RESUMO
Diabetic retinopathy (DR) is a leading cause of blindness and vision impairment worldwide and represents one of the most common complications among diabetic patients. Current treatment modalities for DR, including laser photocoagulation, intravitreal injection of corticosteroid, and anti-vascular endothelial growth factor (VEGF) agents, target primarily vascular lesions. However, these approaches are invasive and have several limitations, such as potential loss of visual function, retinal scars and cataract formation, and increased risk of ocular hypertension, vitreous hemorrhage, retinal detachment, and intraocular inflammation. Recent studies have suggested mitochondrial dysfunction as a pivotal factor leading to both the vascular and neural damage in DR. Given that Coenzyme Q10 (CoQ10) is a proven mitochondrial stabilizer with antioxidative properties, this study investigated the effect of CoQ10 eyedrops [in conjunction with vitamin E d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS)] on DR-induced neurodegeneration using a type 2 diabetes mouse model (C57BLKsJ-db/db mice). Utilizing a comprehensive electroretinography protocol, supported by immunohistochemistry, our results revealed that topical application of CoQ10 eyedrops conjugated with vitamin E TPGS produced a neuroprotective effect against diabetic-induced neurodegeneration by preserving the function and histology of various retinal neural cell types. Compared to the control group, mice treated with CoQ10 exhibited thicker outer and inner nuclear layers, higher densities of photoreceptor, cone cell, and rod-bipolar cell dendritic boutons, and reduced glial reactivity and microglial cell density. Additionally, the CoQ10 treatment significantly alleviated retinal levels of MMP-9 and enhanced mitochondrial function. These findings provide further insight into the role of mitochondrial dysfunction in the development of DR and suggest CoQ10 eyedrops, conjugated with vitamin E TPGS, as a potential complementary therapy for DR-related neuropathy.
RESUMO
In age-related macular degeneration (AMD), hydroquinone (HQ)-induced oxidative damage in retinal pigment epithelium (RPE) is believed to be an early event contributing to dysregulation of inflammatory cytokines and vascular endothelial growth factor (VEGF) homeostasis. However, the roles of antioxidant mechanisms, such as autophagy and the ubiquitin-proteasome system, in modulating HQ-induced oxidative damage in RPE is not well-understood. This study utilized an in-vitro AMD model involving the incubation of human RPE cells (ARPE-19) with HQ. In comparison to hydrogen peroxide (H2O2), HQ induced fewer reactive oxygen species (ROS) but more oxidative damage as characterized by protein carbonyl levels, mitochondrial dysfunction, and the loss of cell viability. HQ blocked the autophagy flux and increased proteasome activity, whereas H2O2 did the opposite. Moreover, the lysosomal membrane-stabilizing protein LAMP2 and cathepsin D levels declined with HQ exposure, suggesting loss of lysosomal membrane integrity and function. Accordingly, HQ induced lysosomal alkalization, thereby compromising the acidic pH needed for optimal lysosomal degradation. Pretreatment with MG132, a proteasome inhibitor and lysosomal stabilizer, upregulated LAMP2 and autophagy and prevented HQ-induced oxidative damage in wildtype RPE cells but not cells transfected with shRNA against ATG5. This study demonstrated that lysosomal dysfunction underlies autophagy defects and oxidative damage induced by HQ in human RPE cells and supports lysosomal stabilization with the proteasome inhibitor MG132 as a potential remedy for oxidative damage in RPE and AMD.