Connexin43 as a novel therapeutic target in age-related macular degeneration

Age-related macular degeneration (AMD) is the major cause of blindness in the elderly. There is currently no cure for AMD although several risk factors have been implicated in the pathogenesis and progression of the disease. These include oxidative stress, inflammation and vascular changes. Connexin43 (Cx43) is the most ubiquitous gap junction protein in mammals playing a role in intercellular communication. Increased Cx43 expression in the vasculature and astrocytes has been reported for many human central nervous system injuries. However, the association between Cx43 and AMD remains unclear. Intense light exposed albino rats are used as animal model of AMD and were employed in the current study. The electroretinogram (ERG) demonstrated that photoreceptoral and postphotorecetoral functions involving both rod and cone pathways were dramatically reduced following light damage (LD) compared to normal non-LD rat eyes. Microglia activation and migration from the retinal plexiform layers into the nuclear layers was confirmed using immunohistochemistry. A significant increase in Cx43 expression was detected in the choroid following light damage as assessed using Western blotting. This increased expression was associated with significantly increased levels of the oxidative stress marker, nitrotyrosine. Intravitreal injection of a Cx43 mimetic peptide was used to modulate the function of Cx43 hemichannels in the AMD animal model. A single dose treatment showed a trend toward improvement in function of both rod and cone pathways when compared to sham-treated rats. Rats given a double dose treatment, one during LD and the second post-LD showed significant functional improvement to both rod and cone pathways compared to the shamtreated animals. Cellular analysis demonstrated that the glia-mediated inflammatory response was down-regulated in treated animals with decreased expression of glial fibrillary acidic protein (GFAP) and fewer activated microglia in the retina, and fewer macrophages in the choroid. A comparison of the animal model pathology with AMD affected human eyes was conducted using human post-mortem tissues. Up-regulated Cx43 immunoreactivity was found to be associated with increased GFAP expression in drusen-free areas of AMD affected retina. Activated and migrating microglia were also discovered in this area. These findings indicate a close association between increased Cx43 expression with disease progression in human AMD. The combined animal and human data indicate that modulation of Cx43 channels provides a potential target for the treatment of AMD.

Name thesis:degree_name

PhD

Level thesis:degree_level

Doctoral

Grantor dc:publisher

ResearchSpace@Auckland

Year dc:date.issued

2014

Author dc:creator

• Guo, Xiaopeng

Advisors dc:contributor.advisor

• Acosta, M
• Green, C
• Danesh-Meyer, H

Statement dc:rights

• Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher.

Licence dc:rights.uri

• https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Handle dc:identifier.uri

https://hdl.handle.net/2292/22219

OAI identifier oai:identifier

oai:researchspace.auckland.ac.nz:2292/22219