Increased Connexin43 hemichannel opening is associated with inflammasome pathway activation and inflammation in a range of pathologies including ocular disorders, such as age-related macular degeneration (AMD) and diabetic retinopathy (DR). In this study, the effect on retinal function and morphology of clinically safe doses of orally delivered tonabersat, a small molecule connexin hemichannel blocker, was investigated in the light-damaged retina animal model of dry AMD and in a spontaneous rat model of DR. Clinical parameters (fundus imaging, optical coherence tomography (OCT), and electroretinography) and inflammatory markers (immunohistochemistry for Iba-1 microglial marker, astrocyte marker glial fibrillary acidic protein, and Connexin43 protein expression) were assessed. Tonabersat treatment reduced inflammation in the retina in parallel with preservation of retinal photoreceptor function when assessed up to 3 months post light damage in the dry AMD model. In the DR model, clinical signs, including the presence of aneurysms confirmed using Evans blue dye perfusion, were reduced after daily tonabersat treatment for 2 weeks. Inflammation was also reduced and retinal electrical function restored. Tonabersat regulates assembly of the inflammasome (NLRP3) through Connexin43 hemichannel block, with the potential to reduce inflammation, restore vascular integrity and improve anatomical along with some functional outcomes in retinal disease.

中文翻译：

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使用口服 Tonabersat 的连接蛋白半通道阻滞可改善视网膜疾病动物模型的结果。

连接蛋白 43 半通道开放增加与炎症小体通路激活和炎症相关，包括眼部疾病，如年龄相关性黄斑变性 (AMD) 和糖尿病视网膜病变 (DR)。在这项研究中，在干性 AMD 的光损伤视网膜动物模型和 DR 的自发大鼠模型中研究了临床安全剂量的口服 tonabersat（一种小分子连接蛋白半通道阻滞剂）对视网膜功能和形态的影响。评估了临床参数（眼底成像、光学相干断层扫描 (OCT) 和视网膜电图）和炎症标志物（Iba-1 小胶质细胞标志物的免疫组织化学、星形胶质细胞标志物胶质纤维酸性蛋白和连接蛋白 43 蛋白表达）。在干燥 AMD 模型中光损伤后长达 3 个月评估时，Tonabersat 治疗减少了视网膜炎症，同时保留了视网膜光感受器功能。在 DR 模型中，临床症状，包括使用伊文思蓝染料灌注证实的动脉瘤的存在，在每天使用 tonabersat 治疗 2 周后减少。炎症也减少了，视网膜电功能恢复了。Tonabersat 通过 Connexin43 半通道阻滞调节炎症小体 (NLRP3) 的组装，具有减少炎症、恢复血管完整性和改善解剖结构以及视网膜疾病的一些功能结果的潜力。包括使用埃文斯蓝染料灌注证实的动脉瘤的存在，在每日托纳贝萨治疗 2 周后减少。炎症也减少了，视网膜电功能恢复了。Tonabersat 通过 Connexin43 半通道阻滞调节炎症小体 (NLRP3) 的组装，具有减少炎症、恢复血管完整性和改善解剖结构以及视网膜疾病的一些功能结果的潜力。包括使用埃文斯蓝染料灌注证实的动脉瘤的存在，在每日托纳贝萨治疗 2 周后减少。炎症也减少了，视网膜电功能恢复了。Tonabersat 通过 Connexin43 半通道阻滞调节炎症小体 (NLRP3) 的组装，具有减少炎症、恢复血管完整性和改善解剖结构以及视网膜疾病的一些功能结果的潜力。