1. Protective effect of RIPK1-inhibitory compound in in vivo models for retinal degenerative disease
- Author
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Yun-Ju Do, Hyun Ju Bae, Eunhee Kim, Ki-Hong Jang, Tae-Sung Koo, Jun-Sub Choi, Eun Ju Song, Yeseong Hwang, and Lee Juhee
- Subjects
Male ,Retinal Ganglion Cells ,0301 basic medicine ,Retinal degeneration ,genetic structures ,Necroptosis ,Iodates ,Administration, Ophthalmic ,Pharmacology ,Protective Agents ,Retinal ganglion ,Propanolamines ,Rats, Sprague-Dawley ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,0302 clinical medicine ,In vivo ,Geographic Atrophy ,hemic and lymphatic diseases ,Electroretinography ,medicine ,Animals ,Retina ,Retinal pigment epithelium ,business.industry ,Phenyl Ethers ,Retinal Degeneration ,Retinal ,Macular degeneration ,medicine.disease ,eye diseases ,Sensory Systems ,Rats ,Ophthalmoscopy ,Disease Models, Animal ,Ophthalmology ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Receptor-Interacting Protein Serine-Threonine Kinases ,030221 ophthalmology & optometry ,Rabbits ,sense organs ,business - Abstract
Receptor interacting protein kinase 1 (RIPK1) plays a key role in necroptosis, which is a type of programmed necrosis that is involved in ocular diseases, including glaucoma and dry age-related macular degeneration (AMD). We previously introduced RIPK1-inhibitory compound (RIC), which has biochemical characteristics and a mode of action that are distinct from those of the prototype RIPK1 inhibitor necrostatin-1. The intraperitoneal administration of RIC exerts a protective effect on retinal ganglion cells against a glaucomatous insult. In this study, we examined the protective effect of RIC on retinal pigment epithelium (RPE) against sodium iodate (SI) insult, which is associated with dry AMD pathogenesis. The eye drop administration of RIC that reached on the retina prevented RPE loss in SI-induced retinal degeneration. RIC consistently demonstrated retinal protection in the funduscopy and electroretinogram analyses in SI-injected rabbits and iodoacetic acid-treated mini-pigs. Moreover, the in vivo protective effects of RIC were superior to those of ACU-4429 and doxycycline, which are other medications investigated in clinical trials for the treatment of dry AMD, and RIC did not induce retinal toxicity following topical administration in rats. Collectively, RIC displayed excellent retinal penetration and prevented retinal degeneration in the pathogenesis of dry AMD with a high in vivo efficacy.
- Published
- 2019