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This Article Full Text (PDF) All Versions of this Article: 18/15/1912 04-2062fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by SÁENZ, D. A. Articles by ROSENSTEIN, R. E. Search for Related Content PubMed PubMed Citation Articles by SÁENZ, D. A. Articles by ROSENSTEIN, R. E.

Effect of melatonin on the retinal glutamate/glutamine cycle in the golden hamster retina

Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental, Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, CONICET, Buenos Aires, Argentina

¹ Correspondence: Departamento de Bioquímica Humana, Facultad de Medicina, UBA. Paraguay 2155, 5°P, (1121), Buenos Aires, Argentina. E-mail: ruthr{at}fmed.uba.ar

SPECIFIC AIMS

The original aim of this study was to analyze the effect of melatonin on the glutamate/glutamine cycle activity in the hamster retina.

Glutamate is the main excitatory neurotransmitter in the retina but is neurotoxic when present in excessive amounts. The metabolic dependence of glutamatergic neurons on glia via the glutamate/glutamine cycle to provide the precursor for neurotransmitter glutamate is well established. An appropriate clearance of synaptic glutamate is required for normal function of retinal excitatory synapses and to prevent neurotoxicity. It was demonstrated that melatonin has a neuroprotective effect against glutamate-induced excitotoxicity in several systems. However, the full range of physiological actions and mechanisms involved in the effects of melatonin is not completely understood.

For the first time, we demonstrate in the present report that physiological concentrations of melatonin significantly modulate the retinal glutamate/glutamine cycle activity.

PRINCIPAL FINDINGS

1. 1. Nanomolar concentrations of melatonin increased glutamine synthetase (GS) activity
   
2. 2. Melatonin increased glutamine uptake (likely mediated by the A- and L- type transporter systems)
   
3. 3. Melatonin significantly decreased glutaminase activity
   

CONCLUSIONS AND SIGNIFICANCE

Taken together, these results indicate that melatonin, probably through a redundant mechanism, may contribute to a decrease in synaptic glutamate concentrations. This effect could provide new insight into the neuroprotective potential of melatonin.

An increase in GS induced by glucocorticoids provides neuroprotection in different tissues, including the retina. Physiological levels of glucocorticoids regulate expression of this enzyme by stimulating transcription of the gene, taking 24 h. This might explain why glucocorticoids must be supplied early to achieve a beneficial effect and suggests that only in programmed neurological interventions might prophylactic administration of glucocorticoids be advisable. In contrast, since the observed effect of melatonin was much faster, treatment with methoxyindole may circumvent this obstacle. Moreover, this beneficial effect of melatonin may be further improved by its effect on glutamate uptake, glutaminase activity, and the nitridergic pathway. In summary, these findings suggest that treatment with melatonin could be considered as a new approach to handling glutamate-mediated neuronal degeneration.

View larger version (24K): [in this window] [in a new window]   Figure 1. Schematic representation of the retinal glutamate/glutamine cycle and its modulation by melatonin. Melatonin increased GS activity and glutamine uptake but decreased glutaminase activity. Positive effects of melatonin (M) are noted by an upward arrow; downward arrow indicates negative modulations. In earlier reports (*) we showed that melatonin inhibits nitric oxide synthase activity and increases glutamate uptake and release.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2062fje;

This Article Full Text (PDF) All Versions of this Article: 18/15/1912 04-2062fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by SÁENZ, D. A. Articles by ROSENSTEIN, R. E. Search for Related Content PubMed PubMed Citation Articles by SÁENZ, D. A. Articles by ROSENSTEIN, R. E.