Abstract

To prevent ocular pathologies, new generation of dietary supplements have been commercially available. They consist of nutritional supplement mixing components known to provide antioxidative properties, such as unsaturated fatty acid, resveratrol or flavonoids. However, to date, only one preclinical study has evaluated the impact of a mixture mainly composed of those components (Nutrof Total®) on the retina and demonstrated that in vivo supplementation prevents the retina from structural and functional injuries induced by light. Considering the crucial role played by the glial Müller cells in the retina, particularly to regulate the glutamate cycle to prevent damage in oxidative stress conditions, we questioned the impact of this ocular supplement on the glutamate metabolic cycle. To this end, various molecular aspects associated with the glutamate/glutamine metabolism cycle in Müller cells were investigated on primary Müller cells cultures incubated, or not, with the commercially mix supplement before being subjected, or not, to oxidative conditions. Our results demonstrated that in vitro supplementation provides guidance of the glutamate/glutamine cycle in favor of glutamine synthesis. These results suggest that glutamine synthesis is a crucial cellular process of retinal protection against oxidative damages and could be a key step in the previous in vivo beneficial results provided by the dietary supplementation.

Highlights

  • Müller cells play a crucial role in maintaining the complex architecture and function of the retina

  • DAVID-based gene clustering chart analysis revealed an enrichment of several GO terms, mainly glutamatergic homeostasis related GO terms, in both molecular function (GO:0004364 Glutathione transferase activity, p = 0.0003) and biological process (GO:0006541 Glutamine metabolic process, p = 0.0778; GO:0006749 Glutathione metabolic process, p = 0.18) (Figure 2)

  • Ocular supplements are routinely reecommended for rreettiinnaall ddeeggeenneerraattiivve ddiisseeaasseess such as Age-related Macular Degeneration (AMD)

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Summary

Introduction

Müller cells play a crucial role in maintaining the complex architecture and function of the retina. Müller cells are radially oriented, spanning the entire retina from the inner to the distal end of the outer nuclear layer (ONL) and presenting close contacts with photoreceptors and bipolar cells. These strong interactions with retinal neurons ensure numerous metabolic exchanges maintaining retinal integrity, in particular by participating in the control of retinal homeostasis and especially redox and glutamatergic homeostasis [2,3,4,5]. In the tripartite glutamatergic synapse (photoreceptor, bipolar and Müller cells), Müller cells regulate the glutamate/glutamine metabolic cycle in order to control glutamate level This cycle aims to recapture glutamate from the synaptic cleft, avoiding excitotoxicity [6,7] and providing glutamine to replenish neurotransmitter pools in neurons. Glutamine is taken into photoreceptor cells through a Na+-dependent transporter (SNAT) and converted into glutamate by glutaminase [6]

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