RESUMO
Fuchs endothelial corneal dystrophy is a heterogenous disease with multifactorial etiology, and genetic, epigenetic, and exogenous factors contributing to its pathogenesis. DNA damage plays a significant role, with ultraviolet-A (UV-A) emerging as a key contributing factor. We investigate the potential application of neuropeptide α-melanocyte stimulating hormone (α-MSH) in mitigating oxidative stress induced endothelial damage. First, we examined the effects of α-MSH on a cultured human corneal endothelial cell line (HCEnC-21T) exposed to hydrogen peroxide (H2O2) induced oxidative DNA damage. We performed immunofluorescence and flow cytometry to assess DNA damage and cell death in the cultured cells. Additionally, we used an established mouse model that utilizes ultraviolet light to induce corneal endothelial cell damage resulting in decreased CEnC number, increased cell size variability, and decreased percentage of hexagonal cells. This endothelial decompensation leads to an increase in corneal thickness. Following UV-A exposure, the mice were systemically treated with α-MSH, either immediately after exposure (early treatment) or beginning two weeks post-exposure (delayed treatment). To evaluate treatment efficacy, we analyzed CEnC density and morphology using in vivo confocal microscopy, and central corneal thickness using anterior segment optical coherence tomography. Our findings demonstrated that α-MSH treatment effectively protects HCEnC-21T from free-radical induced oxidative DNA damage and subsequent cell death. In vivo, α-MSH treatment, mitigated the loss of CEnC density, deterioration of cell morphology and suppression of the resultant corneal swelling. These results underline the potential application of α-MSH as a therapeutic agent for mitigating corneal endothelial damage.
Assuntos
Dano ao DNA , Modelos Animais de Doenças , Endotélio Corneano , Distrofia Endotelial de Fuchs , Estresse Oxidativo , alfa-MSH , Animais , alfa-MSH/farmacologia , Camundongos , Endotélio Corneano/efeitos dos fármacos , Endotélio Corneano/patologia , Humanos , Distrofia Endotelial de Fuchs/patologia , Distrofia Endotelial de Fuchs/tratamento farmacológico , Dano ao DNA/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Raios Ultravioleta/efeitos adversos , Linhagem Celular , Peróxido de Hidrogênio/farmacologiaRESUMO
Descemet's Stripping Only (DSO) is a surgical technique that utilizes the peripheral corneal endothelial cell (CEnC) migration for wound closure. Ripasudil, a Rho-associated protein kinase (ROCK) inhibitor, has shown potential in DSO treatment; however, its mechanism in promoting CEnC migration remains unclear. We observed that ripasudil-treated immortalized normal and Fuchs endothelial corneal dystrophy (FECD) cells exhibited significantly enhanced migration and wound healing, particularly effective in FECD cells. Ripasudil upregulated mRNA expression of Snail Family Transcriptional Repressor (SNAI1/2) and Vimentin (VIM) while decreasing Cadherin (CDH1), indicating endothelial-to-mesenchymal transition (EMT) activation. Ripasudil activated Rac1, driving the actin-related protein complex (ARPC2) to the leading edge, facilitating enhanced migration. Ex vivo studies on cadaveric and FECD Descemet's membrane (DM) showed increased migration and proliferation of CEnCs after ripasudil treatment. An ex vivo DSO model demonstrated enhanced migration from the DM to the stroma with ripasudil. Coating small incision lenticule extraction (SMILE) tissues with an FNC coating mix and treating the cells in conjunction with ripasudil further improved migration and resulted in a monolayer formation, as detected by the ZO-1 junctional marker, thereby leading to the reduction in EMT. In conclusion, ripasudil effectively enhanced cellular migration, particularly in a novel ex vivo DSO model, when the stromal microenvironment was modulated. This suggests ripasudil as a promising adjuvant for DSO treatment, highlighting its potential clinical significance.
Assuntos
Movimento Celular , Distrofia Endotelial de Fuchs , Quinases Associadas a rho , Humanos , Quinases Associadas a rho/metabolismo , Quinases Associadas a rho/antagonistas & inibidores , Movimento Celular/efeitos dos fármacos , Distrofia Endotelial de Fuchs/patologia , Distrofia Endotelial de Fuchs/tratamento farmacológico , Isoquinolinas/farmacologia , Sulfonamidas/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Corneano/efeitos dos fármacos , Endotélio Corneano/metabolismo , Endotélio Corneano/patologia , Lâmina Limitante Posterior/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Proliferação de Células/efeitos dos fármacos , Modelos Biológicos , Cicatrização/efeitos dos fármacosRESUMO
PURPOSE: This exhaustive review of published literature aims to put forth the current understanding, and experiences of the role Rho-kinase inhibitors play in the management of corneal endothelial disorders. METHODS: A meticulous search for PubMed and Medline databases was carried out using keywords 'rho-kinase inhibitors', 'corneal endothelial disorders', 'rho-kinase inhibitors in corneal endothelial disorders', and 'fuchs endothelial corneal dystrophy'. The articles published in last five years relevant to the area of interest were selected and compiled in a chronological order to write this review. RESULTS: Published research shows the proven role of rho-kinase inhibitors in promoting endothelial proliferation and suppressing its apoptosis. It has shown to be effective in the treatment of endothelial diseases and endothelial cell loss due to other causes in small clinical studies. It has also shown to promote growth of human corneal endothelial cell culture suitable for transplantation. The side effects of topical rho-kinase inhibitors are minimal and self-limiting. CONCLUSION: Rho-kinase inhibitors show immense promise in providing a non-surgical therapy for treatment of endothelial disorders. If consistent results are demonstrated through large clinical trials then this can be a major breakthrough in treating endothelial decompensation and reduce our dependence on endothelial keratoplasty for the same.
Assuntos
Doenças da Córnea , Transplante de Córnea , Distrofia Endotelial de Fuchs , Humanos , Quinases Associadas a rho/farmacologia , Quinases Associadas a rho/uso terapêutico , Doenças da Córnea/cirurgia , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/cirurgia , Endotélio CorneanoRESUMO
OBJECTIVE: To describe 5-year postoperative outcomes of a small series of Fuchs' endothelial dystrophy (FED) patients who underwent Descemet stripping only (DSO) with a scraping technique. METHODS: DSO technique and early clinical outcomes of 5 patients with mild central FED were previously reported. In the same cohort of patients, corrected distance visual acuity, central corneal ultrasound pachymetry, refractive spherical equivalent, endothelial cell count, slit-lamp photography, and corneal Scheimpflug tomography were obtained at baseline, 6 months, and 1 and 5 years postoperatively. No patient used topical Rho-kinase inhibitors at any point in time. RESULTS: One patient (20%) failed to clear the early postoperative edema and 1 patient (20%) developed corneal decompensation 1 year after DSO. Both patients underwent successful Descemet stripping automated endothelial keratoplasty. The remaining 3 patients had stable corrected distance visual acuity, progressive reduction of corneal ultrasound pachymetry, and mild myopic shift of the refractive spherical equivalent over the follow-up time. An improvement in posterior stromal opacities and irregular astigmatism was observed, whereas posterior elevation at Scheimpflug tomography remained unchanged. CONCLUSION: At 5 years postoperatively, DSO with a scraping technique and without Rho-kinase inhibitors resulted in sustained clinical amelioration of 3 of 5 patients (60%) with mild FED.
Assuntos
Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Distrofia Endotelial de Fuchs , Humanos , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/cirurgia , Quinases Associadas a rho , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Seguimentos , Paquimetria Corneana , Endotélio CorneanoRESUMO
ABSTRACT: The current understanding on the clinical efficacy of Rho-associated protein kinase (ROCK) inhibitor for treating Fuchs endothelial corneal dystrophy is summarized to clarify whether the "off-label" ROCK-inhibitor eye-drop application are appropriate. ROCK-inhibitor eye drops may eventually be deemed a cutting-edge therapy for Fuchs endothelial corneal dystrophy patients with acute corneal endothelial defect.
Assuntos
Distrofia Endotelial de Fuchs/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinases Associadas a rho/antagonistas & inibidores , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Administração Oftálmica , Benzoatos/administração & dosagem , Ensaios Clínicos como Assunto , Humanos , Isoquinolinas/administração & dosagem , Soluções Oftálmicas , Sulfonamidas/administração & dosagem , Resultado do Tratamento , beta-Alanina/administração & dosagem , beta-Alanina/análogos & derivadosRESUMO
PURPOSE: The Eye Drops for Early Morning-Associated Swelling (EDEMAS) trial assessed the efficacy of hyperosmolar eye drops on corneal edema resolution. DESIGN: Double-masked, randomized controlled trial of hyperosmolar eye drops. PARTICIPANTS: Participants with Fuchs' dystrophy scheduled for Descemet membrane endothelial keratoplasty. METHODS: One eye was randomized to hyperosmolar eye drops (treatment); the fellow eye was randomized to artificial tears (placebo). After baseline examination in the afternoon, corneas were examined using Scheimpflug tomography after eye opening in the morning. Participants received eye drops twice. Imaging was repeated every 30 minutes up to 4 hours. MAIN OUTCOME MEASURES: Decrease in central corneal thickness 1 hour after eye opening (primary end point), corneal thickness, subjective visual function, glare, visual acuity, and adverse events (AEs) (secondary end points). RESULTS: A total of 68 participants received the allocated intervention (59 eyes received treatment; 55 eyes received placebo). All eyes had stromal edema; none had epithelial edema. Corneal thickness was 626 µm in the treatment arm and 622 µm in the placebo arm after eye opening, indicating an early morning edema compared with baseline of +21 µm and +24 µm, respectively. Decrease in corneal thickness after 1 hour was -10.5 µm in the treatment arm (95% confidence interval [CI], -12.8 to -8.2) and -11.2 µm (95% CI, -13.6 to -8.9) in the placebo arm (between-arm difference, 0.7 µm, 95% CI, -2.0 to 3.5; P = 0.59), indicating no clinically relevant effect of hyperosmolar eye drops on early morning corneal edema. Results were not compatible with a relevant treatment effect on corneal thickness, visual acuity, and glare over the entire course of the study. Increase in subjective visual function was less rapid in the treatment arm than in the placebo arm. Adverse events, most commonly burning after eye drop application, were more common with treatment (30 eyes) than placebo (1 eye; risk difference, 49 percentage points; 95% CI, 36-62). CONCLUSIONS: In this double-masked, randomized controlled trial, resolution of early morning stromal edema was not accelerated by hyperosmolar eye drops, which more frequently caused AEs. These results are not compatible with a clinically relevant effect of hyperosmolar eye drops and do not support their routine use.
Assuntos
Córnea/patologia , Edema da Córnea/tratamento farmacológico , Distrofia Endotelial de Fuchs/complicações , Soluções Oftálmicas/administração & dosagem , Acuidade Visual , Idoso , Edema da Córnea/diagnóstico , Paquimetria Corneana , Método Duplo-Cego , Feminino , Distrofia Endotelial de Fuchs/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Estudos ProspectivosAssuntos
Tecnologia Disruptiva/métodos , Aprovação de Drogas/legislação & jurisprudência , Desenvolvimento de Medicamentos/legislação & jurisprudência , Medicamentos Genéricos/normas , Administração Tópica , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Produtos Biológicos/uso terapêutico , Desenvolvimento de Medicamentos/métodos , Medicamentos Genéricos/provisão & distribuição , Síndromes do Olho Seco/tratamento farmacológico , Equipamentos e Provisões/provisão & distribuição , Distrofia Endotelial de Fuchs/tratamento farmacológico , Terapia Genética/métodos , Humanos , Soluções Oftálmicas/administração & dosagem , Presbiopia/tratamento farmacológico , Doenças Retinianas/tratamento farmacológico , Estados Unidos , United States Food and Drug AdministrationRESUMO
PURPOSE: To evaluate off-label use of netarsudil 0.02% for treatment of corneal edema associated with Fuchs dystrophy. DESIGN: Prospective, randomized clinical trial. METHODS: Twenty-nine subjects with symptomatic Fuchs dystrophy were enrolled and randomized to use netarsudil or placebo eye drops once daily for 3 months. The primary outcomes were the change in central corneal thickness between baseline and 1 month and between baseline and 3 months. Secondary outcomes included change in scotopic corrected distance visual acuity (CDVA) at 3 months and change in scores on a visual disability questionnaire validated for use with Fuchs dystrophy. RESULTS: Compared with use of placebo, use of netarsudil produced significant reduction in central corneal thickness at 1 month (mean difference, -20 µm; 95% confidence interval, -32 to -9 µm) and 3 months (mean difference, -26 µm; 95% confidence interval, -39 to -12 µm) and significant improvement in scotopic CDVA at 3 months (mean difference +1.6 lines; 95% confidence interval, 0.2-3.0 lines). Scores on the visual disability questionnaire did not change significantly in either arm or differ significantly between arms. One subject assigned to netarsudil had baseline epithelial bullae and withdrew from the study because of disabling glare. CONCLUSIONS: Use of netarsudil was associated with reduction of corneal edema and improvement in scotopic CDVA in Fuchs dystrophy patients. Further study is needed to more fully assess patient satisfaction and visual acuity under various lighting conditions and to compare use of netarsudil with other treatment options such as endothelial keratoplasty.
Assuntos
Benzoatos/uso terapêutico , Edema da Córnea/tratamento farmacológico , Distrofia Endotelial de Fuchs/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , beta-Alanina/análogos & derivados , Quinases Associadas a rho/antagonistas & inibidores , Administração Oftálmica , Idoso , Edema da Córnea/fisiopatologia , Paquimetria Corneana , Método Duplo-Cego , Feminino , Distrofia Endotelial de Fuchs/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Visão Noturna/fisiologia , Uso Off-Label , Soluções Oftálmicas , Projetos Piloto , Estudos Prospectivos , Inquéritos e Questionários , Acuidade Visual/fisiologia , beta-Alanina/uso terapêuticoRESUMO
PURPOSE OF REVIEW: Rho kinase (ROCK) inhibitors are growing increasingly relevant in ophthalmology, and the goal of this review is to summarize their mechanisms of action and potential applications in the subspecialties of glaucoma, retina, and cornea. We will focus specifically on corneal endothelial wound healing, for which ROCK inhibition demonstrates particular promise. RECENT FINDINGS: ROCK inhibition has been shown to promote corneal endothelial cell proliferation, increase intercellular adhesion, and suppress apoptosis. Topical ROCK inhibitor treatment has exhibited potential use in Fuchs endothelial dystrophy, corneal edema from acute surgical trauma and other etiologies, and tissue engineering therapy for the endothelial disease. Ripasudil and netarsudil, the two ROCK inhibitors available for ophthalmic use, are generally very well tolerated with mild and transient local side effects. SUMMARY: ROCK inhibitors are revolutionizing the subspecialty of cornea, and further research is needed to compare long-term outcomes of ROCK inhibitor therapy to those of conventional endothelial keratoplasty, including visual acuity and endothelial cell density. Other possible avenues include the use of ROCK inhibitors to prolong corneal graft survival, and early data appears promising.
Assuntos
Benzoatos/uso terapêutico , Distrofia Endotelial de Fuchs/tratamento farmacológico , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , beta-Alanina/análogos & derivados , Quinases Associadas a rho/antagonistas & inibidores , Distrofia Endotelial de Fuchs/enzimologia , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , beta-Alanina/uso terapêuticoRESUMO
PURPOSE: To report early safety and efficacy of Descemet stripping only (DSO) supplemented with ripasudil. METHODS: A pre-post clinical trial with a historical control group for time to heal and cell count parameters. The study received ethics approval and was conducted with oversight of a data safety monitoring board. All enrolled patients had a superior endothelial cell count of >1000 cells/mm2 and were symptomatic from the presence of central guttata degrading vision and/or producing glare. DSO was carried out with a peeling technique and not combined with any other intervention. Ripasudil 0.4% was applied topically from day 1 postoperatively at a dose of 6 times/d until corneal clearance. Cases with relapse of edema were permitted to restart on ripasudil at a reduced dose of 2 drops/d for a further 2 weeks. Stopping rules with progression to a corneal graft were established. Baseline ocular and systemic investigations were carried out and repeated at varying intervals to monitor for local and systemic adverse events. RESULTS: Twenty-three eyes of 23 patients met the inclusion criteria and underwent DSO. Twenty-two of 23 eyes achieved corneal clearance at a mean time of 4.1 weeks. In all patients achieving clearance, improvement in vision was recorded. Improvement in mean uncorrected visual acuity was 0.20 Logarithm of the minimum angle of resolution (LogMar), and improvement in mean best spectacle corrected visual acuity was 0.156 LogMar. One patient failed to clear and underwent Descemet membrane endothelial keratoplasty at week 12. Twenty-one of 22 patients achieving corneal clearance expressed satisfaction with the procedure. The commonest systemic side effect of topical ripasudil was gastrointestinal upset (24%), and the commonest local side effect was ocular irritation (43%). No patient experienced a serious adverse event in the course of the trial. Thirty-nine percent of patients experienced a relapse of edema on ceasing ripasudil, with clearance again on recommencing. CONCLUSIONS: This trial of DSO supplemented with ripasudil included local and systemic safety analysis. We judge that this treatment option is emerging as a reliable intervention for select patients with Fuchs' Endothelial Corneal Dystrophy (FECD) with an acceptable safety profile. The observation of relapse edema is strong evidence of a drug effect. The longevity of these results remains unknown.
Assuntos
Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior/métodos , Distrofia Endotelial de Fuchs/terapia , Isoquinolinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Sulfonamidas/administração & dosagem , Quinases Associadas a rho/antagonistas & inibidores , Administração Oftálmica , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Terapia Combinada , Sensibilidades de Contraste/fisiologia , Edema da Córnea/induzido quimicamente , Edema da Córnea/fisiopatologia , Paquimetria Corneana , Endotélio Corneano/patologia , Feminino , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/cirurgia , Humanos , Pressão Intraocular/fisiologia , Isoquinolinas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Microscopia com Lâmpada de Fenda , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Acuidade Visual/fisiologiaRESUMO
Many diseases are caused by toxic RNA repeats. Herein, we designed a lead small molecule that binds the structure of the r(CUG) repeat expansion [r(CUG)exp] that causes myotonic dystrophy type 1 (DM1) and Fuchs endothelial corneal dystrophy (FECD) and rescues disease biology in patient-derived cells and in vivo. Interestingly, the compound's downstream effects are different in the two diseases, owing to the location of the repeat expansion. In DM1, r(CUG)exp is harbored in the 3' untranslated region, and the compound has no effect on the mRNA's abundance. In FECD, however, r(CUG)exp is located in an intron, and the small molecule facilitates excision of the intron, which is then degraded by the RNA exosome complex. Thus, structure-specific, RNA-targeting small molecules can act disease specifically to affect biology, either by disabling the gain-of-function mechanism (DM1) or by stimulating quality control pathways to rid a disease-affected cell of a toxic RNA (FECD).
Assuntos
Exossomos/efeitos dos fármacos , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Miotônica/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Expansão das Repetições de Trinucleotídeos/efeitos dos fármacos , Células Cultivadas , Exossomos/metabolismo , Feminino , Distrofia Endotelial de Fuchs/metabolismo , Humanos , Masculino , Distrofia Miotônica/metabolismo , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
PURPOSE: Rho-associated kinase (ROCK) inhibitors have been successfully used as a rescue strategy in eyes that failed to clear after descemetorhexis without endothelial graft for treatment of Fuchs endothelial corneal dystrophy (FECD). The functional mechanisms by which ROCK inhibitors modulate corneal endothelial cell regeneration in FECD patients have, however, not been clarified. Here, we analyzed the effect of the ROCK inhibitor ripasudil on corneal endothelial cells of FECD patients and normal donors using ex vivo tissue and in vitro cellular models. DESIGN: Experimental study: laboratory investigation. METHODS: This institutional study used endothelial cell-Descemet membrane lamellae from FECD patients (n = 450) undergoing Descemet membrane endothelial keratoplasty (FECD ex vivo model), normal research-grade donor corneas (n = 30) after scraping off central endothelial cells (ex vivo wound healing model), normal donor corneas (n = 20) without endothelial injury, and immortalized cell lines (n = 3) generated from FECD patients (FECD in vitro model). Descemet membrane lamellae were dissected into halves and incubated for 24-72 hours in storage medium with or without a single dose of 30 µM ripasudil. The effects of ripasudil on expression of genes and proteins related to endothelial cell proliferation, migration, functionality, and endothelial-to-mesenchymal transition were analyzed and complemented by functional assays on FECD cell lines. RESULTS: A single dose of ripasudil induced significant upregulation of genes and proteins related to cell cycle progression, cell-matrix adhesion and migration, as well as endothelial barrier and pump function up to 72 hours, whereas classical markers of endothelial-to-mesenchymal transition were downregulated in both FECD and normal specimens compared to unstimulated controls ex vivo. In addition to stimulation of proliferation and migration, ripasudil-induced changes in expression of functional signature genes could be also verified in FECD cell lines in vitro. CONCLUSIONS: These data support the concept that inhibition of ROCK signaling represents a potent tool in regenerative therapies in FECD patients through reactivation of cell proliferation and migration as well as restoration of endothelial pump and barrier function without inducing adverse phenotypic changes.
Assuntos
Endotélio Corneano/efeitos dos fármacos , Distrofia Endotelial de Fuchs/tratamento farmacológico , Quinases Associadas a rho/antagonistas & inibidores , Idoso , Ciclo Celular/fisiologia , Proteínas de Ciclo Celular/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Junções Célula-Matriz/metabolismo , Células Cultivadas , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Relação Dose-Resposta a Droga , Endotélio Corneano/fisiologia , Feminino , Distrofia Endotelial de Fuchs/metabolismo , Humanos , Isoquinolinas , Masculino , Pessoa de Meia-Idade , SulfonamidasRESUMO
Fuchs endothelial corneal dystrophy (FECD) is a leading cause of corneal endothelial (CE) degeneration resulting in impaired visual acuity. It is a genetically complex and age-related disorder, with higher incidence in females. In this study, we established a nongenetic FECD animal model based on the physiologic outcome of CE susceptibility to oxidative stress by demonstrating that corneal exposure to ultraviolet A (UVA) recapitulates the morphological and molecular changes of FECD. Targeted irradiation of mouse corneas with UVA induced reactive oxygen species (ROS) production in the aqueous humor, and caused greater CE cell loss, including loss of ZO-1 junctional contacts and corneal edema, in female than male mice, characteristic of late-onset FECD. UVA irradiation caused greater mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) damage in female mice, indicative of the sex-driven differential response of the CE to UVA, thus accounting for more severe phenotype in females. The sex-dependent effect of UVA was driven by the activation of estrogen-metabolizing enzyme CYP1B1 and formation of reactive estrogen metabolites and estrogen-DNA adducts in female but not male mice. Supplementation of N-acetylcysteine (NAC), a scavenger of reactive oxygen species (ROS), diminished the morphological and molecular changes induced by UVA in vivo. This study investigates the molecular mechanisms of environmental factors in FECD pathogenesis and demonstrates a strong link between UVA-induced estrogen metabolism and increased susceptibility of females for FECD development.
Assuntos
Citocromo P-450 CYP1B1/metabolismo , Adutos de DNA/efeitos da radiação , Dano ao DNA/efeitos da radiação , Estrogênios/metabolismo , Distrofia Endotelial de Fuchs/etiologia , Raios Ultravioleta/efeitos adversos , Acetilcisteína/administração & dosagem , Animais , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/metabolismo , Humor Aquoso/efeitos da radiação , Adutos de DNA/metabolismo , Dano ao DNA/efeitos dos fármacos , DNA Mitocondrial/metabolismo , DNA Mitocondrial/efeitos da radiação , Modelos Animais de Doenças , Endotélio Corneano/efeitos dos fármacos , Endotélio Corneano/patologia , Endotélio Corneano/efeitos da radiação , Feminino , Sequestradores de Radicais Livres/administração & dosagem , Distrofia Endotelial de Fuchs/diagnóstico , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/patologia , Humanos , Masculino , Camundongos , Estresse Oxidativo/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Índice de Gravidade de DoençaRESUMO
PURPOSE: Fuchs corneal dystrophy (FD) is a common cause of endothelial keratoplasty. Recently, a series of FD cases treated with Descemet stripping only (DSO) demonstrated recovery of the central endothelium without transplantation of donor cells. Ripasudil, a rho kinase inhibitor, has been shown to promote corneal endothelial wound healing in animal models. This study prospectively evaluated the use of ripasudil in patients undergoing DSO for FD. METHODS: Enrolled patients underwent DSO with or without cataract surgery, performed by 1 surgeon. On the first postoperative day, patients were assigned to topical ripasudil 0.4% (Glanatec) 4 times a day for 2 months or no ripasudil and followed up monthly for the first 6 months and then at 9 and 12 months after surgery. Endothelial cell density (ECD) and pachymetry were evaluated at each postoperative visit. RESULTS: Eighteen patients were enrolled, including 8 women and 1 man in each group. Overall, patients who underwent DSO with ripasudil recovered vision more quickly (4.6 vs. 6.5 weeks, P < 0.01). In addition, the ripasudil group had a statistically significantly higher average ECD at 3, 6, and 12 months. The patients in the DSO observation group had a 10% decrease in peripheral ECD when comparing counts before surgery with counts 12 months after surgery (P < 0.05). In the DSO ripasudil group, there was no significant difference between peripheral ECD at preoperative baseline versus 12 months after surgery. CONCLUSIONS: DSO with topical rho kinase inhibitors may be an alternative treatment for patients with FD and a peripheral ECD greater than 1000 cells/mm.
Assuntos
Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/cirurgia , Isoquinolinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Sulfonamidas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Idoso , Contagem de Células , Terapia Combinada , Endotélio Corneano/patologia , Feminino , Humanos , Masculino , Estudos Prospectivos , Acuidade VisualRESUMO
PURPOSE: To report the safety and efficacy of descemetorhexis without grafting as a primary intervention in Fuchs dystrophy, and the use of a ROCK inhibitor, ripasudil as a salvage agent in failing cases. METHODS: Twelve eyes of 11 patients underwent central descemetorhexis not exceeding 4 mm. All had Fuchs dystrophy-producing visual symptoms, requesting intervention. Exclusion criteria were a peripheral endothelial cell count <1000 and central edema. Corneal clearance and visual parameters were recorded monthly until corneal clearance was observed, then at intervals of 6 months. Cases failing to clear by month 2 were considered for salvage treatment. This consisted of treatment with 1 of 2 formulations of Rho-associated kinase inhibitor eye drops. Endothelial keratoplasty was planned as the final salvage procedure in unsuccessful cases. RESULTS: Nine of 12 eyes cleared spontaneously between 2 and 6 months. One eye failed to clear by month 5 and topical Y-27632 was administered, without success. Endothelial keratoplasty was performed. In 2 eyes, healing stalled at 3 and 2 months. In both cases, topical ripasudil administered 6 times a day for 2 weeks resulted in complete corneal clearance. In cases achieving corneal clearance, best spectacle corrected visual acuity improved from a mean of 0.26 to 0.125 (logMAR) with subjective improvement in quality of vision. CONCLUSIONS: In Fuchs dystrophy with visual degradation due to central guttae, descemetorhexis without grafting is a viable procedure for visual rehabilitation. Careful patient selection is required, but the advent of topical ripasudil as a salvage agent suggests that a broader application of the surgery may be possible. Further study into the use of this agent is now needed.
Assuntos
Lâmina Limitante Posterior/cirurgia , Distrofia Endotelial de Fuchs/terapia , Isoquinolinas/uso terapêutico , Sulfonamidas/uso terapêutico , Quinases Associadas a rho/antagonistas & inibidores , Administração Tópica , Adulto , Idoso , Contagem de Células , Terapia Combinada , Ceratoplastia Endotelial com Remoção da Lâmina Limitante Posterior , Feminino , Seguimentos , Distrofia Endotelial de Fuchs/tratamento farmacológico , Distrofia Endotelial de Fuchs/fisiopatologia , Distrofia Endotelial de Fuchs/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Estudos Prospectivos , Refração Ocular/fisiologia , Acuidade Visual/fisiologiaRESUMO
PURPOSE: Corneal involvement in mitochondrial disease is seldom described. Kearns-Sayre syndrome (KSS) is a mitochondrial disorder characterized by retinitis pigmentosa, external ophthalmoplegia, and heart block. We report 2 patients with KSS with corneal lesions involving the endothelium, which improved with Coenzyme Q10 (CoQ10). Based on recent research regarding the role of dysfunctional oxidative metabolism in Fuchs Endothelial Corneal Dystrophy (FECD), we propose that mitochondrial diseases and FECD share a final pathway. METHODS: A chart review was performed and a review of the literature was completed with a PubMed search using the terms "Kearns-Sayre Syndrome", "mitochondria", "endothelium", "Fuchs endothelial corneal dystrophy", and "cornea". RESULTS: There are 19 reports of corneal involvement in clinical phenotypes of mitochondrial disease. Nine of these 19 cases had findings consistent with KSS. Our patients with KSS had microcystic changes throughout the cornea and excrescences on the endothelial surface seen with ultrasound biomicroscopy, similar to the clinical findings in FECD. CoQ10 improved corneal disease in both children. CoQ10 deficiency has been reported in a variety of mitochondrial diseases, and efficacy of supplementation has been demonstrated. It may be beneficial in these patients because of its antioxidant properties and role in oxidative phosphorylation. CONCLUSIONS: The common deletion found in patients with KSS has recently been implicated in FECD, which has recently been shown to be a disease related to dysfunctional oxidative metabolism. Future research should explore the use of antioxidants, such as CoQ10 in patients with FECD.
Assuntos
Edema da Córnea/tratamento farmacológico , Complexo de Proteínas da Cadeia de Transporte de Elétrons/uso terapêutico , Endotélio Corneano/efeitos dos fármacos , Distrofia Endotelial de Fuchs/tratamento farmacológico , Síndrome de Kearns-Sayre/tratamento farmacológico , Ubiquinona/análogos & derivados , Criança , Pré-Escolar , Edema da Córnea/diagnóstico , Endotélio Corneano/patologia , Humanos , Síndrome de Kearns-Sayre/diagnóstico , Masculino , Soluções Oftálmicas , Ubiquinona/uso terapêutico , Acuidade Visual/efeitos dos fármacosRESUMO
PURPOSE: Fuchs endothelial corneal dystrophy (FECD) might be managed by drug treatment before becoming severe enough to require surgery. For a clinical trial of such a drug, we hypothesize that selecting an adequate number of patients with FECD with only moderately compromised cell densities will be challenging. Thus, the purpose of the present study was to measure the prevalence of patients with FECD exhibiting moderately decreased corneal cell densities. METHODS: A retrospective data mining study (cross-sectional study) was performed on patient charts presenting at a large US northwestern academic health center by searching for diagnosis ICD-9 code 371.57 and Fuchs corneal dystrophies, including those with prior cataract surgeries and/or existing glaucoma. Patients with prior corneal transplants were excluded. Noncontact specular photomicroscopic data (Topcon 2000) were obtained from the central region whenever possible, and individual eyes were grouped according to cell density (cells/mm2): severe (<800), moderate (800-1,500), and mild (>1,500). RESULTS: The values for 98 eyes from 61 patients with FECD were as follows (mean ± SD): corneal thickness 573 ± 59 µm, cell size 627 ± 336 µm2/cell, coefficient of variation 23 ± 7, and density 1,883 ± 703 cells/mm2. The moderate subgroup with cell density values averaging 1,184 ± 212 (26) comprised 27% of the total FECD patient pool. CONCLUSIONS: Only approximately 1 out of 4 patients with FECD will show moderately compromised corneal cell densities. A moderate level of damage may be optimal for clinical trials for testing topical drugs on endothelial cell viability. Thus, investigators will need to initially screen a fourfold excess of all patients with FECD.
Assuntos
Proliferação de Células/efeitos dos fármacos , Endotélio Corneano/patologia , Distrofia Endotelial de Fuchs/patologia , Seleção de Pacientes , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Ensaios Clínicos como Assunto , Estudos Transversais , Endotélio Corneano/efeitos dos fármacos , Feminino , Distrofia Endotelial de Fuchs/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: Ripasudil (Glanatec), a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension. The purpose of this study was to investigate the effect of ripasudil eye drops on corneal endothelial morphology, as ROCK signaling is known to modulate the actin cytoskeleton. METHODS: Morphological changes in the corneal endothelium were evaluated in human subjects by specular and slit-lamp microscopy, following topical administration of ripasudil. We also used a rabbit model to evaluate the effect of ripasudil on clinical parameters of the corneal endothelium. Twenty-four hours after ripasudil application, corneal specimens were evaluated by phalloidin staining, immunohistochemical analysis, and electron microscopy. RESULTS: Specular microscopy revealed morphological changes in human eyes, and slit-lamp microscopy showed guttae-like findings. The rabbit model showed morphological changes similar to those seen in human eyes after ripasudil administration. Electron microscopy demonstrated that these alterations are due to the formation of protrusions along the cell-cell borders, but this formation is transient. Expression of corneal endothelial function-related markers was not disrupted; corneal thickness and corneal volume were not changed; and no cell death was observed following ripasudil administration. CONCLUSIONS: Ripasudil induces transient guttae-like findings in humans, most likely due to protrusion formation along intracellular borders caused by the reduction in actomyosin contractility of the corneal endothelial cells. No severe adverse effects were observed. Physicians should be aware that ROCK inhibitors can cause these guttae-like findings, to avoid misdiagnosing patients as having Fuchs endothelial corneal dystrophy. (www.umin.ac.jp/ctr number, UMIN000018340.).