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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online May 2, 2005 as doi:10.1096/fj.04-3313fje. |
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Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina; and
* Laboratorio de Histología, Facultad de Medicina, Universidad de Morón, Buenos Aires, Argentina
1 Correspondence: Departamento de Bioquímica Humana, Facultad de Medicina, UBA Paraguay 2155, No. 5 P, Buenos Aires 1121, Argentina. E-mail: ruthr{at}fmed.uba.ar
SPECIFIC AIMS
Glaucoma is a leading cause of blindness worldwide and a condition in which retinal ganglion cells probably die through an apoptotic process. Elevated intraocular pressure (IOP) plays a causal, albeit not necessarily exclusive, role in glaucomatous visual loss. It was suggested that glutamatergic excitotoxicity could contribute to the death of ganglion cells in glaucoma. This hypothesis is supported by the demonstration that vitreal glutamate levels are elevated in patients with glaucoma, dogs and quail with congenital glaucoma, and in monkeys with experimental glaucoma. In contrast, other authors have shown no significant elevation of glutamate in the vitreous of glaucomatous patients, or in rats and monkeys with anatomic and functional damage from experimental glaucoma. Although these findings do not completely preclude an elevation in synaptic glutamate as a mechanism of cell death, the role of glutamate in glaucoma is still controversial. Therefore, the aim of the present work was to analyze the retinal mechanisms of glutamate clearance and recycling in an experimental model of glaucoma.
We have recently developed a new model of glaucoma in rats through intracameral injections of hyaluronic acid (HA) that exhibits several advantages over previous experimental models and mimics central features of primary open-angle glaucoma.
Glutamate is the main excitatory neurotransmitter in the retina (as in the rest of the central nervous system) but it is neurotoxic when present in excessive amounts. Thus, an appropriate clearance of synaptic glutamate is required for the normal function of retinal excitatory synapses and for prevention of neurotoxicity. Glial cells, mainly astrocytes and Müller glia, surround glutamatergic synapses and express glutamate transporters and the glutamate-metabolizing enzyme glutamine synthetase. Glutamate is transported into glial cells and amidated by glutamine synthetase to the nontoxic amino acid glutamine. Glutamine is then released by the glial cells and taken up by neurons, where it is hydrolyzed by glutaminase to form glutamate again, completing the retinal glutamate/glutamine cycle (Fig. 1
). In this way, the neurotransmitter pool is replenished and glutamate neurotoxicity is prevented.
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The present report demonstrates, for the first time, a significant alteration of the retinal glutamate/glutamine cycle activity in hypertensive eyes.
PRINCIPAL FINDINGS
1. Retinal glutamate uptake significantly decreased in hypertensive eyes
2. The activity of glutamine synthetase (the key glutamate-metabolizing enzyme) decreased in eyes with experimentally elevated IOP
3. Glutamine uptake and release significantly increased in HA-treated eyes
4. Glutaminase activity significantly increased in hypertensive eyes
CONCLUSIONS AND SIGNIFICANCE
The changes of these parameters could contribute synergically and/or redundantly to an excessive increase in synaptic glutamate levels. Thus, these findings strongly support a significant role for glutamate in glaucomatous neuropathy. Present results suggest that an increase in glutamate levels could represent an initial (and probably reversible) insult responsible for initiation of damage that is followed by a slower secondary degeneration that ultimately result in cell death. Although ocular hypertension is probably the most important risk factor in glaucoma, several concomitant factors may significantly contribute to the neurodegeneration. In a previous report, we showed that retinal oxidative stress might be involved in glaucomatous cell death. Other authors have postulated that excessive levels of nitric oxide may contribute to this optic neuropathy. A therapy that prevents the death of ganglion cells is the main goal of treatment, although the current management of glaucoma is mainly directed at the IOP control. On the basis of these and previous results, the impairment of glutamate neurotoxicity, the manipulation of intracellular redox status using antioxidants, the decrease in nitric oxide levels, or preferably the combination of these treatments may be a therapeutic strategy to prevent glaucomatous cell death. Several lines of evidence support that melatonin is an effective retinal antioxidant. Retinal melatonin levels significantly decreased in hypertensive eyes. We have shown that this methoxyindole is a potent inhibitor of the nitridergic pathway and increases glutamate uptake and glutamine synthetase activity and decreases glutaminase activity in the hamster retina. Taken together, these results suggest that a treatment with melatonin could be a promissory resource in the management of glaucoma since melatonin, by itself, exhibits antioxidant and antinitridergic properties, and may increase retinal glutamate clearance.
FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-3313fje; doi: 10.1096/fj.04-3313fje
This article has been cited by other articles:
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  W. Fan, X. Li, and N. G. F. Cooper CaMKII{alpha}B Mediates a Survival Response in Retinal Ganglion Cells Subjected to a Glutamate Stimulus Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3854 - 3863. [Abstract] [Full Text] [PDF]
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N. Belforte, M. C. Moreno, C. Cymeryng, M. Bordone, M. I. Keller Sarmiento, and R. E. Rosenstein Effect of Ocular Hypertension on Retinal Nitridergic Pathway Activity Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 2127 - 2133. [Abstract] [Full Text] [PDF]
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