背景:以氧化应激介导的线粒体功能障碍和细胞死亡为基础的光感受器变性导致进行性和不可逆的视力损害。防止光感受器变性的药物治疗目前在临床环境中是可用的。已经证明金丝桃苷,黄酮醇苷,部分通过抑制氧化应激和维持线粒体的功能完整性来防止神经元丢失。然而,金丝桃苷是否可以防止光感受器变性尚不清楚。
方法:为了解决金丝桃苷抗氧化应激介导的光感受器变性的药理学潜力,细胞,结构和功能层面,本研究采用了多种体外和体内方法,包括活细胞成像,光学相干层析成像,视网膜电图,组织学/免疫组织化学检查,透射电子显微镜,RNA测序和实时qPCR。
结果:体外结果表明,金丝桃苷通过减轻线粒体功能障碍部分抑制氧化应激介导的感光细胞死亡。体内结果表明,金丝桃苷可以抵抗光氧化应激诱导的光感受器形态,功能和超微结构退化。同时,金丝桃苷治疗抵消了光氧化应激对涉及光感受器变性发病机制的多种分子途径的有害影响。最后,金丝桃苷减轻光感受器变性相关的小胶质细胞炎症激活和反应性Müller细胞胶质增生。
结论:所有考虑的事情,本研究首次证明了金丝桃苷能减轻氧化应激诱导的光感受器线粒体功能障碍和细胞死亡。金丝桃苷对光致氧化应激介导的光感受器变性和视网膜稳态扰动的保护作用证实了金丝桃苷的光感受器固有保护作用。保证进一步评估金丝桃苷作为治疗相关光感受器退行性疾病的光感受器保护剂。
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.
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.
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.
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.