A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model

• Published in: Experimental cell research 2017-10, Vol.359 (1), p.30-38
• Main Authors: Do, Yun-Ju, Sul, Jee-Won, Jang, Ki-Hong, Kang, Nam Sook, Kim, Young-Hoon, Kim, Young-Gwan, Kim, Eunhee
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Cell Hypoxia - drug effects; Cells, Cultured; Cycloheximide; Disease Models, Animal; Glaucoma - complications; Glaucoma - drug therapy; Glaucoma - pathology; Glucose - deficiency; HT29 Cells; Humans; Injections, Intraperitoneal; Ischemia - complications; Ischemia - pathology; Male; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Necrosis; Neuroprotection - drug effects; OGD; Oligopeptides; Oxygen; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Rats, Sprague-Dawley; Retinal Degeneration - complications; Retinal Degeneration - drug therapy; Retinal Degeneration - pathology; Retinal Degeneration - prevention & control; Retinal Neurons - drug effects; Retinal Neurons - metabolism; Retinal Neurons - pathology; RGCs; RIPK1; Tumor Necrosis Factor-alpha
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2017.08.012

In glaucoma, retinal ganglion cells (RGCs) are exposed to ischemic stress with elevation of the intraocular pressure and are subsequently lost. Necroptosis, a type of regulated necrosis, is known to play a pivotal role in this loss. We observed that receptor-interacting protein kinase 1 (RIPK1), the key player of necroptosis, was activated by diverse ischemic stresses, including TCZ, chemical hypoxia (CH), and oxygen glucose deprivation (OGD). In this study, we introduce a RIPK1-inhibitory compound (RIC) with a novel scaffold. RIC inhibited downstream events following RIPK1 activation, including necrosome formation and mitochondrial dysfunction in RGC5 cells. Moreover, RIC protected RGCs against ischemic injury in the rat glaucoma model, which was induced by acute high intraocular pressure. However, RIC displayed biochemical characteristics that are distinct from those of previous RIPK1 inhibitors (necrostatin-1; Nec-1 and Compound 27; Cpd27). RIC protected RGCs against OGD insult, while Nec-1 and Cpd27 did not. Conversely, Nec-1 and Cpd27 protected RGCs from TNF-stimulated death, while RIC failed to inhibit the death of RGCs. This implies that RIPK1 activates alternative pathways depending on the context of the ischemic insults.