title: The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice.
abstract: Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ)-induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) or modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ-induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC.
authors.affiliation: Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Choi
authors.affiliation: Department of Ophthalmology, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Yoo-Ri
authors.initials: YR
authors.lastname: Chung
authors.affiliation: Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyae-Ran
authors.initials: HR
authors.lastname: Byun
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
authors.forename: Hwangseo
authors.initials: H
authors.lastname: Park
authors.affiliation: Neural Injury Research Center, Asan Institute for Life Sciences, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: jkko@amc.seoul.kr.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.affiliation: Department of Ophthalmology, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: yhyoon@amc.seoul.kr.
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Yoon
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000818:Animals; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020286:Pericytes / Q000187:drug effects*; D064546:Protein Kinase C beta / Q000378:metabolism; D019782:Riluzole / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D013311:Streptozocin
chemical_list: D013311:Streptozocin; D019782:Riluzole; D064546:Protein Kinase C beta
keywords: Diabetic retinopathy; Pericyte; Protein kinase C; Riluzole