Age-related macular degeneration (AMD) is a leading cause of severe visual loss and irreversible blindness in the elderly population worldwide. Retinal pigment epithelial (RPE) cells are the major site of pathological alterations in AMD. They are responsible for the phagocytosis of shed photoreceptor outer segments (POSs) and clearance of cellular waste under physiological conditions. Age-related, cumulative oxidative stimuli contribute to the pathogenesis of AMD. Excessive oxidative stress induces RPE cell degeneration and incomplete digestion of POSs, leading to the continuous accumulation of cellular waste (such as lipofuscin). Autophagy is a major system of degradation of damaged or unnecessary proteins. However, degenerative RPE cells in AMD patients cannot perform autophagy sufficiently to resist oxidative damage. Increasing evidence supports the idea that enhancing the autophagic process can properly alleviate oxidative injury in AMD and protect RPE and photoreceptor cells from degeneration and death, although overactivated autophagy may lead to cell death at early stages of retinal degenerative diseases. The crosstalk among the NFE2L2, PGC-1, p62, AMPK, and PI3K/Akt/mTOR pathways may play a crucial role in improving disturbed autophagy and mitigating the progression of AMD. In this review, we discuss how autophagy prevents oxidative damage in AMD, summarize potential neuroprotective strategies for therapeutic interventions, and provide an overview of these neuroprotective mechanisms.
Natural visible light is an electromagnetic wave composed of a spectrum of monochromatic wavelengths, each with a characteristic color. Photons are the basic units of light, and their wavelength correlates to the energy of light; short-wavelength photons carry high energy. The retina is a fragile neuronal tissue that senses light and generates visual signals conducted to the brain. However, excessive and intensive light exposure will cause retinal light damage. Within the visible spectrum, short-wavelength light, such as blue light, carries higher energy, and thus the retinal injury, is more significant when exposed to these wavelengths. The damage mechanism triggered by different short-wavelength light varies due to photons carrying different energy and being absorbed by different photosensitive molecules in the retinal neurons. However, photooxidation might be a common molecular step to initiate cell death. Herein, we summarize the historical understanding of light, the key molecular steps related to retinal light injury, and the death pathways of photoreceptors to further decipher the molecular mechanism of retinal light injury and explore potential neuroprotective strategies.
Prolonged light exposure may induce retinal damage and degeneration of cilia and photoreceptor cells. This study investigated the protective effect of poly (ADP-ribose) polymerase (PARP) inhibition on light-induced retinal damage in vitro and in vivo. A murine cone photoreceptor 661W cell line and an animal model of light-induced retinal damage in C57BL mice were used to assess light-induced cell damages and death as well as to elucidate the underlying molecular events. The data showed that light exposure induced 661W cell death by reducing the proportion of cells with cilia and destroying the structure of the outer segments (OS) of photoreceptors. PARP expression knockdown or use of a PARP inhibitor was able to protect cells against light-induced damage in vitro and in vivo. While exposure to light induced photoreceptor degeneration and cell death, PARP expression knockdown and treatment with a selective PARP inhibitor as well as an Akt activator protected retina cells by improving cell survival and maintaining the structure of the OS of photoreceptor cells (including cilia on the cell membrane) during the process of light-induced damage. This study demonstrated that activation of the PI3K/Akt pathway facilitates the protective effect of PARP inhibition on retinal cells damaged by exposure to the light.
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