Papers - IKEDA Yasuhiro
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Long-term surgical outcomes of epiretinal membrane in patients with retinitis pigmentosa Reviewed
Ikeda Y., Yoshida N., Murakami Y., Nakatake S., Notomi S., Hisatomi T., Enaida H., Ishibashi T.
Scientific Reports 5 2015.8
Language：English Publishing type：Research paper (scientific journal) Publisher：Scientific Reports
Macular complications such as an epiretinal membrane (ERM), a cystoid macular edema and a macular hole lead to unexpected central vision impairment especially for patients with retinitis pigmentosa (RP). To evaluate the long-term surgical outcomes of pars plana vitrectomy (PPV) for ERM in patients with RP, we retrospectively reviewed the charts of a consecutive series of 10 RP patients who underwent PPV for ERM at Kyushu University Hospital. Visual acuity (VA) testing, a fundus examination, and an optical coherence tomography (OCT) analysis were conducted. The standard PPV using three sclerotomies was performed for ERM. PPV was performed in 12 eyes of 10 patients. One eye was excluded from the outcome assessment due to short period observation (18 months). There was no significantly deleterious change from the baseline to final VA between the operation eyes and the fellow eyes (P = 0.19). Moreover, morphological improvement was obtained in 9 of 11 eyes based on OCT. Our present data suggest that PPV may be tolerable in the management for ERM in RP patients over the long-term. Furthermore, the appearance of the ellipsoid zone was an important factor in the prediction of visual outcome and determination of surgical indication.
DOI： 10.1038/srep13078
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Relationship between aqueous flare and visual function in retinitis pigmentosa Reviewed
Murakami Y., Yoshida N., Ikeda Y., Nakatake S., Fujiwara K., Notomi S., Nabeshima T., Nakao S., Hisatomi T., Enaida H., Ishibashi T.
American Journal of Ophthalmology 159 ( 5 ) 958 - 963.e1 2015.5
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Ophthalmology
© 2015 by Elsevier Inc. All rights reserved. Purpose To investigate the correlation between aqueous flare values and central visual function in patients with retinitis pigmentosa (RP). Design Retrospective, observational case series. Methods We retrospectively studied 160 patients diagnosed with typical RP and 59 control subjects. Aqueous flare values were measured by laser flare cell meter. The relationships between aqueous flare and best-corrected visual acuity (VA) and mean deviation (MD) of static perimetry tests were analyzed in RP patients. Results The aqueous flare values were significantly higher in the RP patients compared to the control subjects (10.6 ± 7.9 vs 5.0 ± 2.1 photon counts per millisecond [pc/ms], P <.0001). In the RP patients, the aqueous flare values were negatively correlated with VA (r = 0.359, P <.0001) and MD (r = -0.330, P <.0001). Age-subgroup analysis showed a significant correlation between aqueous flare and VA in the RP patients' 40s, 50s, and 60s and between aqueous flare and MD in the 30s, 40s, 50s, and 60s. The RP patients with MD values ≥-15 decibels (dB) showed significantly higher levels of aqueous flare than those with MD values <-15 dB (12.0 ± 6.2 vs 8.7 ± 5.8, P =.0001). Conclusions Aqueous flare is increased in RP patients and negatively correlates with central visual function. These results suggest a close relationship between inflammation and central vision loss in RP.
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Factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa Reviewed
Yoshida N., Ikeda Y., Murakami Y., Nakatake S., Fujiwara K., Notomi S., Hisatomi T., Ishibashi T.
Ophthalmology 122 ( 5 ) 903 - 908 2015.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Ophthalmology
© 2015 American Academy of Ophthalmology. Purpose To investigate the factors affecting visual acuity after cataract surgery in patients with retinitis pigmentosa (RP). Design Retrospective, observational study. Participants We retrospectively reviewed the charts of a consecutive series of 40 patients with RP who underwent cataract surgery. Methods The changes in preoperative and postoperative best-corrected visual acuity (BCVA) were measured. We investigated the relation between preoperative mean deviation (MD) value on the Humphrey Field Analyzer (HFA: the central 10-2 program; Humphrey Instruments, Inc, San Leandro, CA) and final BCVA. We also investigated the relationship between preoperative ellipsoid zone (EZ; also called the inner/outer segment junction) conditions and final BCVA. In addition, we showed the prevalence of macular complications and capsule complications. Main Outcome Measures The BCVA, slit-lamp biomicroscopic analysis, visual field, and optical coherence tomography (OCT) were obtained. Results The mean of the BCVA significantly improved after cataract surgery from 0.76 (range, -0.08 to 2.30) to 0.45 (range, -0.18 to 2.00) (P < 0.005). However, final BCVA did not improve in 30 eyes (53.6%). The preoperative MD value and the final BCVA were significantly correlated, and the final BCVA significantly improved in the less advanced RP group (MD was >-15 decibels [dB]). The final BCVA was significantly better in the group in which preoperative OCT showed a normal EZ than in the groups in which the EZ was abnormal or not visible. Posterior capsular opacification was observed in 47 eyes (83.9%), and 23 eyes (41.1%) underwent YAG laser capsulotomy within a mean follow-up time of 3 years. Conclusions Final BCVA in approximately half of the eyes improved after cataract surgery in patients with RP. The preoperative ophthalmic examinations that may reflect macular (or foveal) function, such as HFA 10-2 program and OCT, are important parameters to assess postoperative visual outcome.
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Hisatomi T., Notomi S., Tachibana T., Oishi S., Asato R., Yamashita T., Murakami Y., Ikeda Y., Enaida H., Sakamoto T., Ishibashi T.
Retina 35 ( 2 ) 310 - 318 2015.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Retina
Copyright © by Ophthamic Communications Society. PURPOSE:: Brilliant Blue G is used as a surgical adjuvant for retinal surgery. Although BBG double or multiple staining was reported, the effectiveness and safety of repeated staining is still elusive. To further examine the effectiveness and safety, we examined BBG in clinical cases in vivo, primary cell culture in vitro, and surgically resected specimen ex vivo. METHODS:: A retrospective interventional case series with in vitro and ex vivo studies were performed. Vitrectomy was performed in 28 cases of epiretinal membrane with BBG single to multiple staining. The surgically resected membranes were stained by BBG with or without cellular fixation. Primary cell cultures were examined with BBG and live/death cell markers, such as Calcein AM and TUNEL. RESULTS:: Single staining provided satisfactory staining in seven cases. Double or multiple staining substantially visualized internal limiting membrane (21 cases), especially the edges of remaining internal limiting membrane (11 cases). Adverse retinal staining was not noted and the final visual acuity showed no difference with multiple staining. The live cells barely stained with BBG, while some dead cells were stained. CONCLUSION:: Brilliant Blue G multiple staining substantially enhanced the visualization of internal limiting membrane. The absence of abnormal staining supports the safety of repeated BBG staining.
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Proteomic study of retinal proteins associated with transcorneal electric stimulation in rats Reviewed
Kanamoto T., Souchelnytskyi N., Kurimoto T., Ikeda Y., Sakaue H., Munemasa Y., Kiuchi Y.
Journal of Ophthalmology 2015 2015
Language：English Publishing type：Research paper (scientific journal) Publisher：Journal of Ophthalmology
© 2015 Takashi Kanamoto et al. Background. To investigate how transcorneal electric stimulation (TES) affects the retina, by identifying those proteins up-and downregulated by transcorneal electric stimulation (TES) in the retina of rats. Methods. Adult Wistar rats received TES on the left eyes at different electrical currents while the right eyes received no treatment and served as controls. After TES, the eye was enucleated and the retina was isolated. The retinas were analyzed by proteomics. Results. Proteomics showed that twenty-five proteins were upregulated by TES. The identified proteins included cellular signaling proteins, proteins associated with neuronal transmission, metabolic proteins, immunological factors, and structural proteins. Conclusions. TES induced changes in expression of various functional proteins in the retina.
DOI： 10.1155/2015/492050
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Ikeda Y., Suzuki E., Kuramata T., Kozaki T., Koyama T., Kato Y., Murakami Y., Enaida H., Ishibashi T.
Japanese Journal of Ophthalmology 59 ( 1 ) 43 - 47 2015
Language：English Publishing type：Research paper (scientific journal) Publisher：Japanese Journal of Ophthalmology
© 2014, Japanese Ophthalmological Society. Purpose: Patients in the early stage of retinitis pigmentosa (RP) suffer from night blindness and, therefore, have mobility problems at night. To assist such patients with walking in the dark, we developed a wearable visual aid utilizing a see-through display upon which assistive images from a high-sensitivity video camera are superimposed. We evaluated the efficacy of our new visual aid for RP patients. Methods: The device is equipped with a camera with a minimum illuminance of 0.08 lux and a view angle of 53° × 40°. The experiment was conducted in a room with dimmed light (illuminance level 0.2–1.2 lux). Eight subjects with RP were instructed to arrive at a goal 16 m away from the starting point, both with and without the device, passing through four 1.5-m-wide gates consisting of pairs of black square carpet pieces, white poles, red and white traffic cones and cardboard boxes with and without the device in a darkened room. Three gates, except for the boxes, which were nearest the goal, were randomly arranged along the x-axis at each trial. The number of trial failures and the time required to walk the course were assessed as outcomes. Results: Seven of the 8 subjects could walk with the aid of the device without any failure. With the device, the number of trial failures significantly decreased in number (p < 0.05) in all subjects. Conclusions: This device enabled the subjects to see objects that could not be recognized by the unaided eye. Our visual aid effectively assisted RP patients with night blindness.
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Saadat K., Murakami Y., Tan X., Nomura Y., Yasukawa T., Okada E., Ikeda Y., Yanagi Y.
FEBS Open Bio 4 1007 - 1014 2014.12
Language：English Publishing type：Research paper (scientific journal) Publisher：FEBS Open Bio
© 2014 The Authors. In this study, we show augmented autophagy in the retinal pigment epithelial cell line ARPE-19 when cultured in the presence of the lipofuscin pigment A2E. A2E alone does not induce RPE cell death, but cell death was induced in the presence of A2E with the autophagy inhibitor 3-methyladenine (3MA), with a concomitant increase in the generation of mitochondrial reactive oxygen species. On the other hand, the ATP production capacity of mitochondria was decreased in the presence of A2E, and pharmacological inhibition of autophagy had no additional effects. The altered mRNA expression level of mitochondrial function markers was confirmed by real-time polymerase chain reaction, which showed that the antioxidant enzymes SOD1 and SOD2 were not reduced in the presence of A2E alone, but significantly suppressed with the addition of 3MA. Furthermore, transmission electron micrography revealed autophagic vacuole formation in the presence of A2E, and inhibition of autophagy resulted in the accumulation of abnormal mitochondria with loss of cristae. Spheroid culture of human RPE cells demonstrated debris accumulation in the presence of A2E, and this accumulation was accelerated in the presence of 3MA. These results indicate that autophagy in RPE cells is a vital cytoprotective process that prevents the accumulation of damaged cellular molecules.
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Hisatomi T., Notomi S., Tachibana T., Sassa Y., Ikeda Y., Nakamura T., Ueno A., Enaida H., Murata T., Sakamoto T., Ishibashi T.
American Journal of Ophthalmology 158 ( 3 ) 2014.9
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Ophthalmology
Purpose To investigate long-term ultrastructural changes in the retina after internal limiting membrane (ILM) peeling through the examination of morphologic changes 3 years after vitrectomy in cynomolgus monkeys. Design Laboratory investigation. Methods Pars plana vitrectomy was performed, followed by ILM peeling, in 2 primate eyes. Ultrastructural changes were investigated using light microscopy and transmission and scanning electron microscopy 3 years after ILM peeling. Results The remaining posterior vitreous and ILM-peeled areas were clearly recognized after the long-term follow-up. The exposed Müller cell processes were partially damaged, while regenerative spindle-shaped Müller cell processes developed, covering most of the retina. Notably, the nerve fiber layer was found to be uncovered and exposed to the vitreous space owing to misdirection of glial wound healing in some parts. In these areas, glial wound healing occurred beneath the nerve fiber layer. Although the glial cells covered the damaged areas, there was no apparent ILM regeneration in the shape of a continuous flat sheet, with the exception of accumulated deposits of basement membrane materials. Conclusions Although the retinal structures were well preserved after ILM peeling, ILM peeling resulted in mild damage to the vitreoretinal interface, which was not completely restored even after 3 years. The multilinear shape of the exposed nerve fiber may explain the previously reported dissociated optic nerve fiber layer appearance. The glial cells produced basement membrane materials around their processes, although they did not restore the ILM as a flat sheet. © 2014 by Elsevier Inc. All rights reserved.
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Therapeutic efficacy of topical unoprostone isopropyl in retinitis pigmentosa Reviewed
Akiyama M., Ikeda Y., Yoshida N., Notomi S., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Acta Ophthalmologica 92 ( 3 ) 2014.5
Language：English Publishing type：Research paper (scientific journal) Publisher：Acta Ophthalmologica
Purpose To evaluate the therapeutic effect of topical unoprostone isopropyl (unoprostone) on patients with retinitis pigmentosa (RP). Methods Forty patients with typical forms of RP were included in the study. Seventeen of 40 patients were treated with 0.12% topical unoprostone twice daily in a randomly selected eye. Patients underwent follow-up examinations every 3 months after treatment. The efficacy of the treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 programme). Moreover, 12 RP patients who were included this study and 12 normal subjects were evaluated in terms of their macular blood flow of both eyes after instillation of unoprostone using the laser speckle method. Results One year after treatment, the 'macular sensitivity', calculated by HFA as the average sensitivity of the central 12 points, was preserved in the fellow eyes as well as the unoprostone-treated eyes. On the other hand, that in the eyes of the control RP patient was significantly decreased. Moreover, there were significantly greater improvements of the 'macular sensitivity' in the unoprostone-treated eyes than the fellow eyes. The change ratios of macular blood flow obtained from both RP patients and normal subjects were significantly increased in both the treated and the fellow eyes. No severe side-effects were observed. Conclusions These results demonstrate that topical unoprostone might have a therapeutic efficacy in patients with RP as a consequence of the macular blood flow improvement as well as its direct neuroprotective effect. © 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.
DOI： 10.1111/aos.12293
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Murakami Y., Matsumoto H., Roh M., Giani A., Kataoka K., Morizane Y., Kayama M., Thanos A., Nakatake S., Notomi S., Hisatomi T., Ikeda Y., Ishibashi T., Connor K., Miller J., Vavvas D.
Cell Death and Differentiation 21 ( 2 ) 270 - 277 2014.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Cell Death and Differentiation
There is no known treatment for the dry form of an age-related macular degeneration (AMD). Cell death and inflammation are important biological processes thought to have central role in AMD. Here we show that receptor-interacting protein (RIP) kinase mediates necrosis and enhances inflammation in a mouse model of retinal degeneration induced by dsRNA, a component of drusen in AMD. In contrast to photoreceptor-induced apoptosis, subretinal injection of the dsRNA analog poly(I: C) caused necrosis of the retinal pigment epithelium (RPE), as well as macrophage infiltration into the outer retinas. In Rip3-/-mice, both necrosis and inflammation were prevented, providing substantial protection against poly(I: C)-induced retinal degeneration. Moreover, after poly(I: C) injection, Rip3-/-mice displayed decreased levels of pro-inflammatory cytokines (such as TNF- and IL-6) in the retina, and attenuated intravitreal release of high-mobility group box-1 (HMGB1), a major damage-associated molecular pattern (DAMP). In vitro, poly(I: C)-induced necrosis were inhibited in Rip3-deficient RPE cells, which in turn suppressed HMGB1 release and dampened TNF- and IL-6 induction evoked by necrotic supernatants. On the other hand, Rip3 deficiency did not modulate directly TNF- and IL-6 production after poly(I: C) stimulation in RPE cells or macrophages. Therefore, programmed necrosis is crucial in dsRNA-induced retinal degeneration and may promote inflammation by regulating the release of intracellular DAMPs, suggesting novel therapeutic targets for diseases such as AMD. © 2014 Macmillan Publishers Limited.
DOI： 10.1038/cdd.2013.109
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Chromovitrectomy and vital dyes Reviewed
Enaida H., Hisatomi T., Nakao S., Ikeda Y., Yoshida S., Ishibashi T.
Developments in Ophthalmology 54 120 - 125 2014
Language：English Publishing type：Research paper (scientific journal) Publisher：Developments in Ophthalmology
© 2014 S. Karger AG, Basel. It is important to secure visibility during microsurgery. In vitreous surgery, staining and peeling of the internal limiting membrane with vital dyes, such as indocyanine green, have been widely performed since 2000, and surgical outcomes have improved in some vitreoretinal disorders such as macular holes and epiretinal membranes. It has been subsequently shown that triamcinolone acetonide is an adjuvant that is extremely effective for intraoperative vitreous visualization. In recent years, the term 'chromovitrectomy' has been used for performance of a vitrectomy using these surgical adjuvants for improved visibility. While there have been reports that an auxiliary chromovitrectomy with vital dyes is very effective, the question of retinal toxicity with use of these dyes remains. Therefore, a new safer vital dye, i.e. brilliant blue G, was developed and applied in clinical use. Chromovitrectomy using these adjuvants is an important technique that has low invasiveness and is very safe and very helpful in microincision vitrectomy surgery.
DOI： 10.1159/000360457
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Enaida H., Ikeda Y., Yoshida S., Nakao S., Hachisuka Y., Fujita K., Oshima Y., Kadonosono K., Matsui T., Ishibashi T.
Retina 33 ( 9 ) 1923 - 1930 2013.10
Language：English Publishing type：Research paper (scientific journal) Publisher：Retina
PURPOSE:: The study was conducted to develop a new viewing system as a clinical prototype that enables visibility during surgery. METHODS:: The system was composed of several filters attached to the microscope. This nonrandomized, retrospective, observational case series study involved 33 eyes from 32 patients who presented with various diseases and underwent surgery. The authors evaluated the changes in visualization focusing on controlling intraoperative visibility under air infusion and enhancing Brilliant Blue G staining focusing a sharp-cut filter Y (SCY). Visibility was compared under various surgical conditions, including cataract surgery, both with and without this system. Quantitative analysis of changes in intraoperative reflection including halation under air infusion and Brilliant Blue G intensity was carried out using the International Commission on Illumination 1976 (L*, a*, b*) color space method. RESULTS:: A SCY reduced the reflection and halation by a maximum of 69.6%, when compared with use of no filter under air infusion (P < 0.01). The color difference between Brilliant Blue G-stained and nonstained areas was improved by 127.8% relative to values with no filter and using SCY (P < 0.01) in macular hole cases. Furthermore, in cataract surgery with corneal opacity, improvement of visibility was observed by SCY insertion. CONCLUSION:: The system improved intraoperative visibility under air infusion and the Brilliant Blue G staining intensity by use of SCY during vitrectomy. © by Ophthalmic CommunicationSociety Inc.
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Ikeda Y., Yoshida N., Notomi S., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
British Journal of Ophthalmology 97 ( 9 ) 1187 - 1191 2013.9
Language：English Publishing type：Research paper (scientific journal) Publisher：British Journal of Ophthalmology
Aim: To evaluate the therapeutic effect of continuous treatment with topical dorzolamide (a carbonic anhydrase inhibitor) for cystoid macular oedema (CME) associated with retinitis pigmentosa (RP). Methods: 18 eyes in 10 patients with CME secondary to RP were included. Baseline visual acuity, visual field and optical coherence tomography (OCT) measurements were obtained for all patients. All patients used 1% dorzolamide three times daily in each affected eye. Patients underwent follow-up examinations at 1, 3, 6, 12 and 18 months after treatment. The response to treatment was monitored by the Humphrey field analyser (HFA: the central 10-2 program); in addition, foveal thickness was measured by OCT. Evaluation of 'macular sensitivity' was calculated by HFA as the average of 12 central points. Results: The 'macular sensitivity' in 10 eyes in which CME was almost completely resolved was significantly improved (p<0.05). In eight of the nine eyes in which CME was almost completely resolved within 6 months, the therapeutic efficacy persisted through 18 months. Five eyes which were almost completely resolved or showed an initial response within 6 months experienced recurrence of CME. Conclusions: The prolonged (longer than 1 year) use of topical dorzolamide is effective for the treatment of CME in patients with RP. Therefore, we propose topical dorzolamide treatment as a first choice.
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Enaida H., Ueno A., Nakao S., Ikeda Y., Yoshida S., Kumano Y., Ishibashi T.
Retina 33 ( 6 ) 1270 - 1272 2013.6
Language：English Publishing type：Research paper (scientific journal) Publisher：Retina
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Enaida H., Yoshida S., Nakao S., Ikeda Y., Hachisuka Y., Oshima Y., Kadonosono K., Ueno A., Ishibashi T.
Ophthalmologica 230 27 - 32 2013.4
Language：English Publishing type：Research paper (scientific journal) Publisher：Ophthalmologica
© 2013 S. Karger AG, Basel. Purpose: We developed a new artificial image enhancement system aimed at intraoperative visibility improvement as a clinical prototype. We examined each optical characteristic and change in intraoperative visibility using brilliant blue G (BBG) staining with various sharp cut filters (SCFs). Method: This was a retrospective and observational study. The system was composed of several filters attached to the operating microscope. Six eyes from 6 patients who presented with macular hole and underwent surgery using this system were studied. As a clinical examination, the intraoperative visibility of BBG staining intensities was compared for 4 kinds of SCFs during vitrectomy. Quantitative evaluation was calculated using the International Commission on Illumination 1976 (L∗, a∗, b∗) color space (CIELAB) method. Furthermore, we evaluated each optical characteristic of 4 types of SCFs using extracted porcine eyes and a spectroradiometer as a clinical simulation. Results: Suitable filter selection was possible for this system. The observed color tone and spectral irradiance changes with SCF insertion changed dynamically. In macular hole cases, the color intensities between BBG-stained and nonstained areas were improved using SCF-455 and SCF-520, which was statistically significant (p < 0.05) by CIELAB. Conclusion: The system improved BBG staining intensity with the use of selective SCFs.
DOI： 10.1159/000353868
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Enaida H., Hachisuka Y., Yoshinaga Y., Ikeda Y., Hisatomi T., Yoshida S., Oshima Y., Kadonosono K., Ishibashi T.
Graefe's Archive for Clinical and Experimental Ophthalmology 251 ( 2 ) 441 - 451 2013.2
Language：English Publishing type：Research paper (scientific journal) Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology
Purpose: We developed a new artificial image enhancement system and evaluated its usefulness in controlling intraoperative reflection and enhancing of Brilliant Blue G (BBG) staining. Methods: The system was composed of three kinds of filters (a polarizing filter, a blue-enhancing filter, and a sharp-cut filter Y) and attached to the inferior surface of the operating microscope. Twenty-seven post-mortem extracted porcine eyes were used for a series of examinations. We performed surgery using the 23G-vitrectomy system with a halogen light and xenon lights and compared the reduction of intraoperative reflection under air condition and visibility and BBG contrast with and without this system. The evaluation of images was calculated in CIE 1976 (L*, a*, b*) color space (CIELAB) carried out by ImageJ software. The transmission of each filter and absorbance of BBG was measured by a spectrophotometer. We measured spectral irradiance at each wavelength about each filter from each light source with a spectroradiometer. Results: Under both light sources, intraoperative reflection was controlled using a polarizing (PL) filter or combination of filters under air condition. Evaluation of the value of L*within the cutter surface was changed by 37.8 % under the halogen light, and 61.6 % (averaged) under the xenon light with inserted filters versus no filter. The BBG intensity difference was obtained with sharp-cut Y filter under both light source and PL with blue enhancing filter under the halogen light using each L*, a*, b*parameter with statistically significant (p < 0.01, 0.05). However, there was a relative decrease in the observation illuminance when the filter inserted according to the attenuation total spectral irradiance. Conclusions: This system can reduce intraoperative reflections under the air condition and obtain an excellent BBG staining intensity induced by various light sources. © 2012 Springer-Verlag.
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Notomi S., Hisatomi T., Murakami Y., Terasaki H., Sonoda S., Asato R., Takeda A., Ikeda Y., Enaida H., Sakamoto T., Ishibashi T.
PLoS ONE 8 ( 1 ) 2013.1
Language：English Publishing type：Research paper (scientific journal) Publisher：PLoS ONE
Photoreceptor degeneration is the most critical cause of visual impairment in age-related macular degeneration (AMD). In neovascular form of AMD, severe photoreceptor loss develops with subretinal hemorrhage due to choroidal neovascularization (CNV), growth of abnormal blood vessels from choroidal circulation. However, the detailed mechanisms of this process remain elusive. Here we demonstrate that neovascular AMD with subretinal hemorrhage accompanies a significant increase in extracellular ATP, and that extracellular ATP initiates neurodegenerative processes through specific ligation of Purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7; P2X7 receptor). Increased extracellular ATP levels were found in the vitreous samples of AMD patients with subretinal hemorrhage compared to control vitreous samples. Extravascular blood induced a massive release of ATP and photoreceptor cell apoptosis in co-culture with primary retinal cells. Photoreceptor cell apoptosis accompanied mitochondrial apoptotic pathways, namely activation of caspase-9 and translocation of apoptosis-inducing factor (AIF) from mitochondria to nuclei, as well as TUNEL-detectable DNA fragmentation. These hallmarks of photoreceptor cell apoptosis were prevented by brilliant blue G (BBG), a selective P2RX7 antagonist, which is an approved adjuvant in ocular surgery. Finally, in a mouse model of subretinal hemorrhage, photoreceptor cells degenerated through BBG-inhibitable apoptosis, suggesting that ligation of P2RX7 by extracellular ATP may accelerate photoreceptor cell apoptosis in AMD with subretinal hemorrhage. Our results indicate a novel mechanism that could involve neuronal cell death not only in AMD but also in hemorrhagic disorders in the CNS and encourage the potential application of BBG as a neuroprotective therapy. © 2013 Notomi et al.
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Clinical evidence of sustained chronic inflammatory reaction in retinitis pigmentosa Reviewed
Yoshida N., Ikeda Y., Notomi S., Ishikawa K., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Ophthalmology 120 ( 1 ) 100 - 105 2013.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Ophthalmology
Purpose: To study the nature of inflammatory reaction in eyes of patients with retinitis pigmentosa (RP) and its possible role in the pathogenesis of RP. Design: Retrospective, observational study. Participants and Controls: Three hundred seventy-one consecutive patients diagnosed with typical RP were included in this study. We included 165 patients without active inflammatory diseases, including 20 patients diagnosed with cataract, and 36 patients diagnosed with idiopathic epiretinal membrane as controls. Methods: Density of the inflammatory cells in the anterior vitreous cavity was measured and graded by slit-lamp biomicroscopy. A multiplex enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the concentration of cytokines and chemokines in aqueous humor and vitreous fluid of patients with RP and controls. In addition, we investigated the relationship between visual function and anterior vitreous cells in these patients. Main Outcome Measures: Slit-lamp biomicroscopic analysis, best-corrected visual acuity, visual field analysis, and multiplex ELISA. Results: In 190 of 509 eyes with RP (37.3%), "1+" (5-9 cells per field) or more cells were observed in the anterior vitreous cavity. Strong inflammatory reaction with "2+" cells (10-30 cells per field) was associated with younger age. In the elderly patients with RP, significantly decreased visual function was seen in a group with "1+" or more cells (P<0.05). Moreover, the levels of a variety of proinflammatory cytokines and chemokines, including monocyte chemotactic protein-1, were increased both in the aqueous humor and vitreous fluid of RP patients compared with the levels in control patients. Conclusions: Sustained chronic inflammatory reaction may underlie the pathogenesis of RP, suggesting interventions for ocular inflammatory reaction as a potential treatment for patients with RP. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2013 American Academy of Ophthalmology.
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Laboratory evidence of sustained chronic inflammatory reaction in retinitis pigmentosa Reviewed
Yoshida N., Ikeda Y., Notomi S., Ishikawa K., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Ophthalmology 120 ( 1 ) 2013.1
Language：English Publishing type：Research paper (scientific journal) Publisher：Ophthalmology
Purpose: To study the nature of retinal inflammatory response in rd10 mice, an animal model of retinitis pigmentosa (RP), and to investigate the effect of an antioxidant on retinal inflammation and photoreceptor apoptosis. Design: Experimental study. Participants and Controls: This study included 42 untreated rd10 mice, 30 N-acetylcysteine (NAC)-treated rd10 mice, and 20 C57BL/6 mice as controls. Methods: Real-time polymerase chain reaction (PCR) was performed to evaluate the expression levels of inflammatory factors (proinflammatory cytokines and chemokines) in rd10 mouse retinas. Rd10 mice were treated with an antioxidant NAC, and its effect on retinal inflammation and photoreceptor apoptosis were examined by immunohistochemistry. Main Outcome Measures: Real-time PCR and immunohistochemistry. Results: We demonstrated sequential events involving increased expression of proinflammatory cytokines and chemokines, activation of microglia, and photoreceptor apoptosis during retinal degeneration of rd10 mice. Furthermore, antioxidant treatment with NAC prevented the photoreceptor cell death along with suppression of inflammatory factors and microglial activation. Conclusions: Sustained chronic inflammatory reaction may contribute to the pathogenesis of retinal degeneration in rd10 mice, suggesting interventions for ocular inflammatory reaction using antioxidants as a potential treatment for patients with RP. Financial Disclosure(s): The authors have no proprietary or commercial interest in any of the materials discussed in this article. © 2013 American Academy of Ophthalmology.
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Murakami Y., Ikeda Y., Yoshida N., Notomi S., Hisatomi T., Oka S., De Luca G., Yonemitsu Y., Bignami M., Nakabeppu Y., Ishibashi T.
American Journal of Pathology 181 ( 4 ) 1378 - 1386 2012.10
Language：English Publishing type：Research paper (scientific journal) Publisher：American Journal of Pathology
Retinitis pigmentosa (RP) is a genetically heterogenous group of inherited retinal degenerative diseases resulting from photoreceptor cell death and affecting >1 million persons globally. Although oxidative stress has been implicated in the pathogenesis of RP, the mechanisms by which oxidative stress mediates photoreceptor cell death are largely unknown. Here, we show that oxidation of nucleic acids is a key component in the initiation of death-signaling pathways in rd10 mice, a model of RP. Accumulation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) increased in photoreceptor cells, and especially within their nuclei, in rd10 mice as well as in Royal College of Surgeons rats, another model of RP caused by different genetic mutations. Vitreous samples from humans with RP contained higher levels of 8-oxo-dG excreted than samples from nondegenerative controls. Transgenic overexpression of human MutT homolog-1, which hydrolyzes oxidized purine nucleoside triphosphates in the nucleotide pool, significantly attenuated 8-oxo-dG accumulation in nuclear DNA and photoreceptor cell death in rd10 mice, in addition to suppressing DNA single-strand break formation, poly(ADP-ribose) polymerase activation, and nuclear translocation of apoptosis-inducing factor. These findings indicate that oxidative DNA damage is an important process for the triggering of photoreceptor cell death in rd10 mice and suggest that stimulation of DNA repair enzymes may be a novel therapeutic approach to attenuate photoreceptor cell loss in RP. © 2012 American Society for Investigative Pathology.