Effects of connexin modulators in animal models of retinal degeneration : delivery and treatment efficacy
Worldwide, age-related macular degeneration (AMD) is one of the most frequently ocurring diseases associated with blindness. Previous studies have provided evidence for the role of inflammation and oxidative stress in AMD progression. 11 has also been found that connexin hemichannels playa role in t...
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| Format: | Thesis Book |
| Language: | English |
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| Summary: | Worldwide, age-related macular degeneration (AMD) is one of the most frequently ocurring diseases associated with blindness. Previous studies have provided evidence for the role of inflammation and oxidative stress in AMD progression. 11 has also been found that connexin hemichannels playa role in the disease's pathology. In the normal eye, hemichannels are in a closed state or docked together forming gap junctions for intercellular communication. However, there is undocking of hemichannels and abnormal opening during inflammation and oxidative stress leading to a eries of events that result in vascular leakage, further inflammation and cell death. Connexin43 mimetic peptides are connexin modulators that have been successfully applied to prevent blood vessel leak and to control inflammation in in vitro and in vivo models of acute ocular disease. A novel connexin modulator, tonabersat, that previously reached phase 11 clinical trials for the treatment of migraine, has been shown to reduce the activity of neurons after cellular injury. Despite its therapeutic potential, the impact of this connexin modulator on ocular injury, particularly its effect on inflammation and retinal function, had not been established. It is proposed that hemichannels confer damage by releasing excessive amounts of ATP that change the tissue environment in pathologies. Pannexin channels are also classically described as ATP releasing channels during injury. Therefore the role of pannexins and connexins in injury of the retina in this animal model needed further experimental evidence. Thus, the aim of this thesis was to determine the effect of hemichannel blocker(Cx43 mimetic peptides, tonabersat) and pannexin channel-blockers (probenecid) in an animal model of oxidative stress and inflammation mimicking the early stages of AMD. The animal model used was the bright light-induced chorio-retinal damage model that has been extensively used as a model of retinal degeneration.The treatment delivery method has been an important factor in the success of other ocular therapies and therefore intravitreal, systemic and oral delivery methods together with novel drug carrier formulations (nanoparticles) were trialled to assess the efficacy of the treatment long term. Using electroretinography, optical coherence tomography imaging and molecular approaches investigation was performed to further understand the potential of these novel connexin based treatments in the treatment of early signs of the disease.The study of tonabersat treatment was further extended to its effect on diabetes-induced ocular indications. A spontaneous diabetic rat was discovered during routine analysis of the University of Auckland Sprague-Dawley rat colony. The rats developed ocular vascular lesions, inflammation and cell damage typical of signs seen in diabetic retinopathy (DR). Tonabersat treatment was applied and lesions were monitored. Taken together, this study provides a thorough understanding for the potential of in vivo connexinbased therapies to reduce functional and structural damage associated with retinal degeneration conditions such as AMD and DR. |
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| Physical Description: | xix, 239 leaves: illustrations; 31 cm. |
| Bibliography: | Includes bibliographical references(p. 213-239) |