Abstract

Retinitis pigmentosa (RP) is a series of inherited retinal degenerative diseases mostly caused by the gene mutations in rod photoreceptors, which lead to the primary loss of rod photoreceptors, and the secondary loss of cone photoreceptors. More than 1.5 million people worldwide lose their sight every year as a result of RP disorder. RP is a hereditary disease with complex causes, there are currently no ideal treatments that are either against primary gene mutations or against the secondary neuronal degeneration. Therapies that aim to preserve photoreceptor function may represent an effective alternative for improving the quality of life of many RP patients. The main focus of this thesis was to investigate the pathological mechanism of RP and to explore possible therapeutic strategies for it. Although the mechanisms of photoreceptor death remain elusive in RP, multiple mechanisms are suggested to have a role in photoreceptor death. To confirm the involvement of multiple pathways in RP, we systemically applied three multi-target iron-chelator based compounds: VK28, M30, VAR10303 and one multi-target traditional Chinese medicine LBP (Lycium III barbarum polysaccharides) to the rd10 mouse model of RP. The effectiveness of these drugs was evaluated by morphological, electrophysiological, behavioral and molecular biological analysis. We found that VK28, M30, VAR10303 and LBP appeared to have both short-term and long-term neuroprotective effects on photoreceptor cell. We further identified that these compounds exerted their effects through anti-apoptotic, antioxidant and anti-inflammatory mechanisms. The findings provided more evidence on the involvement of multiple mechanisms in photoreceptor degeneration of RP, suggesting a multi-target drug therapy is more sufficient than a single-targeted manipulation in protecting photoreceptors from degeneration in RP treatment. Neuroinflammation is suggested to be involved in pathology of glaucoma, but the mechanisms regulating microglia activation are not yet clear. We thus investigated the mechanisms underlying microglia activation in a mouse model of glaucoma. We found that microglia activation played a pathogenic role in AOH-caused retinal ganglion cell (RGC). We also demonstrated that chemokine receptor CX3CR1 in microglia played an important role in regulating microglia activation. Our findings indicate that suppressing neuroinflammation might be a therapeutic option for improving RGC survival in patients with glaucoma。