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Originally published online as doi:10.2353/ajpath.2008.080518 on November 13, 2008

Published online before print November 13, 2008
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(American Journal of Pathology. 2008;173:1702-1713.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080518

Therapeutic Effect of Melatonin in Experimental Uveitis

Pablo Horacio Sande*, Diego Carlos Fernandez*, Hernán Javier Aldana Marcos{dagger}, Mónica Silvia Chianelli*, Julieta Aisemberg{ddagger}, Dafne Magalí Silberman*, Daniel Alberto Sáenz* and Ruth Estela Rosenstein*

From the Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental,* Departamento de Bioquímica Humana, Universidad de Buenos Aires, Centro de Estudios Farmacológicos y Botánicos Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina, Laboratorio de Histología,{dagger} Facultad de Medicina, Universidad de Morón, Buenos Aires, Argentina, Laboratorio de Fisiopatología de la Preñez,{ddagger} Centro de Estudios Farmacológicos y Botánicos/Consejo Nacional de Investigaciones Cientícas y Técnicas Buenos Aires, Argentina

Uveitis is a common ophthalmic disorder that can be induced in hamsters by a single intravitreal injection of bacterial lipopolysaccharide (LPS). To examine the therapeutic effects of melatonin on uveitis, a pellet of melatonin was implanted subcutaneously 2 hours before the intravitreal injection of either vehicle or LPS. Both 24 hours and 8 days after the injection, inflammatory responses were evaluated in terms of i) the integrity of the blood-ocular barrier, ii) clinical signs, iii) histopathological studies, and iv) retinal function. Melatonin reduced the leakage of proteins and cells in the anterior segment of LPS-injected eyes, decreased clinical signs such as dilation of the iris and conjunctival vessels, and flare in the anterior chamber, and protected the ultrastructure of the blood-ocular barrier. A remarkable disorganization of rod outer segment membranous disks was observed in animals injected with LPS, whereas no morphological changes in photoreceptor outer segments were observed in animals treated with melatonin. Furthermore, melatonin prevented a decrease in LPS-induced electroretinographic activity. In addition, melatonin significantly abrogated the LPS-induced increase in retinal nitric-oxide synthase activity, tumor necrosis factor-{alpha}, and nuclear factor {kappa}B p50 and p65 subunit levels. These results indicate that melatonin prevents the clinical, biochemical, histological, ultrastructural, and functional consequences of experimental uveitis, likely through a nuclear factor {kappa}B-dependent mechanism, and support the use of melatonin as a new therapeutic strategy for the treatment of uveitis.






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