Protective effects of PF‐4708671 against N‐methyl‐d‐aspartic acid‐induced retinal damage in rats. (10th August 2016)

• Record Type: Journal Article
• Authors: Hayashi, Ikumi; Aoki, Yuto; Ushikubo, Hiroko; Asano, Daiki; Mori, Asami; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio
• Is Part Of: Fundamental & clinical pharmacology. Volume 30:Number 6(2016:Dec.)
• Page Start: 529
• Page End: 536
• Publication Date: 2016-08-10
• Subjects: excitotoxicity -- mammalian target of rapamycin -- neuroinflammation -- S6 kinase; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/fcp.12216
• Languages: English
• ISSNs: 0767-3981

Abstract

Abstract: We previously demonstrated that rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), protects against N ‐methyl‐d ‐aspartic acid (NMDA)‐induced retinal damage in rats. Rapamycin inhibits mTOR activity, thereby preventing the phosphorylation of ribosomal protein S6, which is a downstream target of S6 kinase. Therefore, we aimed to determine whether PF‐4708671, an inhibitor of S6 kinase, protects against NMDA‐induced retinal injury. Intravitreal injection of NMDA (200 nmol/eye) caused cell loss in the ganglion cell layer and neuroinflammatory responses, such as an increase in the number of CD45‐positive leukocytes and Iba1‐positive microglia. Surprisingly, simultaneous injection of PF‐4708671 (50 nmol/eye) with NMDA significantly attenuated these responses without affecting phosphorylated S6 levels. These results suggest that PF‐4708671 and rapamycin likely protect against NMDA‐induced retinal damage via distinct pathways. The neuroprotective effect of PF‐4708671 is unlikely to be associated with inhibition of the S6 kinase, even though PF‐4708671 is reported to be a S6 kinase inhibitor.