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Glutamate Inhibits the Pro-Survival Effects of Insulin-Like Growth Factor-1 on Retinal Ganglion Cells in Hypoxic Neonatal Rat Retina

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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.

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Acknowledgments

This study was supported by research grants R-181-000-148-750 and R-181-000-162-733 from the National University Health System (NUHS), Singapore

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Authors and Affiliations

  1. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Blk MD10, 4 Medical Drive, Singapore, 117594, Singapore

    Gurugirijha Rathnasamy, Eng Ang Ling & Charanjit Kaur

  2. Singapore Eye Research Institute Level 6, The Academia, Discovery Tower, 20 College Road, Singapore, 169856, Singapore

    Wallace S. Foulds & Charanjit Kaur

  3. Emeritus Professor, University of Glasgow, Glasgow, G12 8QQ, Scotland

    Wallace S. Foulds

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  1. Gurugirijha Rathnasamy
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Correspondence to Charanjit Kaur.

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Rathnasamy, G., Foulds, W.S., Ling, E.A. et al. Glutamate Inhibits the Pro-Survival Effects of Insulin-Like Growth Factor-1 on Retinal Ganglion Cells in Hypoxic Neonatal Rat Retina. Mol Neurobiol 54, 3453–3464 (2017). https://doi.org/10.1007/s12035-016-9905-3

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