PurposePrevious studies have demonstrated that melatonin has an important role in the modulation of photoreceptor viability during aging and may be involved in the pathogenesis of age-related macular degeneration.This hormone exerts its influence by binding to G-protein coupled receptors named melatonin receptor 1 (MT1) and 2 (MT2). Melatonin receptors 1 and 2 activate a wide variety of signaling pathways.MethodsMelatonin-proficient mice (C3H/f+/+) and melatonin-proficient mice lacking MT1 or MT2 receptors (MT1−/− and MT2−/−) were used in this study. Mice were killed at the ages of 3 and 18 months, and photoreceptor viability was determined by counting nuclei number in the outer nuclear layer (ONL). Cones were identified by immunohistochemistry using peanut agglutinin (PNA) and green/red and blue opsin antibodies. Protein kinase B (AKT) and forkhead box O (FOXO1) were assessed by Western blotting and immunohistochemistry.ResultsThe number of nuclei in the ONL was significantly reduced in C3Hf+/+, MT1−/−, and MT2−/− mice at 18 months of age with respect to 3-month-old animals. In 18-month-old MT1−/− and MT2−/− mice, but not in C3H/f+/+, the number of cones was significantly reduced with respect to young MT1−/− and MT2−/− mice or age-matched C3H/f+/+. In C3H/f+/+, activation of the AKT-FOXO1 pathway in the photoreceptors showed a significant difference between night and day.ConclusionsOur data indicate that disruption of MT1/MT2 heteromer signaling induces a reduction in the number of photoreceptors during aging and also suggest that the AKT-FOXO1 survival pathway may be involved in the mechanism by which melatonin protects photoreceptors.

Knowledge about melatonin synthesis and its potential roles within the retina remains fragmented, especially in mammals where studies have focused on the penultimate enzyme of melatonin synthesis arylalkylamine N-acetyltransferase (AA-NAT), whereas the final enzyme necessary for melatonin production is hydroxyindole-O-methytransferase (HIOMT). We explored multiple parameters of the melatonin synthetic pathway in the cone-rich retina of a diurnal rodent, Arvicanthis ansorgei, cones being previously implicated as probable reservoirs of melatonin production. We analyzed the temporal and spatial expression of Aa-nat mRNA and AA-NAT protein and enzymatic activity of AA-NAT, HIOMT, as well as the melatonin receptor type 1 and melatonin itself. We report that Aa-nat mRNA was localized principally to cones and ganglion cells (retinal ganglion cell [RGC]) with opposing cyclic expression, being maximal in cones during the night, and maximal in RGC in the daytime. AA-NAT protein was also immunolocalized to these same populations, and was present and active throughout the 24-hour period. HIOMT immunolocalization mirrored that of AA-NAT, but expression levels and activity were extremely low and remained uniform throughout the 24-hour period. MT1 showed a complementary expression pattern to the synthetic enzymes, present in rod photoreceptors, some inner retinal neurons and RGC. Surprisingly, melatonin levels were consistently low throughout the day/night cycle, in accordance with the low activity levels of HIOMT. These data demonstrate that the melatonin synthetic pathway in a diurnal rodent differs from that described for other tissues and species (nocturnal and diurnal), the contrasting phase expression in photoreceptors and RGC, suggesting distinct roles in these populations.

Mitomycin C is a powerful antineoplastic agent. If used at high dosage, it may cause a secondary form of adult hemolytic-uremic syndrome (HUS). Blood transfusions worsen the evolution of this peculiar form of HUS. We describe a patient who developed HUS after treatment with mitomycin C (total dose 144 mg/m²) due to a carcinoma of the ascending colon. Repeated blood transfusions were associated with rapidly evolving renal failure coupled with anemia and thrombocytopenia. Haptoglobin was undetectable. Soon after starting subcutaneous erythropoietin, the velocity of progression of renal failure slowed whilst no more blood transfusions were required and haptoglobin levels returned to normal. Thereafter, the patient’s renal function slowly worsened and she started chronic hemodialysis 5 years later. Up to now, all investigations have failed to show a relapse of her adenocarcinoma. A possible explanation of these data is that erythropoietin permitted the termination of blood transfusions which both triggered and perpetuated the syndrome. However, we cannot exclude a primitive effect of erythropoietin on the endothelium or on the platelets.