Eye Institute, Eye and ENT Hospital, College of Medicine, Fudan University, Shanghai, China.
Shanghai Key Laboratory of Visual Impairment and Restoration, Science and Technology Commission of Shanghai Municipality, Shanghai, China.
J Transl Med. 2024 May 13;22(1):447. doi: 10.1186/s12967-024-05260-1.
Retinal ischemia/reperfusion (RIR) is implicated in various forms of optic neuropathies, yet effective treatments are lacking. RIR leads to the death of retinal ganglion cells (RGCs) and subsequent vision loss, posing detrimental effects on both physical and mental health. Apigenin (API), derived from a wide range of sources, has been reported to exert protective effects against ischemia/reperfusion injuries in various organs, such as the brain, kidney, myocardium, and liver. In this study, we investigated the protective effect of API and its underlying mechanisms on RGC degeneration induced by retinal ischemia/reperfusion (RIR).
An in vivo model was induced by anterior chamber perfusion following intravitreal injection of API one day prior to the procedure. Meanwhile, an in vitro model was established through 1% oxygen and glucose deprivation. The neuroprotective effects of API were evaluated using H&E staining, spectral-domain optical coherence tomography (SD-OCT), Fluoro-Gold retrograde labeling, and Photopic negative response (PhNR). Furthermore, transmission electron microscopy (TEM) was employed to observe mitochondrial crista morphology and integrity. To elucidate the underlying mechanisms of API, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, flow cytometry assay, western blot, cell counting kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) assay, JC-1 kit assay, dichlorofluorescein-diacetate (DCFH-DA) assay, as well as TMRE and Mito-tracker staining were conducted.
API treatment protected retinal inner plexiform layer (IPL) and ganglion cell complex (GCC), and improved the function of retinal ganglion cells (RGCs). Additionally, API reduced RGC apoptosis and decreased lactate dehydrogenase (LDH) release by upregulating Bcl-2 and Bcl-xL expression, while downregulating Bax and cleaved caspase-3 expression. Furthermore, API increased mitochondrial membrane potential (MMP) and decreased extracellular reactive oxygen species (ROS) production. These effects were achieved by enhancing mitochondrial function, restoring mitochondrial cristae morphology and integrity, and regulating the expression of OPA1, MFN2, and DRP1, thereby regulating mitochondrial dynamics involving fusion and fission.
API protects RGCs against RIR injury by modulating mitochondrial dynamics, promoting mitochondrial fusion and fission.
视网膜缺血/再灌注（RIR）与各种形式的视神经病变有关，但缺乏有效的治疗方法。RIR 导致视网膜神经节细胞（RGC）死亡，随后视力丧失，对身心健康都有不利影响。芹菜素（API）来源于多种来源，据报道，它对大脑、肾脏、心肌和肝脏等各种器官的缺血/再灌注损伤具有保护作用。在这项研究中，我们研究了 API 对视网膜缺血/再灌注（RIR）诱导的 RGC 变性的保护作用及其潜在机制。
在手术前一天通过玻璃体内注射 API 预先诱导体内模型，同时通过 1%氧气和葡萄糖剥夺建立体外模型。使用 H&E 染色、谱域光相干断层扫描（SD-OCT）、荧光金逆行标记和光峰负反应（PhNR）评估 API 的神经保护作用。此外，还使用透射电子显微镜（TEM）观察线粒体嵴形态和完整性。为了阐明 API 的潜在机制，进行了末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）检测、流式细胞术检测、western blot、细胞计数试剂盒-8（CCK-8）检测、乳酸脱氢酶（LDH）检测、JC-1 试剂盒检测、二氯荧光素二乙酸酯（DCFH-DA）检测以及 TMRE 和 Mito-tracker 染色。
API 治疗可保护视网膜内丛状层（IPL）和节细胞复合体（GCC），并改善视网膜神经节细胞（RGC）的功能。此外，API 通过上调 Bcl-2 和 Bcl-xL 的表达，同时下调 Bax 和 cleaved caspase-3 的表达，减少 RGC 凋亡和乳酸脱氢酶（LDH）释放。此外，API 增加了线粒体膜电位（MMP）并减少了细胞外活性氧（ROS）的产生。这些作用是通过增强线粒体功能、恢复线粒体嵴形态和完整性以及调节 OPA1、MFN2 和 DRP1 的表达来实现的，从而调节涉及融合和裂变的线粒体动力学。
API 通过调节线粒体动力学，促进线粒体融合和裂变，保护 RGC 免受 RIR 损伤。
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