title: Rapamycin prevents N-methyl-D-aspartate-induced retinal damage through an ERK-dependent mechanism in rats.
abstract: Recent studies have demonstrated that inhibition of the mammalian target of rapamycin (mTOR) protects against neuronal injury, but the mechanisms underlying this protection are not fully understood. The present study investigates whether rapamycin, an inhibitor of the mTOR pathway, protects against N-methyl-D-aspartate (NMDA)-induced retinal neurotoxicity and whether the extracellular signal-regulated kinase (ERK) pathway contributes to this protective effect in rats. Significant cell loss in the ganglion cell layer and a reduction in thickness of the inner plexiform layer were observed 7 days after a single intravitreal injection of NMDA (200 nmol/eye). These NMDA-induced morphological changes were significantly reduced by rapamycin (20 nmol/eye). The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive apoptotic cells had increased 6 hr after NMDA injection, an effect that was significantly attenuated by rapamycin. The ERK inhibitor U0126 (1 nmol/eye) almost completely abolished rapamycin's inhibition of NMDA-induced apoptosis. Immunohistochemical studies showed that NMDA caused a time-dependent increase in levels of the phosphorylated form of the ribosomal protein S6 (pS6), a downstream indicator of mTOR activity. The increased pS6 levels were markedly decreased by rapamycin. Both NMDA and rapamycin increased the level of phosphorylated ERK (pERK) in Müller cells, and coinjection of both agents further increased pERK levels. These results suggest that rapamycin has a neuroprotective effect against NMDA-induced retinal neurotoxicity and that this effect could be patially mediated by activation of the ERK pathway in retinal Müller cells.
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.
authors: Atsuko
authors: A
authors: Ichikawa
authors: Tsutomu
authors: T
authors: Nakahara
authors: Yuki
authors: Y
authors: Kurauchi
authors: Asami
authors: A
authors: Mori
authors: Kenji
authors: K
authors: Sakamoto
authors: Kunio
authors: K
authors: Ishii
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D018696:Neuroprotective Agents; D016202:N-Methylaspartate; D048049:Extracellular Signal-Regulated MAP Kinases; D020123:Sirolimus
keywords: Müller cells; excitotoxicity; extracellular signal-regulated kinase; glutamate; mammalian target of rapamycin