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Abstract #74145 Published in IGR 19-1
A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model
Do YJ; Sul JW; Jang KH; Kang NS; Kim YH; Kim YG; Kim EExperimental Cell Research 2017; 359: 30-38
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.
Department of Biological Sciences, Chungnam National University, Daejeon 34134, Republic of Korea.
Full articleClassification:
5.1 Rodent (Part of: 5 Experimental glaucoma; animal models)
11.14 Investigational drugs; pharmacological experiments (Part of: 11 Medical treatment)
11.8 Neuroprotection (Part of: 11 Medical treatment)
