Volume 3, Number 2: 194-225; April 2012 Review Melatonin in Aging and Disease ―Multiple Consequences of Reduced Secretion, Options and Limits of Treatment Rüdiger Hardeland Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, D-37073 Göttingen, Germany [Received January 24, 2011; Revised February 7, 2012; Accepted February 7, 2012] ABSTRACT: Melatonin is a pleiotropically acting regulator molecule, which influences numerous physiological functions. Its secretion by the pineal gland progressively declines by age. Strong reductions of circulating melatonin are also observed in numerous disorders and diseases, including Alzheimer’s disease, various other neurological and stressful conditions, pain, cardiovascular diseases, cases of cancer, endocrine and metabolic disorders, in particular diabetes type 2. The significance of melatonergic signaling is also evident from melatonin receptor polymorphisms associated with several of these pathologies. The article outlines the mutual relationship between circadian oscillators and melatonin secretion, the possibilities for readjustment of rhythms by melatonin and its synthetic analogs, the consequences for circadian rhythm-dependent disorders concerning sleep and mood, and limits of treatment. The necessity of distinguishing between short-acting melatonergic effects, which are successful in sleep initiation and phase adjustments, and attempts of replacement strategies is emphasized. Properties of approved and some investigational melatonergic agonists are compared. Key words: Alzheimer’s Disease; Circadian Rhythms; Diabetes; Melatonin; Mood Disorders; Parkinson’s Disease; Sleep The indoleamine melatonin (N-acetyl-5-metho- amounts have been reported to enter the blood from the xytryptamine) is usually known as the hormone of the GIT in response to nutritional factors, as a post-prandial pineal gland. This role is of particular importance in a response of short duration [7-9]. These pulses of chronobiological context, especially with regard to its melatonin are of minor importance to the circadian effects on the hypothalamic circadian pacemaker, the system, not so much because of its brevity, but rather as suprachiasmatic nucleus (SCN). However, its spectrum a consequence of shape and phase position of the so- of functions is considerably broader, in terms of sites of called phase response curve (PRC). The PRC describes both biosynthesis and action [1-5]. Melatonin is formed the resetting of a rhythm by entraining signals in in numerous organs and cells, such as the gastrointestinal dependence of the phase (i.e., the time point within the tract (GIT), bone marrow, several leukocytes, circadian cycle) of administration of the signal. Usually, membranous cochlea and, presumably, skin and other a PRC contains phases in which the rhythm is delayed, regions of the central nervous system. It is frequently others in which it is advanced and also a silent zone in overlooked that, in quantitative terms, extrapineal which the rhythm is poorly affected. In humans, the PRC melatonin exceeds by far that found in the pineal and in for melatonin has been determined, which mainly the circulation. Owing to the size of the organ, the reflects the resetting in the SCN [10, 11]. A post-prandial amounts of melatonin present in the GIT are several release of melatonin during the day mostly occurs in the hundred-fold higher than those in the pineal [6, 7]. silent zone, whereas much stronger effects are observed Extrapineal melatonin is either poorly released to the in phases of pineal melatonin secretion in which the circulation or for short periods of time. Relatively high hormone is capable of readjusting the rhythmicity of the *Correspondence should be addressed to: Prof. Rüdiger Hardeland, Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Berliner Str. 28, D-37073 Göttingen, Germany. E-mail: [email protected] ISSN: 2152-5250 194 R. Hardeland Melatonin in Aging and Disease SCN. In mammals, pineal melatonin biosynthesis and irrelevant. Sufficiently high amounts of the precursor release are, in turn, under the control of the SCN and serotonin are usually available, but an exception was largely confined to the night. From the pineal gland, described for a defect mutation of the sepiapterin melatonin is not only secreted to the circulation, but also, reductase gene [20]. The product of this enzyme, via the pineal recess, to the third ventricle [12-14]. tetrahydrobiopterin (BH4), is required by aromatic Collectively, all these findings indicate that amino acid hydroxylases. BH4 deficiency causes, beside melatonin serves numerous functions in various organs other effects, poor synthesis of 5-hydroxytryptophan and that effects at the SCN constitute an important, but and, thus, serotonin, with the further consequence of a by far not the exclusive function. The awareness of this flattened melatonin rhythm [20]. multiplicity of roles and actions gains increasing importance, because melatonin and synthetic NH melatonergic drugs come more and more into use, e.g., HO 2 for treating sleep difficulties and mood disorders. These N Serotonin compounds should not be simply regarded as sleeping H pills or antidepressants, which might be easily compared AANAT with classic drugs for the respective indications. They H CH HO N 3 strongly differ in their mode of action, but, additionally, O N N-acetylserotonin they exert numerous other effects beyond the reason for H treatment. This insight can be of great practical HIOMT CYP2C19 relevance, especially concerning the immunological role (= ASMT) (CYP1A2) H CH of melatonin. Again, the actions are diverse. They O N 3 H3C comprise antiinflammatory, but also immunoenhancing O N effects [2-5]. This latter property can be highly undesired H Melatonin Pyrrole ring cleavage* in cases of autoimmune diseases and should be regarded MelDA O O or AAAs AANAT O N H C CH3 as a contraindication for melatonin and melatonergic 3 H O NH2 CHO AFMK drugs in these patients. Despite some controversies on H C N 3 H this issue and the clearly antiinflammatory actions of N H AAF** CYP1A2 O O melatonin in another context, the methoxyindole 5-Methoxytryptamine CYP1A1 O N CYP1B1 H C CH3 obviously aggravates symptoms of rheumatoid arthritis 3 H (RA) via stimulation of proinflammatory cytokines [15- NH2 AMK H CH 17]. Moreover, blood melatonin levels were enhanced in O N 3 H3C RA patients and the circadian peak of the hormone was O HO N 6-Hydroxymelatonin advanced [16]. For caveats concerning other diseases, H but also adolescents and pregnant women see refs. [18, Sulfotransferase 19]. H CH O N 3 H C The remarkable pleiotropy of melatonin unavoidably 3 O 6-Sulfatoxymelatonin leads to a plethora of effects if the hormone or synthetic -O3SO N H melatonergic drugs are administered. Many of these actions can be beneficial, but not necessarily all of them. However, the other side of the coin is that a pathological Figure 1: Biosynthesis and catabolism of melatonin. The decrease in melatonin formation and secretion has also main pathway is indicated by bold arrows. Abbreviations: numerous consequences on the functioning of a body, as AAAs, aryl acylamidases; AAF, arylamine formamidase; will be outlined in this article. AANAT, arylalkylamine N-acetyltransferase; AFMK, N1- acetyl-N2-formyl-5-methoxykynuramine; AMK, N1-acetyl- Biosynthesis, Metabolism and Signal 5-methoxykynuramine; ASMT, acetylserotonin Transduction Mechanisms methyltransferase; CYP, cytochrome P450 monooxygenase or dealkylase; HIOMT, hydroxyindole O-methyl- For the better understanding of several aspects to be transferase; MelDA, melatonin deacetylase. * Pyrrole ring discussed, the biosynthetic, catabolic and signaling cleavage is catalysed by various enzymes, such as pathways are briefly described. Melatonin is synthesized indoleamine 2,3-dioxygenase, myeloperoxidase, other peroxidases, and by several reactive oxygen species. ** from serotonin in two steps, N-acetylation to N- Alternately, AFMK can be deformylated by acetylserotonin (NAS) followed by O-methylation hemoperoxidases and photochemical mechanisms. For (Figure 1). The reverse sequence of these steps is further metabolites see ref. [3]. possible, but remains in vertebrates physiologically Aging and Disease • Volume 3, Number 2, April 2012 195 R. Hardeland Melatonin in Aging and Disease In the pineal gland and several other sites, N- cleavage, which leads to N1-acetyl-N2-formyl-5- acetylation of serotonin is catalysed by arylalkylamine methoxykynuramine (AFMK). This process can be N-acetyltransferase (AANAT) [21] and O-methylation of catalyzed by remarkably many agents and includes NAS by hydroxyindole O-methyltransferase (HIOMT, various enzymes, especially dioxygenases and alias acetylserotonin methyltransferase, ASMT). peroxidases, and several pseudoenzymatic, free radical- AANAT is usually regarded as the rate-limiting enzyme mediated and photochemical reactions (summarized in of melatonin biosynthesis, but this conclusion has been ref. [30]). AFMK was originally believed to be a major disputed for maximal nocturnal values in the rat pineal, brain metabolite, since it was detected in large amounts in which a limitation by HIOMT has been reported [22]. after injection of melatonin into the cisterna magna of The situation may be different in some extrapineal sites rats [31]. Although AFMK was reported to be also of melatonin synthesis. Preliminary data indicate that the formed by several cell types, such as macrophages