title: Glutamate Inhibits the Pro-Survival Effects of Insulin-Like Growth Factor-1 on Retinal Ganglion Cells in Hypoxic Neonatal Rat Retina.
abstract: Glutamate that accumulates in injured brain tissue has been shown to hinder the neuroprotection rendered by insulin-like growth factor-1 (IGF-1). However, its role in attenuating the neuroprotective effect of IGF-1 in the hypoxic retina is unknown and the current study was aimed at elucidating this. One-day-old Wistar rats were exposed to hypoxia for 2 h and the retinas were studied at 3 h to 14 days after exposure. Following hypoxia, the concentrations of glutamate and IGF-1 were significantly increased over control values in the immature retina and in cultured retinal ganglion cells (RGCs). In addition to IGF-1, the relative expression of insulin receptor substrate-1 (IRS1) phosphorylated at the tyrosine residue (p-IRS1tyr), phosphorylated protein kinase B (p-AKT) and phosphorylated protein kinase A (p-PKA), which are involved in IGF-1 signalling, was also studied in hypoxic retinas and in cultured RGCs. Glutamate-mediated inhibition of the IGF-1 pathway in hypoxic RGCs was evident with a reduced expression of p-IRS1tyr and p-AKT and an increased expression of p-PKA. However, the addition of exogenous IGF-1 reversed this. Glutamate enables the phosphorylation of IRS1 at the serine residue (p-IRS1ser) through a PKA-dependent pathway. The increased expression of p-IRS1ser and its increased association with IGF-1 receptors in hypoxic RGCs suggested a possible interference by glutamate with the IGF-1 pathway. Moreover, there was increased caspase-3/7 activity in hypoxic RGCs. These results suggest that glutamate, by blocking IGF-1-mediated neuroprotection, could cause the apoptosis of RGCs in the hypoxic neonatal retina.
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, 117594, Singapore.
authors.forename: Gurugirijha
authors.initials: G
authors.lastname: Rathnasamy
authors.affiliation: Singapore Eye Research Institute Level 6, The Academia, Discovery Tower, 20 College Road, Singapore, 169856, Singapore.|Emeritus Professor, University of Glasgow, Glasgow, G12 8QQ, Scotland.
authors.forename: Wallace S
authors.initials: WS
authors.lastname: Foulds
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, 117594, Singapore.
authors.forename: Eng Ang
authors.initials: EA
authors.lastname: Ling
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, 117594, Singapore. antkaurc@nus.edu.sg.|Singapore Eye Research Institute Level 6, The Academia, Discovery Tower, 20 College Road, Singapore, 169856, Singapore. antkaurc@nus.edu.sg.
authors.forename: Charanjit
authors.initials: C
authors.lastname: Kaur
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017208:Rats, Wistar; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010768:Phosphoserine; D018698:Glutamic Acid; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Glutamate; Hypoxia; IGF-1; Immature retina; Retinal ganglion cells