Neuroprotective actions of growth hormone (GH) in the neuroretina include Notch signaling activation and involve changes in the expression of local growth factors

Abstract

Purpose : Current research on GH has demonstrated that it acts neurotrophic factor with a possible use as therapeutic for brain trauma, spinal cord injury and neurodegeneration due to its ability to protect, enhance and restore neural function. Our group has demonstrated anti-apoptotic and anti-excitotoxic actions for GH in both, embryonic and postnatal retinal tissue. It is well established that retinal GH-R activation induces the canonical JAK/STAT signaling pathway, which promotes the production of neurotrophins such as BDNF and NT3, in addition to its classical mediator, IGF-I. However, the molecular mechanisms and cellular interactions participating in the GH-neural actions are still largely unknown.

Methods : In this study, we used the chicken retina as experimental model. Changes in mRNA levels were determined by qPCR. Phosphorylation and immunoreactivity changes were determined by western blotting. Kainate (KA; 30 μg/eye) was used as excitotoxic agent. Histology (H/E) and IHC were performed for morphology analysis.

Results : In this work, we show that postnatal chicken retinal tissue is able respond to GH stimulation through alternative signaling pathways. These include pERK and pAkt, since upregulation of their immunoreactivity was observed after short GH exposure. Treatment with GH upregulated expression of BMP4, FGF2, PEDF, CNTF-R and TGFα demonstrating the existence of a network of intra- and intercellular signals regulated by GH. After an intravitreal injection of KA, GH treatment exerted its neuroprotective effect, in part, through the Notch signaling pathway, increasing Notch1 and Hes5 expression. The neuroprotective effect of GH was reversed with DAPT treatment (γ-secretase inhibitor). GH administration before a KA insult also resulted in a decrease of FGF2, Sox2 and PCNA mRNA, and an increase of DCX immunoreactivity in comparison with damaged retinas.

Conclusions : Neuroprotective effects of GH prevented damage required for the initiation of the regenerative process observed in avian models after a retina excitotoxic injury, since molecular markers for Müller cells trans-differentiation and proliferation were downregulated. Our results demonstrate that GH-mediated neuroprotection occurs through alternative signaling pathways (MAPK, Akt & Notch) and induces the expression of genes associated with neuroprotection in the retina.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.