growth factors as well as receptors in retina and superior colliculus compared to the ischemic situation. The increased expression of several growth factors represents a coordinated growth factor system response that differs from the ischemia-induced changes and is likely part of the neuroprotective activity that is elicited by BMD pre-treatment.
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Affiliation(s)
- Ulrika Lönngren
- Department of Neuroscience, Uppsala University, Uppsala, Sweden
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Pavlidis M, Stupp T, Georgalas I, Georgiadou E, Moschos M, Thanos S. Multifocal Electroretinography Changes in the Macula at High Altitude: A Report of Three Cases. Ophthalmologica 2005; 219:404-12. [PMID: 16286804 DOI: 10.1159/000088387] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2004] [Accepted: 11/25/2004] [Indexed: 11/19/2022]
Abstract
BACKGROUND To evaluate the short- and long-term effects of high-altitude hypobaric hypoxia on macula morphology and function during ascents, acclimatizations, and descents between 500 m and 5,650 m, macula function was evaluated in three healthy climbers of a trekking expedition. METHODS Macula physiology was tested with multifocal electroretinography (MF ERG), near and farvisual acuity, and Amsler grid tests. Macula morphology was tested with optical coherence tomography (OCT) and with stereoscopic fundoscopy obtained 1 week before ascent, as well as 1 week and 2 weeks after high-altitude exposure. The following physiological parameters indicative of acclimatization were compared daily during the expedition at altitudes between 500 m and 5,050 m: hemoglobin, oxygen saturation, resting heart rate, retinal findings, and the Lake Louise score of acclimatization. RESULTS The central macula MF ERG responses were significantly reduced 1 week after high-altitude exposure, and had recovered by the follow-up examination performed during the following week. Near visual acuity and Amsler grid tests remained unaffected at both follow-up examinations. No significant changes were found in the follow-up OCT and daily fundoscopy examinations in all three well-acclimatized climbers. CONCLUSIONS High-altitude hypobaric hypoxia affects the function of the highly sensitive macula region. This suggests that the exposure of persons with macula diseases such as age-related macula degeneration, tapetoretinal degeneration, or diabetic retinopathy to high altitudes may influence the disease progression. For this reason, this population should avoid prolonged and unnecessary high-altitude exposure without proper acclimatization.
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Sakamoto K, Yonoki Y, Kubota Y, Kuwagata M, Saito M, Nakahara T, Ishii K. Inducible nitric oxide synthase inhibitors abolished histological protection by late ischemic preconditioning in rat retina. Exp Eye Res 2005; 82:512-8. [PMID: 16198335 DOI: 10.1016/j.exer.2005.08.011] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2005] [Revised: 08/04/2005] [Accepted: 08/11/2005] [Indexed: 01/26/2023]
Abstract
Brief ischemia was reported to protect retinal cells against injury induced by subsequent ischemia-reperfusion with de novo protein synthesis, and this phenomenon is known as late ischemic preconditioning. The aims of the present study were to determine whether nitric oxide synthase (NOS) was involved in the mechanism of late ischemic preconditioning in rat retina using pharmacological tools. Under anesthesia with pentobarbital sodium, male Sprague-Dawley rats were subjected to 60 min of retinal ischemia by raising intraocular pressure to 130 mm Hg. Ischemic preconditioning was achieved by applying 5 min of ischemia 24 hrs before 60 min of ischemia. Retinal sections sliced into 5 microm thick were examined 7 days after ischemia. Additional groups of rats received NG-nitro-L-arginine and NG-monomethyl-L-arginin, non-selective NO synthase inhibitors, 7-nitroindazole, a neuronal NOS inhibitor, and aminoguanidine and L-N6-(1-iminoethyl) lysine, inducible NO synthase (iNOS) inhibitors before preconditioning, and were subjected to 60 min of ischemia. In the non-preconditioned group, cell loss in the ganglion cell layer and thinning of the inner plexiform and inner nuclear layer were observed 7 days after 60 min of ischemia. Ischemic preconditioning for 5 min completely protected against the histological damage induced by 60 min of ischemia applied 24 hrs thereafter. Treatment of rats with aminoguanidine and L-N6-(1-iminoethyl) lysine, but not NG-nitro-L-arginine, NG-monomethyl-L-arginine or 7-nitroindazole, wiped off the protective effect of ischemic preconditioning. The inhibitory effect of aminoguanidine was abolished by L-arginine, but not D-arginine. The results in the present study suggest that NO synthesized by iNOS is involved in the histological protection by late ischemic preconditioning in rat retina.
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Affiliation(s)
- Kenji Sakamoto
- Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, 9-1 Shirokane 5-chome, Minato-ku, Tokyo 108-8641, Japan.
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Zhu Y, Ohlemiller KK, McMahan BK, Park TS, Gidday JM. Constitutive nitric oxide synthase activity is required to trigger ischemic tolerance in mouse retina. Exp Eye Res 2005; 82:153-63. [PMID: 16045907 DOI: 10.1016/j.exer.2005.06.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2005] [Revised: 05/16/2005] [Accepted: 06/02/2005] [Indexed: 01/08/2023]
Abstract
Profound morphologic and functional protection against retinal ischemic injury can be achieved if the tissue is 'preconditioned' one day earlier with a brief, noninjurious ischemic challenge. To begin to address the mechanistic basis of this 'ischemic tolerance', we used genetic and pharmacologic approaches to test the hypothesis that nitric oxide (NO) derived from one of the three NO synthase (NOS) isoforms was responsible for triggering the adaptive response to brief preconditioning ischemia. Retinae of adult mice were preconditioned with 5-min preconditioning ischemia and subjected to 45-min injurious ischemia 24 hr later. Some animals were treated with the constitutive NOS inhibitor L-nitroarginine (5 mg/kg, i.p.) 1 hr before preconditioning. Retinal layer thicknesses and cell counts were determined one week postischemia in 5-mum thin sections, and flash electroretinograms were obtained at 1 and 7 days postischemia. We confirmed that ischemic preconditioning afforded morphologic and functional protection in the strains of wild-type mice studied. Histopathologic analyses of inducible NOS (iNOS) knockout mice revealed that ischemic preconditioning was completely effective, whereas ischemic tolerance was not achieved in the retinae of endothelial NOS (eNOS) and neuronal NOS (nNOS) knockout mice. The participation of the constitutive NOS enzymes in preconditioning-induced tolerance was confirmed by the finding that administration of the NOS inhibitor L-NA to wild-type mice prior to ischemic preconditioning blocked the development of ischemic tolerance. These cross-validating genetic and pharmacologic findings indicate that NO derived from both eNOS and nNOS is a required molecular signal in the adaptive response to ischemic preconditioning in the retina.
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Affiliation(s)
- Yanli Zhu
- Department of Neurosurgery, Washington University School of Medicine, Box 8057, 660 S. Euclid Ave., St Louis, MO 63110, USA
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