Cocchiaro Pasquale, Di Donato Vincenzo, Rubbini Davide, Mastropasqua Rodolfo, Allegretti Marcello, Mantelli Flavio, Aramini Andrea, Brandolini Laura
Dompé Farmaceutici SpA, Napoli, Italy.
ZeClinics SL, IGTP (Germans Trias I Pujol Research Institute), Barcelona, Spain.
Front Pharmacol. 2022 Mar 7;13:822359. doi: 10.3389/fphar.2022.822359. eCollection 2022.
Nerve growth factor (NGF) is the best characterized neurotrophin, and it is known to play an important role in ocular homeostasis. Here, we demonstrated the expression of NGF receptors in adult zebrafish retina and optimized a light-induced retina degeneration (LID) zebrafish model that mimics human cone-rod disorders, demonstrating that intravitreal (IV) administration of rhNGF can boost zebrafish retinal regeneration in this model. Adult zebrafish retinae exposed to 60 h of light irradiation (60 h LID) displayed evident reduction of outer nuclear layer (ONL) thickness and cell number with presence of apoptotic cells. Retinal histologic evaluation at different time points showed that IV therapeutic injection of rhNGF resulted in an increase of ONL thickness and cell number at late time points after damage (14 and 21 days post injury), ultimately accelerating retinal tissue recovery by driving retinal cell proliferation. At a molecular level, rhNGF activated the ERK1/2 pathway and enhanced the regenerative potential of Müller glia and expressing cells by stimulating at early time points the expression of the photoreceptor regeneration factor Drgal1-L2. Our results demonstrate the highly conserved nature of NGF canonical pathway in zebrafish and thus support the use of zebrafish models for testing new compounds with potential retinal regenerative properties. Moreover, the pro-regenerative effects of IV-injected NGF that we observed pave the way to further studies aimed at evaluating its effects also in mammals, in order to expedite the development of novel rhNGF-based therapeutic approaches for ophthalmological disorders.
神经生长因子（NGF）是特征最明确的神经营养因子，已知其在眼内稳态中发挥重要作用。在此，我们证明了NGF受体在成年斑马鱼视网膜中的表达，并优化了一种模拟人类视锥 - 视杆细胞疾病的光诱导视网膜变性（LID）斑马鱼模型，证明玻璃体内（IV）注射重组人神经生长因子（rhNGF）可促进该模型中斑马鱼视网膜的再生。暴露于60小时光照（60小时LID）的成年斑马鱼视网膜显示外核层（ONL）厚度和细胞数量明显减少，且存在凋亡细胞。不同时间点的视网膜组织学评估表明，IV治疗性注射rhNGF导致损伤后晚期（损伤后14天和21天）ONL厚度和细胞数量增加，最终通过驱动视网膜细胞增殖加速视网膜组织恢复。在分子水平上，rhNGF激活ERK1/2通路，并通过在早期刺激光感受器再生因子Drgal1-L2的表达，增强了穆勒胶质细胞和表达细胞的再生潜能。我们的结果证明了NGF经典通路在斑马鱼中的高度保守性，因此支持使用斑马鱼模型来测试具有潜在视网膜再生特性的新化合物。此外，我们观察到的IV注射NGF的促再生作用为进一步研究铺平了道路，这些研究旨在评估其在哺乳动物中的作用，以便加速开发基于rhNGF的新型眼科疾病治疗方法。
