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.

Caffeic acid phenethyl ester attenuates nuclear factor‑κB‑mediated inflammatory responses in M�ller cells and protects against retinal ganglion cell death

“…Several animal models have been developed to study glaucoma (27–29) among which optic nerve crush (ONC) is widely used to evaluate the survival of injured retinal ganglion cells (RGCs) and inflammation of glia. ONC is an acute injury that kills the majority of RGCs within the first 2 weeks and triggers atypical inflammatory response within the injured eye (30–33). In the present study, using a rat ONC model, we have demonstrated for the first time that caffeic acid phenethyl ester (CAPE), exerted a neuroprotective role and attenuated inflammatory responses by inhibiting nuclear factor kappa light-chain-enhancer of activated B cells (NF-κB) activation.…”

Tongqiao Mingmu formula alleviates retinal ganglion cell autophagy through PI3K/AKT/mTOR pathway

“…Glutamate, a neuroexcitatory transmitter, can be absorbed by the retina (Thoreson & Witkovsky, 1999), a high concentration of which might give rise to neurotoxicity (Rathnasamy et al, 2017). A previous study found that increased glutamate levels can be observed in glaucoma patients and glaucomatous animal models, and the neurotoxicity of glutamate can lead to apoptosis of RGCs (Dreyer et al, 1996).…”