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Notes: : In a previous work we demonstrated that melatonin is able to prevent apoptosis induced by low doses of 6-hydroxydopamine (6-OHDA) in undifferentiated and neuronal PC 12 cells. We also reported how this neurohormone was able to prevent the decrease in the mRNA for antioxidant enzymes caused by 6-OHDA. Although the antioxidant capability of melatonin seems to be clearly implicated in its antiapoptotic activity, literature suggests that its antiproliferative property could also be involved in its prevention of apoptosis. In the present work we demonstrated that melatonin is able to inhibit cell proliferation in undifferentiated PC 12 cells, decreasing cell number and the total amount of DNA, and the mRNA for the histone H4, which are known to increase during DNA synthesis. Melatonin does not decrease the number of cells in nonproliferating PC12 cells, indicating that it does not cause cell death. Additionally, we demonstrate that other inhibitors of cell proliferation, as well as other antioxidants, are able to mimic the antiapoptotic effect of melatonin. This is interpreted to mean that melatonin acts by both mechanisms to inhibit apoptosis caused by 6-OHDA and the findings support the hypothesis of a relationship between oxidative stress and regulation of the cell cycle.

Notes: Abstract: Melatonin is widely abundant in many eukaryotic taxa, including vari-ous animal phyla, angiosperms, and unicells. In the bioluminescent dinoflagellate Gonyaulax polyedra, melatonin is produced in concentrations sometimes exceed-ing those found in the pineal gland, exhibits a circadian rhythm with a pro-nounced nocturnal maximum, and mimics the short-day response of asexual encystment. Even more efficient as a cyst inducer is 5-methoxytryptamine (5MT), which is also periodically formed in Gonyaulax. In this unicell, the photoperiodic signal-transduction pathway presumably involves melatonin formation, its deace-tylation to 5MT, 5MT-dependent transfer of protons from an acidic vacuole, and cytoplasmic acidification. According to this concept, we observe that cyst forma-tion can be induced by various monoamine oxidase inhibitors and protonophores, that 5MT dramatically stimulates H+-dependent bioluminescence and leads to a decrease of cytoplasmic pH, as shown by measurements of dicyanohydroquinone fluorescence. Cellular components from Gonyaulax catalyze the photooxidation of melatonin. Its property of being easily destroyed by light in the presence of cel-lular catalysts may have been the reason that many organisms have developed mechanisms utilizing this indoleamine as a mediator of darkness. Photooxidative reactions of melatonin, as studied with crude Gonyaulax extracts and, more in de-tail, with protoporphyrin IX as a catalyst, lead to the formation of N1 -acetyl-N -formyl-5-methoxykynuramine (AFMK) as one of the main products. Photochemical mechanisms involve interactions with a photooxidant cation radi-cal leading to the formation of a melatonyl cation radical, which subsequently combines with a superoxide anion. Photooxidation of melatonin represents one of several possibilities of a more general, biologically highly important property of this indoleamine to act as an extremely efficient radical scavenger, including its feature of terminating radical reaction chains by a final combination with the su-peroxide anion. Trapping of free radicals may reflect the primary and evolutionar-ily most ancient role of melatonin in living beings.