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      Photopic Negative Response Reflects Severity of Ocular Circulatory Damage after Central Retinal Artery Occlusion

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          Abstract

          Purpose: To determine the relationship of the photopic negative response (PhNR) of the photopic electroretinogram (ERG) with the degree of circulatory disturbances in eyes following central retinal artery occlusion (CRAO). Methods: The circulatory disturbance was graded as mild (group 1) when the arm-to-retina transmission time was <30 s, moderate (group 2) when the time was >30 s and severe (group 3) when concurrent choroidal circulatory damage was found. For statistical analysis, groups 1, 2 and 3 were scored as 1, 2 and 3, respectively. Photopic ERGs were elicited by either short-flash (SF) or long-flash (LF) stimuli. Results: Both the SF and LF PhNR were significantly reduced in groups 2 and 3. The PhNR amplitude was negatively correlated with the severity of the ocular circulatory disturbances (p = 0.0498, ρ = –0.507 for SF PhNR; p = 0.0050, ρ = –0.750 for LF PhNR). Conclusion: The amplitude of the PhNR became more reduced as the severity of the circulatory disturbances increased in eyes with CRAO.

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          Most cited references 10

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          Photopic ERGs in patients with optic neuropathies: comparison with primate ERGs after pharmacologic blockade of inner retina.

          To determine whether anterior ischemic optic neuropathy and compressive optic neuropathy in humans alter the photopic flash ERG and to investigate the cellular origins of the waves that are affected by pharmacologic agents in primates. Photopic flash ERGs were recorded differentially, with DTL electrodes, between the two eyes of 22 patients with diagnosed optic neuropathy (n = 17, anterior ischemic optic neuropathy [AION]; n = 5, compressive optic neuropathy) and 25 age-matched control subjects and in 17 eyes of 13 monkeys (Macaca mulatta). The stimulus consisted of brief (<5 ms) red (lambda(max) = 660 nm) Ganzfeld flashes (energy range, 0.5-2.0 log td-s) delivered on a rod-saturating blue background of 3.7 log sc td (lambda(max) = 460 nm). An eye of the patient with ischemic changes at the disc was classified as symptomatic if it showed visual field defects with a mean deviation (MD) of P < 2%. Recordings in macaque monkeys were made before and after inner retinal blockade with tetrodotoxin (TTX) (1.2-2.1 microM; n = 7), TTX+N-methyl-d-aspartate (NMDA; 1.4-6.4 mM; n = 7), and cis-2, 3 piperidine dicarboxylic acid (PDA; 3.3-3.8 mM; n = 3). The PhNR amplitude was significantly reduced in both symptomatic (P = 3.4 x 10(-8)) and asymptomatic (P = 0.036) eyes of patients with AION or compressive optic neuropathy (P = 0.0054) compared with control subjects. The PhNR amplitude in the symptomatic eye showed a moderate correlation with field defects (P < 0.05) similar to previous findings in open-angle glaucoma. The a-wave also was reduced significantly in the symptomatic eye (P = 0.0002) of patients with AION. The i-wave, a positive wave on the trailing edge of the b-wave peaking around 50 ms, became more prominent in eyes in which the PhNR was significantly reduced. In monkeys, the PhNR was eliminated by TTX. The a-wave at the peak and later times was reduced by TTX, further reduced by NMDA, and eliminated after PDA in response to the red stimuli. PDA also eliminated the i-wave. PhNR amplitude is significantly reduced in eyes with open-angle glaucoma, AION, and compressive optic neuropathy. Experiments in primates indicate that this reduction reflects loss of a spike-driven contribution to the photopic ERG. There also are small spike-driven contributions to the a-wave elicited by full-field red stimuli. The i-wave, which becomes more prominent when the PhNR is reduced, has origins in the off-pathway distal to the ganglion cells.
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            Activation of the mitochondrial apoptotic pathway in a rat model of central retinal artery occlusion.

            Apoptosis is known to play a role in cell death in transient retinal ischemia. Little is known about the specific molecular pathways involved. The purpose of the current study was to evaluate a rat model of central retinal artery occlusion (CRAO) that simulates the clinical features of CRAO in humans and to elucidate whether the mitochondrial apoptotic pathway is involved. CRAO was induced in the central retinal artery by intravenous injection of rose bengal and green laser irradiation of the artery. CRAO was documented at 1, 3, 6, and 24 hours after laser irradiation. Changes in Bax (proapoptotic Bcl-2-associated X protein), cytochrome c, and caspase-9 cleavage in the cytosolic and mitochondrial fractions of neural retinal tissues were measured by Western blot analysis. Apoptosis within the retina was examined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). Complete CRAO was induced; however, occlusion became incomplete with spontaneous reperfusion of branch arteries, starting at 3 hours after laser irradiation. Only one or two branch arteries remained occluded at the 24-hour time point. Time-dependent, apoptotic changes were observed in inner and outer retinal cell layers. Western blot analysis revealed mitochondrial translocation of Bax from the cytoplasm, starting at 3 hours and peaking at 6 hours after laser irradiation. This translocation was accompanied by cytosolic accumulation of cytochrome c and cleavage of caspase-9. This model is highly relevant to clinical manifestations of CRAO and is an ideal animal model for research. These findings indicate the activation of the mitochondrial pathway in ischemic retina induced by CRAO. The model provides a better understanding of ischemia-induced retinal apoptosis. Antiapoptosis therapy directly targeting the mitochondrial pathway in CRAO or other retinal ischemic diseases may be beneficial.
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              Push–pull model of the primate photopic electroretinogram: A role for hyperpolarizing neurons in shaping the b-wave

              Existing models of the primate photopic electroretinogram (ERG) attribute the light-adapted b –wave to activity of depolarizing bipolar cells (DBCs), mediated through a release of potassium that is monitored by Müller cells. However, possible ERG contributions from OFF-bipolar cells (HBCs) and horizontal cells (HzCs) have not been explored. We examined the contribution of these hyperpolarizing second-order retinal cells to the photopic ERG of monkey by applying glutamate analogs to suppress photoreceptor transmission selectively to HBC/HzCs vs. DBCs. ERGs of Macaca monkeys were recorded at the cornea before and after intravitreal injection of drugs. Photopic responses were elicited by bright 200–220 ms flashes on a steady background of 3.3 log scotopic troland to suppress rod ERG components. 2–amino-4–phosphonobutyric acid (APB), which blocks DBC light responses, abolished the photopic b –wave and indicated that DBC activity is requisite for photopic b –wave production. However, applying cis –2,3–piperidine dicarboxylic acid (PDA) and kynurenic acid (KYN), to suppress HBCs/HzCs and third-order neurons, revealed a novel ERG response that was entirely positive and was sustained for the duration of the flash. The normally phasic b –wave was subsumed into this new response. Applying n –methyl-dl-aspartate (NMA) did not replicate the PDA+KYN effect, indicating that third-order retinal cells are not involved. This suggests that HBC/HzC activity is critical for shaping the phasic b –wave. Components attributable to depolarizing vs. hyperpolarizing cells were separated by subtracting waveforms after each drug from responses immediately before. This analysis indicated that DBCs and HBC/HzCs each can produce large but opposing field potentials that nearly cancel and that normally leave only the residual phasic b –wave response in the photopic ERG. Latency of the DBC component was 5–9 ms slower than the HBC/HzC component. However, once activated, the DBC component had a steeper slope. This resembles properties known for the two types of cone synapses in lower species, in which the sign-preserving HBC/HzC synapse has faster kinetics but probably lower gain than the slower sign-inverting G-protein coupled DBC synapse. A human patient with “unilateral cone dystrophy” was found to have a positive and sustained ERG that mimicked the monkey ERG after PDA+KYN, indicating that these novel positive photopic responses can occur naturally even without drug application. These results demonstrate that hyperpolarizing second-order neurons are important for the primate photopic ERG. A “Push-Pull Model” is proposed in which DBC activity is requisite for b –wave production but in which HBC/HzC activity limits the amplitude and controls the shape of the primate photopic b –wave.
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                Author and article information

                Journal
                OPH
                Ophthalmologica
                10.1159/issn.0030-3755
                Ophthalmologica
                S. Karger AG
                0030-3755
                1423-0267
                2009
                October 2009
                08 July 2009
                : 223
                : 6
                : 362-369
                Affiliations
                Department of Brain and Neuroscience, Ophthalmology, Oita University, Oita, Japan
                Article
                227782 Ophthalmologica 2009;223:362–369
                10.1159/000227782
                19590251
                © 2009 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, Tables: 1, References: 23, Pages: 8
                Categories
                Original Paper

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