Abstract
Loss of retinal ganglion cells occurs in a variety of pathological conditions, including central retinal artery occlusion, diabetes and glaucoma. Using an experimental model of retinal ischemia induced by transiently raise the intraocular pressure (IOP), In this study, we report the original observation that ischemic retinal ganglion cells death is associated with the transient deactivation of the pro-survival kinase Akt and activation of GSK-3beta followed, during reperfusion, by a longer lasting, PI3K-dependent, activation of Akt and phosphorylation of GSK-3beta. Under these experimental conditions, retinal ischemia induced the expression of Bad, a pro-apoptotic protein, member of the Bcl-2 family. The detrimental effects yielded by the ischemic stimulus were minimized by intravitreal administration of the NMDA receptor antagonist, MK801, that reduced the expression of Bad and significantly increased Akt phosphorylation. In conclusion, our present results contribute to unravel the mechanisms underlying retinal damage by high IOP-induced transient ischemia in rat. In addition, these data implicate the pro-survival PI3K/Akt pathway and the observed reduced expression of Bad in the neuroprotection afforded by MK801.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Androstadienes / pharmacology
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Animals
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Cell Death / physiology
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Chromones / pharmacology
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Dizocilpine Maleate / pharmacology
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Enzyme Inhibitors / pharmacology
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Intraocular Pressure / physiology
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Ischemia / complications
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Ischemia / physiopathology
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Male
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Morpholines / pharmacology
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Oncogene Protein v-akt / metabolism
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PTEN Phosphohydrolase / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Rats
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Rats, Wistar
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Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
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Receptors, N-Methyl-D-Aspartate / physiology*
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Reperfusion Injury / etiology
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Reperfusion Injury / physiopathology*
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Retinal Diseases / complications
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Retinal Diseases / pathology
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Retinal Diseases / physiopathology*
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Serine / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Time Factors
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Wortmannin
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bcl-Associated Death Protein / metabolism
Substances
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Androstadienes
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Chromones
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Enzyme Inhibitors
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Morpholines
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Proto-Oncogene Proteins c-bcl-2
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Receptors, N-Methyl-D-Aspartate
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bcl-Associated Death Protein
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Serine
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Dizocilpine Maleate
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Oncogene Protein v-akt
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Glycogen Synthase Kinase 3
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PTEN Phosphohydrolase
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Wortmannin