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: Jeong A Choi, Yoo-Ri Chung, Hyae-Ran Byun, Hwangseo Park, Jae-Young Koh, Young Hee Yoon
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 315 Pg. 80-89 (Jan 15 2017) ISSN: 1096-0333 [Electronic] United States
• PMID: 27939241 (Publication Type: Journal Article)
• Copyright: Copyright © 2016. Published by Elsevier Inc.

Chemical References

• Streptozocin
• Riluzole
• Protein Kinase C beta

Topics

• Amyotrophic Lateral Sclerosis (drug therapy)
• Animals
• Diabetic Retinopathy (drug therapy, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Pericytes (drug effects)
• Protein Kinase C beta (metabolism)
• Riluzole (metabolism, pharmacology, therapeutic use)
• Streptozocin