The synthesis of MEL is markedly increased at night in all species studied to date, independent of whether the animal is diurnally or nocturnally active, and the duration of the nocturnal peak is positively related to the duration of the night.5,6 In nonmammalian vertebrates, the rhythmic synthesis and secretion of MEL is the direct

output of the clock located within the pineal. Inhibitors,research,lifescience,medical In mammals, however, the pineal does not. retain clock and photoreceptive properties. The synthesis of MEL is driven through multisynaptic neural pathways7,8 by the circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus, and is therefore also an output of the circadian clock. MEL is synthesized Inhibitors,research,lifescience,medical from the amino acid tryptophan, which is first converted into BEZ235 clinical trial 5-hydroxytryptophan by tryptophan hydroxylase, before being decarboxylated into serotonin (5-hydroxytryptamine, 5-HT). From 5-HT, two major enzymatic steps are involved. The first, is N-acetylation by the arylalkylamine-N-acetyltransferase (AA-NAT) to yield Af-acetylserotonin.The regulation of AA-NAT, with Inhibitors,research,lifescience,medical its sharp increase in activity at night, has received considerable attention as a major regulatory step in rhythmic MEL synthesis.9,10 The second step is

the transfer of a methyl group from 5-adenosylmethionine to the 5-hydroxy group of N-acetylserotonin catalyzed by the hydroxyindolc O-methyltransferase (HIOMT),to yield MEL.11 The rapid Inhibitors,research,lifescience,medical 6-hydroxylation of MEL in the liver means that. it. has a short half-life in the circulation and, therefore, the circulating MEL concentrations precisely reflect its pineal synthesis. MEL is produced primarily by the pineal gland. However, numerous other MEL sources have been identified. The retina

is an important source in nonmammalian vertebrates: not only is MEL rhythmically synthesized in Inhibitors,research,lifescience,medical this structure, but its release from here also contributes to the nocturnal pattern of circulating MEL. In mammals, MEL synthesis within the retina was demonstrated a long time ago.12 However, it is only since the demonstration of a true circadian release of MEL from the hamster retina in vitro (suggesting the presence of a retinal clock) aminophylline that the importance of this structure as an extrapincal source of MEL has been recognized.13 In contrast to nonmammalian vertebrates, mammalian retinal MEL does not contribute to circulating MEL. The Harderian and lachrymal glands, gastrointestinal tract, red blood cells, platelets, and mononuclear cells have also been identified as sites of MEL synthesis. MEL does not seem to be released into the general circulation from these tissues, at least, not under normal physiological conditions.14 Moreover, in these tissues the synthesis of MEL is not rhythmic. The presence of MEL is not restricted to vertebrates. MEL has been found in the head, eyes, optic lobe, and brain of various invertebrates in many taxa.