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Polydopamine nanoparticles attenuate retina ganglion cell degeneration and restore visual function after optic nerve injury. J Nanobiotechnology 2021; 19:436. [PMID: 34930292 PMCID: PMC8686547 DOI: 10.1186/s12951-021-01199-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 12/09/2021] [Indexed: 12/12/2022] Open
Abstract
Background Oxidative stress contributes to retina ganglion cells (RGCs) loss in variety of ocular diseases, including ocular trauma, ocular vein occlusion, and glaucoma. Scavenging the excessed reactive oxygen species (ROS) in retinal neurovascular unit could be beneficial to RGCs survival. In this study, a polydopamine (PDA)-based nanoplatform is developed to protect RGCs. Results The PDA nanoparticles efficiently eliminate multi-types of ROS, protect endothelia and neuronal cells from oxidative damage, and inhibit microglia activation in retinas. In an optic nerve crush (ONC) model, single intravitreal injection of PDA nanoparticles could significantly attenuate RGCs loss via eliminating ROS in retinas, reducing the inflammatory response and maintaining barrier function of retinal vascular endothelia. Comparative transcriptome analysis of the retina implied that PDA nanoparticles improve RGCs survival probably by altering the expression of genes involved in inflammation and ROS production. Importantly, as a versatile drug carrier, PDA nanoparticles could deliver brimonidine (a neuroprotection drug) to synergistically attenuate RGCs loss and promote axon regeneration, thus restore visual function. Conclusions The PDA nanoparticle-based therapeutic nanoplatform displayed excellent performance in ROS elimination, providing a promising probability for treating retinal degeneration diseases. Graphical Abstract ![]()
Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-01199-3.
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Chen T, Ma J, Shan G, Zhong Y. The polymorphisms of ATOH 7, ET-1 and ACE in non-arteritic anterior ischemic optic neuropathy. Exp Eye Res 2018; 174:147-151. [PMID: 29792847 DOI: 10.1016/j.exer.2018.05.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/02/2018] [Accepted: 05/20/2018] [Indexed: 12/14/2022]
Abstract
Non-arteritic anterior ischemic optic neuropathy (NAION) is a common cause of acute optic neuropathy in the elderly. The role of the genetic polymorphisms of Atonal Homolog 7 (ATOH7), Endothelin-1 (ET-1) and Angiotensin Converting Enzyme (ACE) in NAION and the combined effects of the gene-gene and gene-medical comorbidities on NAION were not clear. We conducted a perspective, case-control study. 71 NAION patients and 142 age and sex-matched healthy controls were enrolled. Single nucleotide polymorphisms of ATOH7 (rs1900004), ET-1 (rs5370) and ACE (rs1799752) were identified by polymerase chain reaction (PCR) method and all PCR products were screened with Sanger sequencing. The prevalence of genetic factors in NAION patients were compared to normal people, and assessed in conditional logistic regression models. The modified effects of gene-gene or gene-medical comorbidities on NAION development were assessed with a multiplicative model. A significant high risk was found in the T allele of ATOH7 in NAION, with an odds ratio (OR) of 1.55 (P = 0.04). Conditional logistic regression analysis, including diabetes and hypertension, revealed that ATOH7 TT genotype carriers conferred a significantly increased risk of NAION (TT/CC + CT, OR = 3.32, 95% confidence interval (CI) = 1.16-9.53, P = 0.03). Interaction analysis showed that ET-1 (P = 0.01), ACE (P = 0.046) and hypertension (P = 0.02) have modified effects on NAION development. Our results showed that the polymorphism of optic disc associated gene-ATOH7 conferred a significant risk of NAION. Combination of ATOH7 and ET-1, ATOH7 and ACE, as well as ATOH7 and hypertension, increased the susceptibility of NAION. Our data may be useful for NAION predicting.
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Affiliation(s)
- Ting Chen
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China; Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jin Ma
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Guangliang Shan
- Department of Epidemiology and Statistics, Institute of Basic Medical Science, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yong Zhong
- Department of Ophthalmology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
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Ramírez C, Cáceres-del-Carpio J, Chu J, Chu J, Moustafa MT, Chwa M, Limb GA, Kuppermann BD, Kenney MC. Brimonidine Can Prevent In Vitro Hydroquinone Damage on Retinal Pigment Epithelium Cells and Retinal Müller Cells. J Ocul Pharmacol Ther 2015; 32:102-8. [PMID: 26624556 DOI: 10.1089/jop.2015.0083] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
PURPOSE Brimonidine is a selective alpha-2 adrenergic agonist used to reduce intraocular pressure and it has been shown to have some neuroprotective effects. Hydroquinone (HQ) is a toxicant present in cigarette smoke, and other sources. In this study, we investigated the cyto-protective effects in vitro of Brimonidine on human retinal pigment epithelium cells (ARPE-19) and human retinal Müller cells (MIO-M1) that had been treated with HQ. METHODS Cells were pretreated for 6 h with different doses of Brimonidine tartrate 0.1% (1/2×, 1×, 5×, 10×), followed by a 24-h exposure to 100 μM of HQ, while the Brimonidine was still present. Assays were used to measure cell viability, mitochondrial membrane potential (ΔΨm), reactive oxygen species (ROS) production, and lactate dehydrogenase (LDH) release. RESULTS Brimonidine increased the cell viability at all concentrations studied in both cell lines studied. ΔΨm also improved at all Brimonidine doses in ARPE-19 cells and in the 5× and 10× dosages MIO-M1 cells. The ROS levels decreased at 1×, 5×, and 10× doses of Brimonidine in ARPE-19 but only at 10× on MIO-M1 cells. The 10×-Brimonidine ARPE-19 cells had decreased LDH release, but no LDH changes were observed on MIO-M1 cells. CONCLUSION HQ-induced toxicity is mediated through mitochondrial damaging, oxidative stress-related and necrosis-related pathways; Brimonidine significantly prevented the mitochondrial damaging and oxidative stress-related effects but had little effect on blocking the necrosis component of HQ-toxicity. Brimonidine protective effects differ between the different retinal cell types and high concentrations of Brimonidine (10×) have minimal damaging effects on human retinal cells.
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Affiliation(s)
- Claudio Ramírez
- 1 Gavin Herbert Eye Institute, University of California , Irvine, Irvine, California
| | | | - Justin Chu
- 1 Gavin Herbert Eye Institute, University of California , Irvine, Irvine, California
| | - Joshua Chu
- 1 Gavin Herbert Eye Institute, University of California , Irvine, Irvine, California
| | - M Tarek Moustafa
- 1 Gavin Herbert Eye Institute, University of California , Irvine, Irvine, California.,2 Ophthalmology Department, Minia University , Minia, Egypt
| | - Marilyn Chwa
- 1 Gavin Herbert Eye Institute, University of California , Irvine, Irvine, California
| | - G Astrid Limb
- 3 Division of Ocular Biology and Therapeutics, UCL Institute of Ophthalmology , London, United Kingdom
| | - Baruch D Kuppermann
- 1 Gavin Herbert Eye Institute, University of California , Irvine, Irvine, California
| | - M Cristina Kenney
- 1 Gavin Herbert Eye Institute, University of California , Irvine, Irvine, California.,4 Department of Pathology and Laboratory Medicine, University of California Irvine , Irvine, California
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Chao HM, Chuang MJ, Liu JH, Liu XQ, Ho LK, Pan WHT, Zhang XM, Liu CM, Tsai SK, Kong CW, Lee SD, Chen MM, Chao FP. Baicalein protects against retinal ischemia by antioxidation, antiapoptosis, downregulation of HIF-1α, VEGF, and MMP-9 and upregulation of HO-1. J Ocul Pharmacol Ther 2013; 29:539-49. [PMID: 23537149 DOI: 10.1089/jop.2012.0179] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
PURPOSE Retinal ischemia-associated ocular disorders are vision threatening. This study examined whether the flavonoid baicalein is able to protect against retinal ischemia/reperfusion. METHODS Using rats, the intraocular pressure was raised to 120 mmHg for 60 min to induce retinal ischemia. In vitro, an ischemic-like insult, namely oxidative stress, was established by incubating dissociated retinal cells with 100 μM ascorbate and 5 μM FeSO4 (iron) for 1 h. The rats or the dissociated cells had been pretreated with baicalein (in vivo: 0.05 or 0.5 nmol; in vitro: 100 μM), vehicle (1% ethanol), or trolox (in vivo: 5 nmol; in vitro: 100 μM or 1 mM). The effects of these treatments on the retina or the retinal cells were evaluated by electrophysiology, immunohistochemistry, terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) staining, Western blotting, or in vitro dichlorofluorescein assay. In addition, real-time-polymerase chain reaction was used to assess the retinal expression of hypoxia-inducible factor-1α (HIF-1α), matrix metalloproteinase-9 (MMP-9), vascular endothelium growth factor (VEGF), and heme oxygenase-1 (HO-1). RESULTS The retinal changes after ischemia included a decrease in the electroretinogram b-wave amplitude, a loss of choline acetyltransferase immunolabeling amacrine cell bodies/neuronal processes, an increase in vimentin immunoreactivity, which is a marker for Müller cells, an increase in apoptotic cells in the retinal ganglion cell layer linked to a decrease in the Bcl-2 protein, and changes in the mRNA levels of HIF-1α, VEGF, MMP-9, and HO-1. Of clinical importance, the ischemic detrimental effects were concentration dependently and/or significantly (0.05 nmol and/or 0.5 nmol) altered when baicalein was applied 15 min before retinal ischemia. Most of all, 0.5 nmol baicalein significantly reduced the upregulation of MMP-9; in contrast, 5 nmol trolox only had a weak attenuating effect. In dissociated retinal cells subjected to ascorbate/iron, there was an increase in the levels of reactive oxygen species, which had been significantly attenuated by 100 μM baicalein and trolox (100 μM or 1 mM; a stronger antioxidative effect at 1 mM). CONCLUSIONS Baicalein would seem to protect against retinal ischemia via antioxidation, antiapoptosis, upregulation of HO-1, and downregulation of HIF-1α, VEGF, and MMP-9. The antioxidative effect of baicalein would appear to play a minor role in downregulation of MMP-9.
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Affiliation(s)
- Hsiao-Ming Chao
- Department of Ophthalmology, Cheng Hsin General Hospital, Taipei, Taiwan, Republic of China.
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Munemasa Y, Kitaoka Y. Molecular mechanisms of retinal ganglion cell degeneration in glaucoma and future prospects for cell body and axonal protection. Front Cell Neurosci 2013; 6:60. [PMID: 23316132 PMCID: PMC3540394 DOI: 10.3389/fncel.2012.00060] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Accepted: 12/06/2012] [Indexed: 12/20/2022] Open
Abstract
Glaucoma, which affects more than 70 million people worldwide, is a heterogeneous group of disorders with a resultant common denominator; optic neuropathy, eventually leading to irreversible blindness. The clinical manifestations of primary open-angle glaucoma (POAG), the most common subtype of glaucoma, include excavation of the optic disc and progressive loss of visual field. Axonal degeneration of retinal ganglion cells (RGCs) and apoptotic death of their cell bodies are observed in glaucoma, in which the reduction of intraocular pressure (IOP) is known to slow progression of the disease. A pattern of localized retinal nerve fiber layer (RNFL) defects in glaucoma patients indicates that axonal degeneration may precede RGC body death in this condition. The mechanisms of degeneration of neuronal cell bodies and their axons may differ. In this review, we addressed the molecular mechanisms of cell body death and axonal degeneration in glaucoma and proposed axonal protection in addition to cell body protection. The concept of axonal protection may become a new therapeutic strategy to prevent further axonal degeneration or revive dying axons in patients with preperimetric glaucoma. Further study will be needed to clarify whether the combination therapy of axonal protection and cell body protection will have greater protective effects in early or progressive glaucomatous optic neuropathy (GON).
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Affiliation(s)
- Yasunari Munemasa
- Department of Ophthalmology, St. Marianna University School of Medicine Kawasaki, Kanagawa, Japan
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Deokule SP, Baffi JZ, Guo H, Nazzaro M, Kaneko H. Evaluation of extended release brimonidine intravitreal device in normotensive rabbit eyes. Acta Ophthalmol 2012; 90:e344-8. [PMID: 22676067 DOI: 10.1111/j.1755-3768.2012.02418.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
PURPOSE To evaluate the safety profile of a brimonidine extended release intravitreal implant, in normotensive rabbit eyes. METHODS Devices were made from hollow poly-l-lactic acid (PLA) tubes and contained hundred micrograms of brimonidine pamoate. Device was injected intravitreally in one eye of 12 New Zealand pigmented rabbits, whereas other eye was injected with a sham implant in masked fashion. Ocular examination was conducted at baseline and months 1, 3 and 6 including dilated fundus examination and electro-retinogram (ERG). Four rabbits were sacrificed at each time-point for retinal histology. ERG data were compared between groups and time-points using anova. RESULTS No complications were reported from either eye of any rabbits over a 6-month period. Photopic A wave was reduced in the control eye at 1 month compared with baseline (p < 0.01). There was no significant difference in other ERG parameters between the groups at different time-points. Gross retinal histology was normal at all time-points. CONCLUSION Extended release intravitreal brimonidine device was found to be safe and in normotensive rabbit eyes.
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Affiliation(s)
- Sunil P Deokule
- Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
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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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Chen YQ, Pan WHT, Liu JH, Chen MM, Liu CM, Yeh MY, Tsai SK, Young MS, Zhang XM, Chao HM. The effects and underlying mechanisms of S-allyl l-cysteine treatment of the retina after ischemia/reperfusion. J Ocul Pharmacol Ther 2011; 28:110-7. [PMID: 22054242 DOI: 10.1089/jop.2011.0099] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE Retinal ischemia-associated ocular disorders are vision-threatening. The aim of the present study was to examine whether S-allyl l-cysteine (SAC) is able to protect against retina ischemia/reperfusion injury. METHODS In vivo, retinal ischemia in the rat was induced by raising intraocular pressure (IOP) to 120 mmHg for 60 min. In vitro, an ischemic-like insult, namely oxidative stress, was established by incubating retinal ganglion cell-5 (RGC-5) with 500 μM H(2)O(2) for 24 h. The mechanisms involved in these processes were evaluated by electrophysiology, immunohistochemistry, and molecular biological approaches. RESULTS The retinal changes caused by the high IOP were characterized by a decrease in electroretinogram b-wave amplitudes, a loss of choline acetyltransferase immunolabeling amacrine cell bodies/neuronal processes, and an upregulation of the mRNA levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelium growth factor (VEGF), and matrix metalloproteinase-9 (MMP-9). The increased protein levels of HIF-1α, VEGF, and MMP-9 were also seen in RGC-5 cells subjected to defined oxidative stress. Of clinical importance, the ischemic/ischemic-like detrimental effects were concentration-dependently (least effect at 25 μM) and/or significantly (50 and/or 100 μM) blunted when SAC was applied 15 min before retinal ischemia or ischemic-like insult, respectively. CONCLUSION SAC would seem to protect against retinal ischemia by acting as an antioxidant and inhibiting the upregulation of HIF-1α, VEGF, and MMP-9.
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Affiliation(s)
- Yan-Qing Chen
- Department of Pharmacology, School of Medicine, Shandong University, Jinan, Shandong, People's Republic of China
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