title: Protective Effects of Everolimus against N-Methyl-D-aspartic Acid-Induced Retinal Damage in Rats.
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 neurotoxicity, but the mechanism underlying this protection is not fully understood. The present study aimed to examine the effects of everolimus, another inhibitor of mTOR, on neuronal cell loss and inflammation in a rat model of NMDA-induced retinal neurotoxicity, and to determine whether the extracellular signal-regulated kinase (ERK) pathway contributes to the protective effect of everolimus. Intravitreal injection of NMDA (200 nmol) resulted in (1) cell loss in the ganglion cell layer, (2) increase in the numbers of CD45-positive leukocytes and Iba1-positive microglia, and (3) phosphorylation of ribosomal protein S6 (pS6), a downstream indicator of mTOR activity. Simultaneous injection of everolimus with NMDA significantly attenuated these NMDA-induced responses. The neuroprotective effect of everolimus was almost completely prevented by the mitogen-activated protein kinase/ERK kinase inhibitor U0126 (1 nmol). NMDA increased the level of phosphorylated ERK (pERK) in Müller cells, and increase in pERK levels was also observed after co-injection of NMDA and everolimus. These results suggest that everolimus has a neuroprotective effect against NMDA-induced retinal neurotoxicity, an effect that seems to be mediated partly by activation of the ERK pathway in Müller cells.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences.
authors.forename: Ikumi
authors.initials: I
authors.lastname: Hayashi
authors.forename: Yuto
authors.initials: Y
authors.lastname: Aoki
authors.forename: Daiki
authors.initials: D
authors.lastname: Asano
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ushikubo
authors.forename: Asami
authors.initials: A
authors.lastname: Mori
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D000068338:Everolimus / Q000494:pharmacology / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D058449:Intravitreal Injections; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D016202:N-Methylaspartate / Q000009:adverse effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D016202:N-Methylaspartate; D000068338:Everolimus; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D017493:Leukocyte Common Antigens; D020123:Sirolimus