Hyperoside protects against oxidative stress-mediated photoreceptor degeneration: therapeutic potentials for photoreceptor degenerative diseases

Abstract

Background Photoreceptor degeneration underpinned by oxidative stress-mediated mitochondrial dysfunction and cell death leads to progressive and irreversible vision impairment. Drug treatments that protect against photoreceptor degeneration are currently available in the clinical settings. It has been shown that hyperoside, a flavonol glycoside, protects against neuronal loss in part by suppressing oxidative stress and maintaining the functional integrity of mitochondria. However, whether hyperoside protects against photoreceptor degeneration remains unknown. Methods To address the pharmacological potentials of hyperoside against oxidative stress-mediated photoreceptor degeneration on molecular, cellular, structural and functional levels, multiple in vitro and in vivo methodologies were employed in the current study, including live-cell imaging, optical coherence tomography, electroretinography, histological/immunohistochemical examinations, transmission electron microscopy, RNA-sequencing and real-time qPCR. Results The in vitro results demonstrate that hyperoside suppresses oxidative stress-mediated photoreceptor cell death in part by mitigating mitochondrial dysfunction. The in vivo results reveal that hyperoside protects against photooxidative stress-induced photoreceptor morphological, functional and ultrastructural degeneration. Meanwhile, hyperoside treatment offsets the deleterious impact of photooxidative stress on multiple molecular pathways implicated in the pathogenesis of photoreceptor degeneration. Lastly, hyperoside attenuates photoreceptor degeneration-associated microglial inflammatory activation and reactive Müller cell gliosis. Conclusions All things considered, the present study demonstrates for the first time that hyperoside attenuates oxidative stress-induced photoreceptor mitochondrial dysfunction and cell death. The photoreceptor-intrinsic protective effects of hyperoside are corroborated by hyperoside-conferred protection against photooxidative stress-mediated photoreceptor degeneration and perturbation in retinal homeostasis, warranting further evaluation of hyperoside as a photoreceptor protective agent for the treatment of related photoreceptor degenerative diseases.

Hyperoside mitigates photoreceptor degeneration in part by targeting cGAS and suppressing DNA-induced microglial activation

“…1 , hyperoside mitigates the pro-inflammatory activation of BV-2 cells, raising the possibility that by curtailing microglial activation, hyperoside may alleviate the progression of photoreceptor degeneration. To directly test this hypothesis, instead of delivering a one-dose pre-light damage hyperoside treatment to antagonize photooxidative stress [ 10 ], a post-light damage hyperoside treatment regimen was adopted. Release of non-histone nuclear protein HMGB1 signifies necrotic cell damage and ensuing inflammation [ 11 ].…”

“…5 ). Moreover, our previous RNA-sequencing analysis has demonstrated that in the light-exposed retinas, multiple pathways involved in inflammatory responses are upregulated prior to overt loss of photoreceptors [ 10 ]. Among these pathways, cytosolic DNA-sensing pathway was significantly upregulated in the light-exposed retinas as revealed by our previous gene set enrichment analysis (Fig.…”

“…Image-guided OCT (OCT 2 with Micron IV, Phoenix Research Labs, USA) was performed to scan the retina 7 d post illumination as previously described [ 10 ]. In brief, after administering anesthetic cocktail of ketamine hydrochloride (82.5 mg/kg body weight) and xylazine (8.25 mg/kg body weight), pupil dilation was induced using 1% tropicamide (Santen Pharmaceutical, Japan) to prepare the mice for the OCT imaging.…”

“…Seven days after the illumination, dark-adapted mice were subjected to ERG analysis under a safe light condition (5 lx) as previously described [ 10 ]. Flashes of green light (504 nm) were delivered at intensities of -2 (0.5 msec duration and 5 s inter-stimulus-interval), -0.8 (1 msec duration and 5 s inter-stimulus-interval), 0.4 (1 msec duration and 10 s inter-stimulus-interval), 1.6 (1 msec duration and 20 s inter-stimulus-interval), and 3.1 (1 msec duration and 60 s inter-stimulus-interval) log cd·s·m − 2 .…”

“…It has been shown that hyperoside suppresses the pro-inflammatory activation of microglia and attenuates the loss of dopaminergic neurons in mice recapitulating Parkinson’s disease [ 8 , 9 ], supporting the therapeutic potentials of hyperoside in alleviating neuroinflammation in neurodegenerative disorders. Moreover, our previous work has demonstrated that hyperoside prevents photooxidative stress-induced photoreceptor degeneration, neuroinflammatory responses and microglial activation in vivo [ 10 ]. However, in our previous work, in order to assess the photoreceptor protective effects of hyperoside as an antioxidant, instead of post-light damage treatment, one-dose pre-light damage hyperoside treatment was administered to counteract photooxidative stress that triggers the initial loss of photoreceptors.…”