論文 - 池田 康博
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Therapeutic efficacy of topical unoprostone isopropyl in retinitis pigmentosa 査読あり
Akiyama M., Ikeda Y., Yoshida N., Notomi S., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Acta Ophthalmologica 92 ( 3 ) 2014年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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 査読あり
Enaida H., Hisatomi T., Nakao S., Ikeda Y., Yoshida S., Ishibashi T.
Developments in Ophthalmology 54 120 - 125 2014年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年6月
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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年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年2月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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 査読あり
Yoshida N., Ikeda Y., Notomi S., Ishikawa K., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Ophthalmology 120 ( 1 ) 100 - 105 2013年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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 査読あり
Yoshida N., Ikeda Y., Notomi S., Ishikawa K., Murakami Y., Hisatomi T., Enaida H., Ishibashi T.
Ophthalmology 120 ( 1 ) 2013年1月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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.
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Murakami Y., Matsumoto H., Roh M., Suzuki J., Hisatomi T., Ikeda Y., Miller J., Vavvas D.
Proceedings of the National Academy of Sciences of the United States of America 109 ( 36 ) 14598 - 14603 2012年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America
Retinitis pigmentosa comprises a group of inherited retinal photoreceptor degenerations that lead to progressive loss of vision. Although in most cases rods, but not cones, harbor the deleterious gene mutations, cones do die in this disease, usually after the main phase of rod cell loss. Rod photoreceptor death is characterized by apoptotic features. In contrast, the mechanisms and features of subsequent nonautonomous cone cell death remain largely unknown. In this study, we show that receptor-interacting protein (RIP) kinase mediates necrotic cone cell death in rd10 mice, a mousemodel of retinitis pigmentosa caused by a mutation in a rod-specific gene. The expression of RIP3, a key regulator of programmed necrosis, was elevated in rd10 mouse retinas in the phase of cone but not rod degeneration. Although rd10 mice lacking Rip3 developed comparable rod degeneration to control rd10 mice, they displayed a significant preservation of cone cells. Ultrastructural analysis of rd10 mouse retinas revealed that a substantial fraction of dying cones exhibited necrotic morphology, which was rescued by Rip3 deficiency. Additionally, pharmacologic treatment with a RIP kinase inhibitor attenuated histological and functional deficits of cones in rd10 mice. Thus, necrotic mechanisms involving RIP kinase are crucial in cone cell death in inherited retinal degeneration, suggesting the RIP kinase pathway as a potential target to protect cone-mediated central and peripheral vision loss in patients with retinitis pigementosa.
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Ikeda Y., Hisatomi T., Yoshida N., Notomi S., Murakami Y., Enaida H., Ishibashi T.
Graefe's Archive for Clinical and Experimental Ophthalmology 250 ( 6 ) 809 - 814 2012年6月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
Background: Cystoid macular edema (CME) is one of the common complications of retinitis pigmentosa (RP), and is responsible for patient complications such as blurred and reduced visual acuity and for subsequent atrophic changes in the fovea. The objective of this work was to evaluate the clinical efficacy of a topical dorzolamide (a carbonic anhydrase inhibitor) in CME associated with RP. Methods: Sixteen eyes of nine patients with CME secondary to typical forms of RP were included in the study. 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 eye. Patients underwent follow-up exams at 1, 3, and 6 months after treatment. The response to treatment was monitored by visual acuity and visual field measurement testing using the Humphrey Field Analyzer (HFA: the central 10-2 Program); in addition, foveal thickness was measured by OCT. Evaluation of macular sensitivity calculated by HFA as the average of 12 central points. Results: Thirteen (81.3%) of 16 eyes showed a clear decrease in retinal thickness after treatment. Evaluation of macular sensitivity, calculated by HFA as the average of 12 central points (with the exception of foveal point data, showed an improvement of more than 1.0 dB in nine (56.3%) of 16 eyes. Moreover, both the mean deviation value and macular sensitivity were significantly improved. No severe side-effects were seen in any of the patients examined. Conclusions: The results demonstrated that a topical dorzolamide is effective for the treatment of CME in patients with RP, and that the positive treatment effects last for up to 6 months. © Springer-Verlag 2011.
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The role of mislocalized phototransduction in photoreceptor cell death of retinitis pigmentosa 査読あり
Nakao T., Tsujikawa M., Notomi S., Ikeda Y., Nishida K.
PLoS ONE 7 ( 4 ) 2012年4月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：PLoS ONE
Most of inherited retinal diseases such as retinitis pigmentosa (RP) cause photoreceptor cell death resulting in blindness. RP is a large family of diseases in which the photoreceptor cell death can be caused by a number of pathways. Among them, light exposure has been reported to induce photoreceptor cell death. However, the detailed mechanism by which photoreceptor cell death is caused by light exposure is unclear. In this study, we have shown that even a mild light exposure can induce ectopic phototransduction and result in the acceleration of rod photoreceptor cell death in some vertebrate models. In ovl, a zebrafish model of outer segment deficiency, photoreceptor cell death is associated with light exposure. The ovl larvae show ectopic accumulation of rhodopsin and knockdown of ectopic rhodopsin and transducin rescue rod photoreceptor cell death. However, knockdown of phosphodiesterase, the enzyme that mediates the next step of phototransduction, does not. So, ectopic phototransduction activated by light exposure, which leads to rod photoreceptor cell death, is through the action of transducin. Furthermore, we have demonstrated that forced activation of adenylyl cyclase in the inner segment leads to rod photoreceptor cell death. For further confirmation, we have also generated a transgenic fish which possesses a human rhodopsin mutation, Q344X. This fish and rd10 model mice show photoreceptor cell death caused by adenylyl cyclase. In short, our study indicates that in some RP, adenylyl cyclase is involved in photoreceptor cell death pathway; its inhibition is potentially a logical approach for a novel RP therapy. © 2012 Nakao et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Notomi S., Hisatomi T., Kanemaru T., Takeda A., Ikeda Y., Enaida H., Kroemer G., Ishibashi T.
American Journal of Pathology 179 ( 6 ) 2798 - 2809 2011年12月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Pathology
Stressed cells release ATP, which participates in neurodegenerative processes through the specific ligation of P2RX7 purinergic receptors. Here, we demonstrate that extracellular ATP and the more specific P2RX7 agonist, 2′- and 3′-O-(4-benzoylbenzoyl)-ATP, both induce photoreceptor cell death when added to primary retinal cell cultures or when injected into the eyes from wild-type mice, but not into the eyes from P2RX7 -/- mice. Photoreceptor cell death was accompanied by the activation of caspase-8 and -9, translocation of apoptosis-inducing factor from mitochondria to nuclei, and TUNEL-detectable chromatin fragmentation. All hallmarks of photoreceptor apoptosis were prevented by premedication or co-application of Brilliant Blue G, a selective P2RX7 antagonist that is already approved for the staining of internal limiting membranes during ocular surgery. ATP release is up-regulated by nutrient starvation in primary retinal cell cultures and seems to be an initializing event that triggers primary and/or secondary cell death via the positive feedback loop on P2RX7. Our results encourage the potential application of Brilliant Blue G as a novel neuroprotective agent in retinal diseases or similar neurodegenerative pathologies linked to excessive extracellular ATP. © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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Yoshida N., Hisatomi T., Ikeda Y., Kohno R., Murakami Y., Imaki H., Ueno A., Fujisawa K., Ishibashi T.
Graefe's Archive for Clinical and Experimental Ophthalmology 249 ( 10 ) 1547 - 1552 2011年10月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Graefe's Archive for Clinical and Experimental Ophthalmology
Background: Neovascular glaucoma (NVG) is a serious complication for patients with proliferative diabetic retinopathy (PDR). Bevacizumab is a full-length humanized monoclonal antibody that binds all isoforms of vascular endothelial growth factor (VEGF). Recently, encouraging results regarding the off-label use of intravitreal bevacizumab (IVB) for the treatment of NVG have been reported. We evaluated the histology of bevacizumab-treated trabeculectomy specimens to clarify IVB's biological effects on angle neovascularization. Methods: We retrospectively reviewed the charts of a consecutive series of 15 eyes of 13 patients who underwent trabeculectomy to treat NVG caused by PDR. In ten eyes of eight patients, 1.25 mg bevacizumab was injected intravitreally via the pars plana. Using light or electron microscopy, the surgically excised trabecular tissue was compared to that without IVB. Results: Light microscopy revealed decreased edema, fibrin deposition, inflammation and vascular congestion in the trabecular meshwork in specimens with IVB compared to those without IVB. Electron microscopy revealed endothelial cell degeneration in the bevacizumab-treated specimens. Conclusions: The biological effects on angle neovascularization after IVB may involve reduced vascular permeability, decreased inflammatory reaction, loss of vascular function, and endothelial cell degeneration. © 2011 Springer-Verlag.
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Miyazaki M., Ikeda Y., Yonemitsu Y., Goto Y., Murakami Y., Yoshida N., Tabata T., Hasegawa M., Tobimatsu S., Sueishi K., Ishibashi T.
Human Gene Therapy 22 ( 5 ) 559 - 565 2011年5月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Human Gene Therapy
Lentiviral vectors are promising tools for the treatment of chronic retinal diseases including glaucoma, as they enable stable transgene expression. We examined whether simian immunodeficiency virus (SIV)-based lentiviral vector-mediated retinal gene transfer of human pigment epithelium-derived factor (hPEDF) can rescue rat retinal ganglion cell injury. Gene transfer was achieved through subretinal injection of an SIV vector expressing human PEDF (SIV-hPEDF) into the eyes of 4-week-old Wistar rats. Two weeks after gene transfer, retinal ganglion cells were damaged by transient ocular hypertension stress (110mmHg, 60min) and N-methyl-d-aspartic acid (NMDA) intravitreal injection. One week after damage, retrograde labeling with 4′,6-diamidino-2-phenylindole (DAPI) was done to count the retinal ganglion cells that survived, and eyes were enucleated and processed for morphometric analysis. Electroretinographic (ERG) assessment was also done. The density of DAPI-positive retinal ganglion cells in retinal flat-mounts was significantly higher in SIV-hPEDF-treated rats compared with control groups, in both transient ocular hypertension and NMDA-induced models. Pattern ERG examination demonstrated higher amplitude in SIV-hPEDF-treated rats, indicating the functional rescue of retinal ganglion cells. These findings show that neuroprotective gene therapy using hPEDF can protect against retinal ganglion cell death, and support the potential feasibility of neuroprotective therapy for intractable glaucoma. © 2011 Mary Ann Liebert, Inc.
DOI： 10.1089/hum.2010.132
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Retinitis pigmentosa associated with asteroid hyalosis 査読あり
Ikeda Y., Hisatomi T., Murakami Y., Miyazaki M., Kohno R., Takahashi H., Hata Y., Ishibashi T.
Retina 30 ( 8 ) 1278 - 1281 2010年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：Retina
Background: Asteroid hyalosis (AH) is a condition in which cream-colored or white spherical particles are suspended in the vitreous body. Asteroid hyalosis is considered not to cause decreased vision or any other visual symptoms except in rare cases. There have been a few reports of AH in patients with retinitis pigmentosa (RP). Methods: To assess the prevalence of AH in patients with RP, 320 patients with typical forms of RP were studied. One patient was offered a standard three-port vitrectomy, and the spherical particles obtained from her vitrectomy sample were analyzed using an energy-dispersive x-ray spectrometer. Results: Ten patients (two men and eight women) developed AH. Among them, four had bilateral AH and two had rapidly increasing vitreous opacity that led to decreased vision. One patient was a 48-year-old woman with progressive AH in the left eye. After treatment with a vitrectomy, her vision improved from 0.4 to 0.8. The spherical particles were composed of mainly calcium and phosphorus. Conclusion: The prevalence of AH in RP was higher than in previous reports, and we encountered two rare cases of progressive AH with decreased vision. We conclude that AH might lead to decreased vision in patients with RP. Copyright © by Ophthalmic Communications Society, Inc.
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Kohno R., Hata Y., Mochizuki Y., Arita R., Kawahara S., Kita T., Miyazaki M., Hisatomi T., Ikeda Y., Aiello L., Ishibashi T.
American Journal of Ophthalmology 150 ( 2 ) 223 - 229.e1 2010年8月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：American Journal of Ophthalmology
Purpose: To examine the histopathologic effect of a single intravitreal injection of bevacizumab on newly formed vessels in eyes with proliferative diabetic retinopathy (PDR). Design: Interventional case series and laboratory investigation. Methods: Two days after intravitreal injection of bevacizumab (1.25 mg/eye), pars plana vitrectomy or trabeculectomy was performed for the treatment of PDR or neovascular glaucoma (NVG) associated with PDR. Ten surgically removed preretinal proliferative tissues and 6 deep scleral flaps containing trabecular meshwork were fixed in 2% glutaraldehyde or 4% paraformaldehyde and were subjected to transmission electron microscopic analysis, immunohistochemical analysis, and terminal deoxyuridiine triphosphate (dUTP) nick-end labeling staining. Two surgically removed preretinal proliferative tissues and 2 deep scleral flaps from patients with PDR and NVG, but without preoperative intravitreal injection of bevacizumab (IVB), served as controls. Results: In control tissues, vascular endothelial cells possessed many fenestrations and were accompanied by pericytes. Apoptotic vascular endothelial cells frequently were observed in tissue after intravitreal injection of bevacizumab, whereas they were not observed in control tissues. Additionally, no apparent fenestration was observed in newly formed vessels from either proliferative tissue or trabecular meshwork after intravitreal injection of bevacizumab. In both PDR and NVG tissues after intravitreal injection of bevacizumab, overexpression of smooth muscle actin was observed in newly formed vessels, suggesting that the treatment may have increased pericytes on the vasculature as compared with control tissue. Conclusions: Intravitreal injection of bevacizumab may induce changes in immature, newly formed vessels of PDR or NVG tissue, leading to endothelial apoptosis with vascular regression, while inducing normalization of premature vessels by increasing pericyte coverage and reducing vessel fenestration. © 2010 Elsevier Inc. All Rights Reserved.