Effect of glaucoma on the retinal glutamate/glutamine cycle activity

Abstract

Glutamate-induced excitotoxicity has been proposed to mediate the death of retinal ganglion cells in glaucoma. The metabolic dependence of glutamatergic neurons upon glia via the glutamate/glutamine cycle to provide the precursor for neurotransmitter glutamate is well established. Thus, the aim of the present work was to study the retinal glutamate/glutamine activity in eyes with hypertension induced by intracameral injections of hyaluronic acid (HA). For this purpose, weekly injections of HA were performed unilaterally in the rat anterior chamber, whereas the contralateral eye was injected with saline solution. At 3 or 10 weeks of treatment, glutamate and glutamine uptake and release were assessed using [3H]-glutamate and [3H]-glutamine as radioligands, respectively. In addition, glutamine synthetase activity was assessed by a spectrophotometric assay, whereas glutaminase activity was measured through the conversion of [3H]-glutamine to [3H]-glutamate. At 3 weeks of treatment with HA, a significant decrease (P<0.01) in glutamate uptake and glutamine synthetase activity was observed. Glutamine uptake and release, as well as glutaminase activity, were significantly increased (P<0.01) in eyes injected with HA for 3 weeks compared with vehicle-injected eyes, whereas [3H]-glutamate release did not change in hypertensive eyes. Only the changes in glutamine synthetase activity persisted at 10 weeks of treatment with HA. These results indicate a significant alteration in the retinal glutamate/glutamine cycle activity in hypertensive eyes. Since these changes preceded both functional and histological alterations induced by ocular hypertension, these results support the involvement of glutamate in glaucomatous neuropathy.

Hydrocortisone Stimulates Neurite Outgrowth from Mouse Retinal Explants by Modulating Macroglial Activity

“…64 Glutamate excitotoxicity is a thought to be a key feature of many retinal diseases and is very detrimental to axon regeneration. 55,[97][98][99][100][101][102] Both Glul and Glt1 transcripts are increased in EN2-treated explants relative to EN2 without HC-treated explants. One interpretation of the HC effect on explants is that increased glutamate turnover prevents glutamate excitotoxicity in the explant system, creating an overall better environment for regeneration.…”

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

“…Although recent studies have demonstrated no significant increase in vitreous glutamate concentrations in glaucoma patients and animal models with experimental glaucoma (42 -45), it has been reported that increased IOP induced by intracameral injections of hyaluronic acid alters retinal glutamate / glutamine cycle activity in rat eyes (46) and that in the optic nerve head of rabbits, IOP elevation increases glutamate levels, estimated to be around 2 µM (47). Thus, synaptic glutamate concentrations in retina could increase following IOP elevation in glaucoma, which then overactivates NMDA receptors, leading to RGC death triggered by a large amount of Ca 2+ influx.…”

Melatonin and Its Analog 5-Methoxycarbonylamino-N-Acetyltryptamine Potentiate Adrenergic Receptor-Mediated Ocular Hypotensive Effects in Rabbits: Significance for Combination Therapy in Glaucoma

“…Chronic high intraocular pressure (IOP) produces an excessive release of the neurotransmitter glutamate that evokes an increase in free radicals and finally retinal ganglion cell death (Moreno et al, 2005;Almasieh et al, 2012). Glaucoma is, therefore, commonly treated with ocular hypotensive agents.…”