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1.
Invest Ophthalmol Vis Sci ; 56(2): 893-907, 2015 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-25587060

RESUMO

PURPOSE: Glaucoma is an optic neuropathy commonly associated with elevated intraocular pressure (IOP), leading to optic nerve head (ONH) cupping, axon loss, and apoptosis of retinal ganglion cells (RGCs), which could ultimately result in blindness. Brn3b is a class-4 POU domain transcription factor that plays a key role in RGC development, axon outgrowth, and pathfinding. Previous studies suggest that a decrease in Brn3b levels occurs in animal models of glaucoma. The goal of this study was to determine if adeno-associated virus (AAV)-directed overexpression of the Brn3b protein could have neuroprotective effects following elevated IOP-mediated neurodegeneration. METHODS: Intraocular pressure was elevated in one eye of Brown Norway rats (Rattus norvegicus), following which the IOP-elevated eyes were intravitreally injected with AAV constructs encoding either the GFP (rAAV-CMV-GFP and rAAV-hsyn-GFP) or Brn3b (rAAV-CMV-Brn3b and rAAV-hsyn-Brn3b). Retina sections through the ONH were stained for synaptic plasticity markers and neuroprotection was assessed by RGC counts and visual acuity tests. RESULTS: Adeno-associated virus-mediated expression of the Brn3b protein in IOP-elevated rat eyes promoted an upregulation of growth associated protein-43 (GAP-43), actin binding LIM protein (abLIM) and acetylated α-tubulin (ac-Tuba) both posterior to the ONH and in RGCs. The RGC survival as well as axon integrity score were significantly improved in IOP-elevated rAAV-hsyn-Brn3b-injected rats compared with those of the IOP-elevated rAAV-hsyn-GFP- injected rats. Additionally, intravitreal rAAV-hsyn-Brn3b administration significantly restored the visual optomotor response in IOP-elevated rat eyes. CONCLUSIONS: Adeno-associated virus-mediated Brn3b protein expression may be a suitable approach for promoting neuroprotection in animal models of glaucoma.


Assuntos
Regulação da Expressão Gênica , Glaucoma/genética , Hipertensão Ocular/genética , RNA/genética , Células Ganglionares da Retina/metabolismo , Fator de Transcrição Brn-3B/genética , Animais , Sobrevivência Celular , Células Cultivadas , Modelos Animais de Doenças , Feminino , Glaucoma/metabolismo , Glaucoma/fisiopatologia , Immunoblotting , Imuno-Histoquímica , Pressão Intraocular , Masculino , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Ratos , Ratos Endogâmicos BN , Ratos Sprague-Dawley , Células Ganglionares da Retina/patologia , Transdução de Sinais , Fator de Transcrição Brn-3B/biossíntese
2.
PLoS One ; 7(10): e45469, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23094016

RESUMO

Acute ocular hypertension (AOH) is a condition found in acute glaucoma. The purpose of this study is to investigate the protective effect of Lycium barbarum polysaccharides (LBP) and its protective mechanisms in the AOH insult. LBP has been shown to exhibit neuroprotective effect in the chronic ocular hypertension (COH) experiments. AOH mouse model was induced in unilateral eye for one hour by introducing 90 mmHg ocular pressure. The animal was fed with LBP solution (1 mg/kg) or vehicle daily from 7 days before the AOH insult till sacrifice at either day 4 or day 7 post insult. The neuroprotective effects of LBP on retinal ganglion cells (RGCs) and blood-retinal-barrier (BRB) were evaluated. In control AOH retina, loss of RGCs, thinning of IRL thickness, increased IgG leakage, broken tight junctions, and decreased density of retinal blood vessels were observed. However, in LBP-treated AOH retina, there was less loss of RGCs with thinning of IRL thickness, IgG leakage, more continued structure of tight junctions associated with higher level of occludin protein and the recovery of the blood vessel density when compared with vehicle-treated AOH retina. Moreover, we found that LBP provides neuroprotection by down-regulating RAGE, ET-1, Aß and AGE in the retina, as well as their related signaling pathways, which was related to inhibiting vascular damages and the neuronal degeneration in AOH insults. The present study suggests that LBP could prevent damage to RGCs from AOH-induced ischemic injury; furthermore, through its effects on blood vessel protection, LBP would also be a potential treatment for vascular-related retinopathy.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Degeneração Neural/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Hipertensão Ocular/prevenção & controle , Células Ganglionares da Retina/efeitos dos fármacos , Vasos Retinianos/efeitos dos fármacos , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematorretiniana/efeitos dos fármacos , Barreira Hematorretiniana/metabolismo , Barreira Hematorretiniana/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Medicamentos de Ervas Chinesas/uso terapêutico , Endotelina-1/genética , Endotelina-1/metabolismo , Expressão Gênica/efeitos dos fármacos , Imunoglobulina G/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Degeneração Neural/genética , Degeneração Neural/metabolismo , Degeneração Neural/patologia , Fármacos Neuroprotetores/uso terapêutico , Hipertensão Ocular/genética , Hipertensão Ocular/metabolismo , Hipertensão Ocular/patologia , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Células Ganglionares da Retina/metabolismo , Células Ganglionares da Retina/patologia , Vasos Retinianos/metabolismo , Vasos Retinianos/patologia , Transdução de Sinais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Junções Íntimas/patologia
3.
PLoS One ; 7(8): e43199, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22916224

RESUMO

Glaucoma is an optic neuropathy, commonly associated with elevated intraocular pressure (IOP) characterized by optic nerve degeneration, cupping of the optic disc, and loss of retinal ganglion cells which could lead to loss of vision. Endothelin-1 (ET-1) is a 21-amino acid vasoactive peptide that plays a key role in the pathogenesis of glaucoma; however, the receptors mediating these effects have not been defined. In the current study, endothelin B (ET(B)) receptor expression was assessed in vivo, in the Morrison's ocular hypertension model of glaucoma in rats. Elevation of IOP in Brown Norway rats produced increased expression of ET(B) receptors in the retina, mainly in retinal ganglion cells (RGCs), nerve fiber layer (NFL), and also in the inner plexiform layer (IPL) and inner nuclear layer (INL). To determine the role of ET(B) receptors in neurodegeneration, Wistar-Kyoto wild type (WT) and ET(B) receptor-deficient (KO) rats were subjected to retrograde labeling with Fluoro-Gold (FG), following which IOP was elevated in one eye while the contralateral eye served as control. IOP elevation for 4 weeks in WT rats caused an appreciable loss of RGCs, which was significantly attenuated in KO rats. In addition, degenerative changes in the optic nerve were greatly reduced in KO rats compared to those in WT rats. Taken together, elevated intraocular pressure mediated increase in ET(B) receptor expression and its activation may contribute to a decrease in RGC survival as seen in glaucoma. These findings raise the possibility of using endothelin receptor antagonists as neuroprotective agents for the treatment of glaucoma.


Assuntos
Glaucoma/metabolismo , Receptor de Endotelina B/metabolismo , Células Ganglionares da Retina/metabolismo , Animais , Modelos Animais de Doenças , Glaucoma/genética , Pressão Intraocular/genética , Pressão Intraocular/fisiologia , Masculino , Fibras Nervosas/metabolismo , Hipertensão Ocular/genética , Hipertensão Ocular/metabolismo , Ratos , Ratos Wistar , Receptor de Endotelina B/genética
4.
Ophthalmic Res ; 45(2): 65-72, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-20714194

RESUMO

AIMS: Deduce whether the isoflavone genistein blunts the effect of ischaemia to the retina. METHODS: Ischaemia was induced in rats by raising the intraocular pressure (120 mm Hg) for 50 min. Genistein (10 mg/kg) was injected intraperitoneally 1 h before and after ischaemia. Seven days after ischaemia, the level of mRNAs for neurofilament light (NF-L), caspase 3, caspase 8, glial fibrillary acidic protein (GFAP), poly-ADP ribose polymerase (PARP), Thy-1 and proteins (GFAP, NF-L, PARP) in whole retinas were determined. NF-L and tubulin proteins in optic nerves were also determined. Retinas were also processed for the localization of choline acetyltransferase (ChAT) and GFAP immunoreactivities. RESULTS: Ischaemia caused a significant reduction in ganglion cell proteins in the optic nerve (NF-L and tubulin) and retina (NF-L). Retinal Thy-1 (mRNA and protein) and NF-L (mRNA) were also reduced while mRNAs of caspase 3, caspase 8, PARP and GFAP (also protein) were increased. Changes in the mRNAs and proteins induced by ischaemia were significantly blunted by genistein with the exception of the increase in GFAP and PARP protein/mRNA levels. Ischaemia-induced changes in the localization of ChAT were also clearly attenuated by genistein treatment. CONCLUSIONS: Genistein blunts most of the damaging effects caused to the retina by ischaemia.


Assuntos
Genisteína/uso terapêutico , Pressão Intraocular , Fitoestrógenos/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Doenças Retinianas/prevenção & controle , Animais , Caspase 3/genética , Caspase 8/genética , Ciclofilinas/genética , Modelos Animais de Doenças , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Proteína Glial Fibrilar Ácida/metabolismo , Injeções Intraperitoneais , Proteínas de Neurofilamentos/genética , Hipertensão Ocular/complicações , Hipertensão Ocular/genética , Poli Adenosina Difosfato Ribose/genética , Proteínas/genética , RNA Mensageiro/genética , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/genética , Doenças Retinianas/etiologia , Doenças Retinianas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Antígenos Thy-1/genética
5.
Zhongguo Zhen Jiu ; 30(8): 661-4, 2010 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-20942284

RESUMO

OBJECTIVE: To explore the protection effects of acupuncture on glaucomatous optic nerve damage and its mechanism. METHODS: Experimental glaucoma model was induced by intracameral injection of compound Carbomer solution in rabbits. After 28 days, ocular tension returned to normal by filtration surgery. Twenty rabbits (40 eyes) were randomly divided into a model group, an acupuncture group, a neurotrophy group and a nomal control group, 5 cases in each group. The acupuncture group was treated with acupuncture at bilateral "Qiuhou" (EX-HN 7),"Fengchi" (GB 20) and "Xingjian" (LR 2), twice a day. The neurotrophy group was treated with intramuscular injection of Vitamin B1 (100 mg) and Vitamin B12 (500 microg), once a day, and the other groups with no treatment. The expressions of Bcl-xl and BDNF in rabbits retina were observed after 4 weeks. RESULTS: At the end of the experiment, the positive expression cells of Bcl-xl and BDNF were (31.20 +/- 5.97) per mm2 and (6.3 +/- 1.89) per mm2 in the acupuncture group, being significantly higer than (26.70 +/- 4.32) per mm2 and (4.0 +/- 1.89) per mm2 in the model group (both P<0.05). CONCLUSION: Acupuncture can raise the expression of Bcl-xl and BDNF of retina, so as to prevent optic nerve damage caused by intraocular hypertension.


Assuntos
Terapia por Acupuntura , Fator Neurotrófico Derivado do Encéfalo/genética , Expressão Gênica , Hipertensão Ocular/genética , Hipertensão Ocular/terapia , Retina/metabolismo , Proteína bcl-X/genética , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença Crônica/terapia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Hipertensão Ocular/metabolismo , Coelhos , Distribuição Aleatória , Proteína bcl-X/metabolismo
6.
Graefes Arch Clin Exp Ophthalmol ; 243(4): 294-9, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15864617

RESUMO

BACKGROUND: Primary open-angle glaucoma (POAG) is a leading cause of blindness. High intraocular pressure (IOP) has been shown to be a key risk factor for POAG. Topical application of angiotensin 1-converting enzyme (ACE) inhibitors has been shown to lower IOP, and angiotensin-induced increase in vascular tone has been implicated as a pathogenetic mechanism in glaucomatous cupping and damage to the optic nerve. The objective of this study was to investigate the association between the deletion polymorphism in the ACE gene and ocular signs of POAG. METHODS: Baseline data from the Rotterdam Study was used. The ACE genotype was determined in 6,462 subjects. We used univariate and multiple variable statistical techniques to examine associations between ACE genotype and each of ocular hypertension, glaucomatous optic neuropathy, glaucomatous visual field defects and POAG diagnosis. RESULTS: We found no consistent evidence between ACE genotype and ocular signs of POAG. We did, however, find evidence of an association between ACE genotype and optic disc area, subjects homozygous for the deletion allele tending to have fractionally smaller optic disc areas than those with a single deletion allele subjects, who in turn tended to have fractionally smaller optic discs than those with no deletion alleles (P=0.01). CONCLUSIONS: The data provided little evidence of any association between ocular signs of POAG and the deletion polymorphism of ACE. There was, however, evidence that ACE may be associated with optic disc size-this was an unexpected finding.


Assuntos
Deleção de Genes , Glaucoma de Ângulo Aberto/genética , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Idoso , Inibidores da Enzima Conversora de Angiotensina , Pressão Sanguínea , Feminino , Genótipo , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/genética , Disco Óptico/patologia , Doenças do Nervo Óptico/genética , Reação em Cadeia da Polimerase
7.
Arch Ophthalmol ; 121(8): 1172-80, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12912696

RESUMO

OBJECTIVE: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met. METHOD AND DESIGN: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing. RESULTS: From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype. CONCLUSIONS: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.


Assuntos
Proteínas do Olho/genética , Glaucoma de Ângulo Aberto/genética , Glaucoma de Ângulo Aberto/patologia , Glicoproteínas/genética , Mutação de Sentido Incorreto , Adulto , Idoso , Austrália , Estudos Transversais , Proteínas do Citoesqueleto , Análise Mutacional de DNA , Feminino , Ligação Genética , Haplótipos , Humanos , Pressão Intraocular , Masculino , Pessoa de Meia-Idade , Hipertensão Ocular/genética , Hipertensão Ocular/patologia , Disco Óptico/patologia , Linhagem , Fenótipo , Polimorfismo Conformacional de Fita Simples , Campos Visuais
8.
Invest Ophthalmol Vis Sci ; 39(6): 951-62, 1998 May.
Artigo em Inglês | MEDLINE | ID: mdl-9579474

RESUMO

PURPOSE: To characterize ocular abnormalities associated with iris atrophy in DBA/2J mice and to determine whether mice of this strain develop elevated intraocular pressure (IOP) and glaucoma. METHODS: Different approaches, including slit-lamp biomicroscopy, ophthalmoscopic examination, ultrasound backscatter microscopy, and histology were used to examine the eyes of DBA/2J mice ranging from 2 to 30 months old. IOP was measured in DBA/2J mice of different ages. RESULTS: DBA/2J mice were found to develop pigment dispersion, iris transillumination, iris atrophy, anterior synechias, and elevated IOP. IOP was elevated in most mice by the age of 9 months. These changes were followed by the death of retinal ganglion cells, optic nerve atrophy, and optic nerve cupping. The prevalence and severity of these lesions increased with age. Optic nerve atrophy and optic nerve cupping was present in the majority of mice by the age of 22 months. CONCLUSIONS: DBA/2J mice develop a progressive form of secondary angle-closure glaucoma that appears to be initiated by iris atrophy and the associated formation of synechias. This mouse strain represents a useful model to evaluate mechanisms of pressure-related ganglion cell death and optic nerve atrophy, and to evaluate strategies for neuroprotection.


Assuntos
Síndrome de Exfoliação/patologia , Oftalmopatias Hereditárias/patologia , Glaucoma de Ângulo Fechado/patologia , Iris/patologia , Envelhecimento/patologia , Animais , Segmento Anterior do Olho/patologia , Atrofia , Morte Celular , Modelos Animais de Doenças , Progressão da Doença , Síndrome de Exfoliação/etiologia , Síndrome de Exfoliação/genética , Oftalmopatias Hereditárias/etiologia , Oftalmopatias Hereditárias/genética , Feminino , Glaucoma de Ângulo Fechado/etiologia , Glaucoma de Ângulo Fechado/genética , Pressão Intraocular , Masculino , Camundongos , Camundongos Endogâmicos DBA , Hipertensão Ocular/etiologia , Hipertensão Ocular/genética , Hipertensão Ocular/patologia , Atrofia Óptica/etiologia , Atrofia Óptica/patologia , Células Ganglionares da Retina/patologia
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