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1.
Cell Physiol Biochem ; 54(1): 142-159, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32028545

RESUMO

BACKGROUND/AIMS: It is well established that oxidative stress and inflammation are common pathogenic features of retinal degenerative diseases. ITH12674 is a novel compound that induces the transcription factor Nrf2; in so doing, the molecule exhibits anti-inflammatory, and antioxidant properties, and affords neuroprotection in rat cortical neurons subjected to oxidative stress. We here tested the hypothesis that ITH12674 could slow the retinal degeneration that causes blindness in rd10 mice, a model of retinitis pigmentosa. METHODS: Animals were intraperitoneally treated with 1 or 10 mg/Kg ITH12674 or placebo from P16 to P30. At P30, retinal functionality and visual acuity were analyzed by electroretinography and optomotor test. By immunohistochemistry we quantified the photoreceptor rows and analyzed their morphology and connectivity. Oxidative stress and inflammatory state was studied by Western blot, and microglia reactivity was monitored by flow cytometry. The blood-brain barrier permeation of ITH12674 was evaluated using a PAMPA-BBB assay. RESULTS: In rd10 mice treated with 10 mg/Kg of the compound, the following changes were observed (with respect to placebo): (i) a decrease of vision loss with higher scotopic a- and b-waves; (ii) increased visual acuity; (iii) preservation of cone photoreceptors morphology, as well as their synaptic connectivity; (iv) reduced expression of TNF-α and NF-κB; (v) increased expression of p38 MAPK and Atg12-Atg5 complex; and (vi) decreased CD11c, MHC class II and CD169 positive cell populations. CONCLUSION: These data support the view that a Nrf2 inducer compound may arise as a new therapeutic strategy to combat retinal neurodegeneration. At present, we are chemically optimising compound ITH12674 with the focus on improving its neuroprotective potential in retinal neurodegenerative diseases.


Assuntos
Isotiocianatos/uso terapêutico , Melatonina/análogos & derivados , Fator 2 Relacionado a NF-E2/agonistas , Retinite Pigmentosa/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Eletrorretinografia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/química , Isotiocianatos/farmacologia , Masculino , Melatonina/química , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/patologia , Retina/efeitos dos fármacos , Retina/metabolismo , Retinite Pigmentosa/metabolismo , Retinite Pigmentosa/patologia , Fator de Necrose Tumoral alfa/metabolismo , Acuidade Visual/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
2.
Eur J Ophthalmol ; 30(1): 147-154, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30541351

RESUMO

PURPOSE: To study electroretinograms in infantile nystagmus syndrome associated with idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism. METHODS: A total of 30 children with idiopathic infantile nystagmus, 18 with optic nerve hypoplasia, and 18 with albinism were studied. Three electroretinogram protocols were applied according to child's age: 58 (mean: 2.0 years) were recorded with skin electrode to Great Ormond Street Hospital protocol, 11 (mean: 5.3 years) with skin electrode to International Society for Clinical Electrophysiology of Vision protocol, and 7 children (mean: 12.2 years) with HK electrode to International Society for Clinical Electrophysiology of Vision protocol. The electroretinograms were compared to those of age-matched controls. RESULTS: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were comparable to controls in all protocols. Electroretinogram amplitudes in idiopathic infantile nystagmus group showed increased white scotopic and photopic electroretinograms in 26 children (skin electrode to Great Ormond Street Hospital protocol), no difference to the controls in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol), and increased rod electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol). Optic nerve hypoplasia group showed increased white scotopic, photopic, and blue electroretinograms in 15 children (skin electrode to Great Ormond Street Hospital protocol); increased 30-Hz electroretinogram in 3 children (HK electrode to International Society for Clinical Electrophysiology of Vision protocol); and reduced combined rod-cone, cone, and 30-Hz electroretinograms in 3 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Albinism group showed increased white scotopic, photopic, and 30-Hz electroretinograms in 17 children (skin electrode to Great Ormond Street Hospital protocol), while it showed reduced cone and 30-Hz electroretinograms in 5 children (skin electrode to International Society for Clinical Electrophysiology of Vision protocol). Implicit times were shorter in albinism. CONCLUSION: Electroretinogram waveforms in idiopathic infantile nystagmus, optic nerve hypoplasia, and albinism were normal with mostly increased electroretinograms, while reduced electroretinograms did not show a specific pattern as in early-onset retinal dystrophies.


Assuntos
Anormalidades Múltiplas , Albinismo/fisiopatologia , Eletrorretinografia/métodos , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Nistagmo Congênito/fisiopatologia , /fisiopatologia , Albinismo/diagnóstico , Criança , Pré-Escolar , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Masculino , Nistagmo Congênito/diagnóstico , /diagnóstico
5.
Adv Exp Med Biol ; 1185: 57-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884589

RESUMO

Geographic atrophy (GA), the advanced form of AMD, has been linked to oxidative stress within the RPE and with low-grade inflammation. The RPE-specific Sod2 knockout mouse model of GA develops increase oxidative stress and slow retinal degeneration. Mice of the SOD2floxed::VMD2Cre+ genotype were injected subcutaneously with either saline or 3 mg/kg of lipopolysaccharide (LPS) at 8 weeks of age. Mice were evaluated by electroretinography (ERG) and spectral domain optical coherence tomography. Inflammatory cells within the retina were studied by CD45 immunofluorescence. Systemic low-dose LPS transiently, but significantly, improved both function and structure of RPE-specific Sod2 KO mice retina when compared to saline-injected mice. There was no difference in CD45 positive cells between saline and LPS treatment. Low-grade activation of the immune system leads to a preconditioning effect that transiently protects the retina of a mouse model of geographic atrophy.


Assuntos
Atrofia Geográfica/tratamento farmacológico , Lipopolissacarídeos/farmacologia , Epitélio Pigmentado da Retina/efeitos dos fármacos , Animais , Eletrorretinografia , Injeções Subcutâneas , Lipopolissacarídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Superóxido Dismutase , Tomografia de Coerência Óptica
6.
Adv Exp Med Biol ; 1185: 65-69, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884590

RESUMO

The eye is an excellent target organ for gene therapy. It is physically isolated, easily accessible, immune-privileged, and postmitotic. Furthermore, potential gene therapies introduced into the eye can be evaluated by noninvasive methods such as fundoscopy, electroretinography, and optical coherence tomography. In the last two decades, great advances have been made in understanding the molecular underpinnings of retinal degenerative diseases. Building upon the development of modern techniques for gene delivery, many gene-based therapies have been effectively used to treat loss-of-function retinal diseases in mice and men. Significant effort has been invested into making gene delivery vehicles more efficient, less toxic, and non-immunogenic. However, one challenge for the treatment of more complex gain-of-function diseases, many of which might be benefited by the regulation of cellular stress-responsive signaling pathways, is the ability to control the strategy in a physiological (conditional) manner. This review is focused on promising retinal gene therapy strategies that rely on small molecule-based conditional regulation and the inherent limitations and challenges of these strategies that need to be addressed prior to their extensive use.


Assuntos
Técnicas de Transferência de Genes , Terapia Genética , Degeneração Retiniana/terapia , Eletrorretinografia , Humanos , Transdução de Sinais , Tomografia de Coerência Óptica
7.
Adv Exp Med Biol ; 1185: 103-107, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884596

RESUMO

Mutations in the gene encoding the phosphodiesterase 6 alpha subunit (PDE6A) account for 3-4% of autosomal recessive retinitis pigmentosa (RP), and currently no treatment is available. There are four animal models for PDE6A-RP: a dog with a frameshift truncating mutation (p.Asn616ThrfsTer39) and three mouse models with missense mutations (Val685Met, Asp562Trp, and Asp670Gly) showing a range of phenotype severities. Initial proof-of-concept gene augmentation studies in the Asp670Gly mouse model and dog model used a subretinally delivered adeno-associated virus serotype 8 with a 733 tyrosine capsid mutation delivering species-specific Pde6a cDNAs. These restored some rod-mediated function and preserved retinal structure. Subsequently, a translatable vector (AAV8 with a human rhodopsin promoter and human PDE6A cDNA) was tested in the dog and the Asp670Gly mouse model. In the dog, there was restoration of rod function, a robust rod-mediated ERG, and introduction of dim-light vision. Treatment improved morphology of the photoreceptor layer, and the retina was preserved in the treated region. In the Asp670Gly mouse, therapy also preserved photoreceptors with cone survival being reflected by maintenance of cone-mediated ERG responses. These studies are an important step toward a translatable therapy for PDE6A-RP.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Proteínas do Olho/genética , Terapia Genética , Retinite Pigmentosa/terapia , Animais , Dependovirus , Modelos Animais de Doenças , Cães , Eletrorretinografia , Vetores Genéticos , Humanos , Camundongos , Mutação , Retina , Retinite Pigmentosa/genética
8.
Adv Exp Med Biol ; 1185: 347-352, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884636

RESUMO

To investigate whether intravitreal injection of amyloid ß1-42 (Aß1-42) activates the complement system and induces retinal inflammatory responses and malfunction, Aß1-42 was applied intravitreally in mice. The expressions of key components of complement system were determined by real-time PCR. Retinal function was assessed by electroretinography. We found interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in Aß1-42 treated mice retinas increased from day 1 to day 7. Compared with control group, mRNA expression of C1qa and C3 in the Aß1-42 treated retinas increased at days 1 and 7. The level of CFB, CFD, or CFH increased at day 4 and day 7. Regulator of membrane attack complex (MAC), CD59a, increased from day 1 to day 7. The expression of the main complement components in Aß1-42 treated eyes increased at days 4 and 7. Therefore, our results suggested that exogenous Aß1-42 activated CP and AP of the complement system in mice retinas, induced retinal inflammatory responses, and caused retinal malfunction.


Assuntos
Peptídeos beta-Amiloides/administração & dosagem , Proteínas do Sistema Complemento/imunologia , Inflamação/imunologia , Fragmentos de Peptídeos/administração & dosagem , Retina/fisiopatologia , Animais , Antígenos CD59/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Eletrorretinografia , Interleucina-6/imunologia , Injeções Intravítreas , Camundongos , Retina/imunologia , Fator de Necrose Tumoral alfa/imunologia
9.
Adv Exp Med Biol ; 1185: 371-376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884640

RESUMO

This study was designed to assess risk for retinal toxicity associated with administration of high-dose sildenafil citrate to dogs heterozygous for a functionally null mutation in Pde6a over a 4-month period. Three Pde6a +/- dogs were administered 14.3 mg/kg sildenafil per os and two Pde6a +/- dogs placebo once daily for 16 weeks. Three Pde6a +/+ dogs were administered sildenafil for 7 days. Ophthalmic examination, vision testing, and electroretinography (ERG) were regularly performed. At study termination, dogs were euthanized and globes collected. Retinal layer thickness and photoreceptor nuclei counts were determined from plastic sections. In both Pde6a +/- and Pde6a +/+ sildenafil-treated (ST) dogs, elevation of dark-adapted b-wave threshold and unmasking of the scotopic threshold response (STR) were observed. Sildenafil treated Pde6a +/- dogs had significantly thinner ONL (24.90 +/-1.88 µm, p = 0.004) and lower photoreceptor nuclei counts (273.6 +/- 29.3 cells/100 µm, p = 0.008) compared to measurements (35.90 +/- 1.63 µm) and counts (391.5 +/-27.0 cells/100 µm) from archived untreated Pde6a +/- dogs.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Proteínas do Olho/genética , Retina/efeitos dos fármacos , Retina/patologia , Citrato de Sildenafila/toxicidade , Animais , Cães , Eletrorretinografia , Mutação com Perda de Função , Células Fotorreceptoras
10.
Adv Exp Med Biol ; 1185: 395-400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884644

RESUMO

Mattapallil et al. described that vendor lines for C57BL/6 N mice may carry the rd8 mutation that leads to an ocular phenotype, which could be mistaken for an induced retinal degeneration. This mouse strain is widely used in ophthalmic research as a background for modeling retinal degeneration. In the process of studying Cln3Δex7/8 knock-in mice on a C57BL/6 N background, we became aware of this issue. The aim of this study thus was to use electroretinography to investigate the age-dependent functional loss in Cln3+/+ rd8-/rd8- mice and compare it to C57BL/6 J mice.The scotopic and photopic amplitudes of the a-wave and b-wave decrease significantly in mutant mice with increasing age, and the implicit time is prolonged. Especially the oscillatory potentials arising from inner retinal interaction seem to be notably affected by the rd8 mutation. Surprisingly, the amplitudes in young C57BL/6 J mice were lower than those measured in C57BL/6 N at any time point.Our results indicate that the rd8 mutation present in C57BL/6 N mice affects the function of the inner and outer retina. This is surprising given that the major retinal morphological alterations due to the rd8 mutation are found in the outer retina.We conclude that the rd8 mutation does affect the retinal function in Cln3+/+ rd8-/rd8- mice in a variable manner. Epigenetic factors and modifying genes lead to a phenotype shift in these mice. Interpreting the results of previous studies in mutant mice on C57BL/6 N background is challenging as comparing results obtained in independent studies or on other mouse backgrounds may be misleading. Using littermates as controls remains the only valid option.


Assuntos
Glicoproteínas de Membrana/genética , Chaperonas Moleculares/genética , Proteínas do Tecido Nervoso/genética , Degeneração Retiniana/genética , Envelhecimento , Animais , Modelos Animais de Doenças , Eletrorretinografia , Técnicas de Introdução de Genes , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Retina/fisiopatologia
11.
Adv Exp Med Biol ; 1185: 507-511, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31884662

RESUMO

Mice provide informative models of enormous utility for eye research. Sex as biological variable must be considered when conducting studies exploring mouse models. To determine if sex confounds neural retina or retinal pigment epithelium (RPE) activity in wild-type C57BL/6J mice, we compared male and female mice with respect to retinal light response and RPE phagocytosis. We tested 2-month-old mice at peak fertility and 12-month-old mice past fertility. Retinal function was assessed by quantifying a- and b-wave amplitudes of photopic and scotopic electroretinograms (ERGs). These experiments did not reveal differences between male and female mice at either age. As expected from earlier studies, 12-month-old mice showed reduced light responses compared to 2-month-old mice, but age-related decline was identical for male and female mice. RPE functionality was assessed by quantifying RPE phagosome content 1 h after light onset in mice 2 months of age, an age of maturity of the process of outer segment turnover that includes RPE phagocytosis. These experiments did not reveal differences in RPE phagocytosis between male and female mice. Altogether, male and female C57BL/6J mice do not differ in retinal light response and peak RPE phagocytic activity. Retinal activity is impaired with age to the same extent in male and female mice. Our results justify testing mixed-sex mouse cohorts in studies on outer segment renewal and RPE phagocytosis and illustrate the importance of careful consideration of cohort age.


Assuntos
Eletrorretinografia , Fagocitose , Epitélio Pigmentado da Retina/fisiologia , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fagossomos , Fatores Sexuais
12.
Invest Ophthalmol Vis Sci ; 60(14): 4606-4618, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756254

RESUMO

Purpose: To investigate the neuroprotective effects of Lycium barbarum polysaccharides (LBP) against chronic ocular hypertension (OHT) in rats and to consider if effects differed when treatment was applied before (pretreatment) or during (posttreatment) chronic IOP elevation. Methods: Sprague-Dawley rats (10-weeks old) underwent suture implantation around the limbus for 15 weeks (OHT) or 1 day (sham). Four experimental groups were studied, three OHT groups (n = 8 each) treated either with vehicle (PBS), LBP pretreatment or posttreatment, and a sham control (n = 5) received no treatment. LBP (1 mg/kg) pre- and posttreatment were commenced at 1 week before and 4 weeks after OHT induction, respectively. Treatments continued up through week 15. IOP was monitored twice weekly for 15 weeks. Optical coherence tomography and ERG were measured at baseline, week 4, 8, 12, and 15. Eyes were collected for ganglion cell layer (GCL) histologic analysis at week 15. Results: Suture implantation successfully induced approximately 50% IOP elevation and the cumulative IOP was similar between the three OHT groups. When compared with vehicle control (week 4: -23 ± 5%, P = 0.03), LBP pretreatment delayed the onset of retinal nerve fiber layer (RNFL) thinning (week 4, 8: -2 ± 7%, -11 ± 3%, P > 0.05) and arrested further reduction up through week 15 (-10 ± 4%, P > 0.05). LBP posttreatment intervention showed no significant change in rate of loss (week 4, 15: -25 ± 4.1%, -28 ± 3%). However, both LBP treatments preserved the retinal ganglion cells (RGC) and retinal functions up to week 15, which were significantly reduced in vehicle control. Conclusions: LBP posttreatment arrested the subsequent neuronal degeneration after treatment commencement and preserved RGC density and retinal functions in a chronic OHT model, which was comparable with pretreatment outcomes.


Assuntos
Modelos Animais de Doenças , Medicamentos de Ervas Chinesas/uso terapêutico , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/tratamento farmacológico , Animais , Doença Crônica , Eletrorretinografia , Feminino , Pressão Intraocular/fisiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Fibras Nervosas/patologia , Hipertensão Ocular/metabolismo , Hipertensão Ocular/fisiopatologia , Ratos , Ratos Sprague-Dawley , Retina/fisiopatologia , Células Ganglionares da Retina/patologia , Tomografia de Coerência Óptica
13.
Invest Ophthalmol Vis Sci ; 60(14): 4849-4857, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31747684

RESUMO

Purpose: We reported previously that retinas of mice with inherited retinal degeneration make less protein than retinas of normal mice. Despite recent studies suggesting that diminished protein synthesis rates may contribute to neurologic disorders, a direct link between protein synthesis rates and the progression of neurodegeneration has not been established. Moreover, it remains unclear whether reduced protein synthesis could be involved in retinal pathogenesis. Dysregulation of AKT/mTOR signaling has been reported in the retina during retinal degeneration, but to what extent this signaling contributes to translational attenuation in these mice remains uncertain. Methods: C57BL/6J and rd16 mice were subcutaneously injected with anisomycin to chronically inhibit protein synthesis rates. An AAV2 construct encoding constitutively active 4ebp1 was subretinally delivered in wildtype animals to lower protein synthesis rates. 4ebp1/2 were knocked out in rd16 mice. Results: Anisomycin treatment lowered retinal translation rates, accelerated retinal degeneration in rd16 mice, and initiated cell death in the retinas of C57BL/6J mice. AAV-mediated transfer of constitutively active 4ebp1-4A into the subretinal space of wildtype animals inhibited protein synthesis, and led to reduced electroretinography amplitudes and fewer ONL nuclei. Finally, we report that restoring protein synthesis rates by knocking out 4ebp1/2 was associated with an approximately 2-fold increase in rhodopsin levels and a delay in retinal degeneration in rd16 mice. Conclusions: Our study indicates that protein synthesis inhibition is likely not a cell defense mechanism in the retina by which deteriorating photoreceptors survive, but may be harmful to degenerating retinas, and that restoring protein synthesis may have therapeutic potential in delaying the progression of retinal degeneration.


Assuntos
Biossíntese de Proteínas/fisiologia , Retina/fisiopatologia , Degeneração Retiniana/fisiopatologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Anisomicina/farmacologia , Proteínas de Ciclo Celular/genética , Morte Celular , Eletrorretinografia , Fatores de Iniciação em Eucariotos/genética , Regulação da Expressão Gênica/fisiologia , Marcação In Situ das Extremidades Cortadas , Injeções Subcutâneas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parvovirinae/genética , Inibidores da Síntese de Proteínas/farmacologia , Retina/metabolismo , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Rodopsina/metabolismo , Transfecção
14.
Invest Ophthalmol Vis Sci ; 60(14): 4872-4881, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31747688

RESUMO

Purpose: To assess retinal function in young patients with X-linked juvenile retinoschisis (XLRS), a disorder that is known to alter ERG postreceptor retinal components and also possibly photoreceptor components. Methods: ERG responses to full-field stimuli were recorded under scotopic and photopic conditions in 12 XLRS patients aged 1 to 15 (median 8) years. A- and b-wave amplitudes and implicit times were examined over a range of stimulus intensities. Rod and cone photoreceptor (SROD, RROD, SCONE, RCONE) and rod-driven postreceptor (log σ, VMAX) response parameters were calculated from the a- and b-waves. Data from XLRS patients were evaluated for significant change with age. Results: A- and b-wave amplitudes were smaller in XLRS patients compared with controls under both scotopic and photopic conditions. Saturated photoresponse amplitude (RROD), postreceptor b-wave (log σ), and saturated b-wave amplitude (VMAX) were significantly lower in XLRS patients than in controls; SROD did not differ between the two groups. SCONE and RCONE values were normal. In XLRS patients, neither a- and b-wave amplitudes nor calculated parameters (SROD, RROD, log σ, VMAX,SCONE, and RCONE) changed with age. Conclusions: In these young XLRS patients, RROD and a-wave amplitudes were significantly smaller than in controls. Thus, in addition to XLRS causing postreceptor dysfunction, an effect of XLRS on rod photoreceptors cannot be ignored.


Assuntos
Retina/fisiopatologia , Retinosquise/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Visão de Cores/fisiologia , Adaptação à Escuridão , Eletrorretinografia , Feminino , Humanos , Lactente , Masculino , Visão Noturna/fisiologia , Estimulação Luminosa , Células Fotorreceptoras de Vertebrados/fisiologia , Retinosquise/diagnóstico por imagem , Tomografia de Coerência Óptica , Adulto Jovem
15.
Vestn Oftalmol ; 135(5. Vyp. 2): 267-271, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31691671

RESUMO

INTRODUCTION: Retinitis pigmentosa (RP) is a degenerative retinal disease that leads to blindness. Recently, treatment methods based on new technologies have emerged. Among them is stem cells transplantation (SC). PURPOSE: To make a systematic evaluation of the results of control clinical studies of cellular technologies for the treatment of RP. MATERIAL AND METHODS: The key words - retinitis pigmentosa, stem cells, control study - were used to search literature databases PubMed (250), WOS (172), MEDLINE (32) for the last 5 years. According to preliminary criteria, 88 articles were selected, according to final criteria - 4 articles. A total of 25 patients with RP were found. Control points of the analysis were: baseline, 3 months and 12 months. Methods of analysis (events): visual acuity (VA) and flash electroretinogram (f-ERG). RESULTS: There was no VA increase in 15 (60%) of the blind (or with negligible vision of less than 20/1600 ENDRS) patients, and the f-ERG was unrecordable. In 10 patients (40%), VA improved from 0.1 to 0.4 logMAR and the amplitude of f-ERG increased at about 3 months after injection. At 12 months, the effect returned to the baseline values. CONCLUSION: The use of SC transplantation technology in RP helps achieve short-term (up to 3 months) positive changes in VA and f-ERG, which depend on the initial stage of RP and do not remain in the final stage. This evokes a question of repeated use of SC transplantation in the same patient.


Assuntos
Retinite Pigmentosa , Células-Tronco , Eletrorretinografia , Humanos , Retina , Retinite Pigmentosa/terapia , Acuidade Visual
16.
Vestn Oftalmol ; 135(5): 31-37, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31714510

RESUMO

PURPOSE: To investigate the morphological and functional state of the outer and inner layers of the retina in patients with diabetes mellitus (DM) and nonproliferative diabetic retinopathy (NPDR), to determine the presence and nature of the relationships between structural and functional changes. MATERIAL AND METHODS: The study included 50 patients with subcompensated diabetes and NPDR and 40 people from the control group (healthy). All patients underwent OCT of the retina and optic nerve using RTVue-100 apparatus (Optovue, USA), as well as multifocal electroretinography (mfERG) and pattern electroretinography (PERG) on EP-1000 Multifocal device ('Tomey GmbH', Germany). RESULTS: When analyzing the results of OCT in patients with NPDR, a decrease in the total thickness of the retina and the thickness of its inner layers in the fovea and parafovea regions was found in comparison with the control group (p<0.001), thinning of the retinal ganglion cell (GCS) complex with increased focal losses (FLV) of up to 1.4% (Mann-Whitney test, p=0.001). In the group of patients with diabetes, there was a statistically significant decrease in the density and amplitude of P1 mfERG in all five 'rings' (Mann-Whitney test, p<0.001), increase in implicit time in the first 3 rings, decrease in P50 and N95 amplitude, increase in implicit time of N95 PERG (p=0.001) compared to the control group. CONCLUSION: The study revealed changes in the structure and functioning of the outer and inner layers of the retina in patients with NPDR, and established a reliable correlation between the morphological parameters (according to the OCT) and electrophysiological parameters (according to the mfERG and PERG data).


Assuntos
Retinopatia Diabética , Eletrorretinografia , Humanos , Retina , Células Ganglionares da Retina , Tomografia de Coerência Óptica
17.
Invest Ophthalmol Vis Sci ; 60(14): 4811-4819, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31743939

RESUMO

Purpose: Cone rod dystrophy (CRD) is a group of inherited retinopathies characterized by the loss of cone and rod photoreceptor cells, which results in poor vision. This study aims to clinically and genetically characterize the segregating CRD phenotype in two large, consanguineous Pakistani families. Methods: Funduscopy, optical coherence tomography (OCT), electroretinography (ERG), color vision, and visual acuity assessments were performed to evaluate the retinal structure and function of the affected individuals. Exome sequencing was performed to identify the genetic cause of CRD. Furthermore, the mutation's effect was evaluated using purified, bacterially expressed ADP-ribosylation factor-like protein 3 (ARL3) and mammalian cells. Results: Fundus photography and OCT imaging demonstrated features that were consistent with CRD, including bull's eye macular lesions, macular atrophy, and central photoreceptor thinning. ERG analysis demonstrated moderate to severe reduction primarily of photopic responses in all affected individuals, and scotopic responses show reduction in two affected individuals. The exome sequencing revealed a novel homozygous variant (c.296G>T) in ARL3, which is predicted to substitute an evolutionarily conserved arginine with isoleucine within the encoded protein GTP-binding domain (R99I). The functional studies on the bacterial and heterologous mammalian cells revealed that the arginine at position 99 is essential for the stability of ARL3. Conclusions: Our study uncovers an additional CRD gene and assigns the CRD phenotype to a variant of ARL3. The results imply that cargo transportation in photoreceptors as mediated by the ARL3 pathway is essential for cone and rod cell survival and vision in humans.


Assuntos
Fatores de Ribosilação do ADP/genética , Distrofias de Cones e Bastonetes/genética , Genes Recessivos , Mutação Puntual , Adolescente , Adulto , Animais , Células COS , Criança , Distrofias de Cones e Bastonetes/patologia , Consanguinidade , Eletrorretinografia , Feminino , Expressão Gênica , Células HeLa , Homozigoto , Humanos , Masculino , Oftalmoscopia , Linhagem , Fenótipo , Tomografia de Coerência Óptica , Acuidade Visual , Sequenciamento Completo do Exoma , Adulto Jovem
18.
Invest Ophthalmol Vis Sci ; 60(14): 4681-4690, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31725167

RESUMO

Purpose: To compare the effects of reduced inhibitory neuron function in the retina across behavioral, physiological, and anatomical levels. Methods: Inhibitory neurons were ablated in larval zebrafish retina. The Ptf1a gene, which determines inhibitory neuron fate in developing vertebrates, was used to express nitroreductase. By exposing larvae to the prodrug metronidazole, cytotoxicity was selectively induced in inhibitory neurons. Visual phenotypes were characterized at behavioral, physiological, and anatomical levels using an optomotor response (OMR) assay, electroretinography (ERG), and routine histology, respectively. Nonvisual locomotion was also assessed to reveal any general behavioral effects due to ablation of other nonvisual neurons that also express Ptf1a. Results: Injured larvae showed severely reduced OMR relative to controls. Locomotor assessment showed unaltered swimming ability, indicating that reduced OMR was due to visual deficits. For ERG, injured larvae manifested either reduced (type-I) or absent (type-II) b-wave signals originating from bipolar interneurons in the retina. Histologic analysis showed altered retinal morphology in injured larvae, with reductions in synaptic inner plexiform layer (IPL) thickness and synaptic density more pronounced in type-II than type-I larvae; type-II larvae also had smaller retinae overall. Conclusions: The consequences of inhibitory neuron ablation corresponded closely across behavioral, physiological, and anatomical levels. Inhibitory neuron loss likely increases the ratio of neural excitation to inhibition, leading to hyperexcitability. In addition to modulating visual signals, inhibitory neurons may be critical for maintaining retinal structure and organization. This study highlights the utility of a multidisciplinary approach and provides a template for characterizing other zebrafish models of neurological disease.


Assuntos
Anti-Infecciosos/toxicidade , Comportamento Animal/fisiologia , Metronidazol/toxicidade , Neurônios Motores/efeitos dos fármacos , Retina/fisiologia , Visão Ocular/fisiologia , Animais , Animais Geneticamente Modificados , Eletrorretinografia , Larva , Neurônios Motores/metabolismo , Nitrorredutases/metabolismo , Estimulação Luminosa , Transdução de Sinais , Fatores de Transcrição/metabolismo , Peixe-Zebra
19.
Invest Ophthalmol Vis Sci ; 60(13): 4360-4377, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31634394

RESUMO

Purpose: To investigate the neuroprotective properties of creatine in the retina using in vitro and in vivo models of injury. Methods: Two different rat retinal culture systems (one containing retinal ganglion cells [RGC] and one not) were subjected to either metabolic stress, via treatments with the mitochondrial complex IV inhibitor sodium azide, or excitotoxic stress, via treatment with N-methyl-D-aspartate for 24 hours, in the presence or absence of creatine (0.5, 1.0, and 5.0 mM). Neuronal survival was assessed by immunolabeling for cell-specific antigens. Putative mechanisms of creatine action were investigated in vitro. Expression of creatine kinase (CK) isoenzymes in the rat retina was examined using Western blotting and immunohistochemistry. The effect of oral creatine supplementation (2%, wt/wt) on retinal and blood creatine levels was determined as well as RGC survival in rats treated with N-methyl-D-aspartate (NMDA; 10 nmol) or high IOP-induced ischemia reperfusion. Results: Creatine significantly prevented neuronal death induced by sodium azide and NMDA in both culture systems. Creatine administration did not alter cellular adenosine triphosphate (ATP). Inhibition of CK blocked the protective effect of creatine. Retinal neurons, including RGCs, expressed predominantly mitochondrial CK isoforms, while glial cells expressed exclusively cytoplasmic CKs. In vivo, NMDA and ischemia reperfusion caused substantial loss of RGCs. Creatine supplementation led to elevated blood and retinal levels of this compound but did not significantly augment RGC survival in either model. Conclusions: Creatine increased neuronal survival in retinal cultures; however, no significant protection of RGCs was evident in vivo, despite elevated levels of this compound being present in the retina after oral supplementation.


Assuntos
Creatina/farmacologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Degeneração Retiniana/prevenção & controle , Células Ganglionares da Retina/efeitos dos fármacos , Animais , Western Blotting , Sobrevivência Celular/fisiologia , Células Cultivadas , Creatina Quinase/metabolismo , Eletrorretinografia , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Isoenzimas/metabolismo , N-Metilaspartato/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Retina/enzimologia , Retina/fisiopatologia , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/metabolismo , Azida Sódica/farmacologia , Estresse Fisiológico
20.
Invest Ophthalmol Vis Sci ; 60(13): 4328-4335, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622469

RESUMO

Purpose: We evaluate the effect of choroidal vessel density on the residual length of the ellipsoid zone (EZ) and visual function in patients with retinitis pigmentosa (RP) using optical coherence tomography angiography (OCTA). Methods: Fifty-three patients with RP (n = 101 eyes) and 53 normal participants (n = 76 eyes) were enrolled in this study. Patients with RP were assigned to three groups according to their best-corrected visual acuity (BCVA). All patients underwent ophthalmologic examinations, including BCVA, fundus examination performed with a slit-lamp using an indirect 90 diopter (D) lens, OCTA, full-field electroretinogram (ERG), and visual field. The choroidal vessel density in the choriocapillaris-Sattler's layer (DC-S), Haller's layer (DH), horizontal length of the ellipsoid (HEL), and vertical length of the ellipsoid (VEL) were assessed using OCTA and Adobe Photoshop CS3 extended software. Results: A significantly increasing impairment of choroidal vessel density (DC-S and DH) was characterized in the RP groups compared to those of the controls (P < 0.05 for all). The magnitude of the reduction in the DC-S and DH was much easier to identify for more severely impaired BCVA in the RP groups (P < 0.05 for all). The DC-S had the strongest correlation with the HEL, VEL, BCVA, visual field, and b-wave amplitude (r = 0.735, r = 0.753, r = -0.843, r = 0.579, and r = 0.671, respectively). Conclusions: Using noninvasive OCTA, choroidal microcirculation, especially in the small/middle choroidal vessel layers, was a prominent factor affecting the EZ, visual acuity, visual field, and recordable ERG b-wave amplitude of patients with RP. This may provide new insights into the progress mechanism and treatment of RP.


Assuntos
Vasos Sanguíneos/patologia , Corioide/irrigação sanguínea , Retinite Pigmentosa/fisiopatologia , Acuidade Visual/fisiologia , Adulto , Idoso , Vasos Sanguíneos/diagnóstico por imagem , Estudos Transversais , Eletrorretinografia , Feminino , Angiofluoresceinografia , Humanos , Masculino , Pessoa de Meia-Idade , Retina/fisiopatologia , Tomografia de Coerência Óptica/métodos , Campos Visuais/fisiologia , Adulto Jovem
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