With regard to melatonin's orchestrating role [1
], a plethora of effects can be expected to result from its deficiency. The consequences are not only evident in the CNS but extend to numerous other organs. In part, they are related to disturbances of the circadian oscillator system, but additional defects of different nature may also arise.
In the CNS, membrane and nuclear receptors as well as other, poorly investigated putative melatonin binding sites are widely distributed. However, the functional significance is only clear in a few aspects. The most frequently studied role of melatonin concerns the SCN. In mammals including the human, melatonin released from the pineal gland is notably both an output factor steered by the SCN, via a known neuronal pathway and an input factor feeding back to the SCN. These aspects, and especially the roles of melatonin receptors in this hypothalamic structure, have been frequently reviewed, but mostly in relation to the control of the circadian pacemaker [105
]. A specific effect of melatonin at the SCN is related to sleep. Of course, this action is intertwined with the phase control of the master clock but can be discussed separately, in particular, with regard to sleep initiation. The onset of sleep is favored by MT1
-dependent actions at the SCN that are further mediated to the hypothalamic sleep switch, a structure that responds in an on-off mode. On the basis of mutual inhibition, it alternately activates either wake-related neuronal downstream pathways that involve locus coeruleus, dorsal raphe nucleus, and tuberomammillary nucleus or, under the influence of melatonin, sleep-related pathways via the ventrolateral preoptic nucleus [125
]. However, other brain structures, in which melatonergic receptors are also expressed, are additionally involved. For instance, the thalamus contributes to the soporific effects of melatonin by promoting spindle formation, which is characteristic for the transition from stage 2 sleep to deeper sleep stages and requires a thalamocortical interplay [33
]. Although sleep temporally coincides in humans with high nocturnal melatonin levels, persistent effects of melatonin on sleep maintenance are less evident. Nevertheless, low nocturnal melatonin is, independently of its specific causes, generally associated with sleep difficulties [65
Elderly insomniacs exhibit strongly decreased levels and rhythm amplitudes of the excretion product, 6-sulfatoxymelatonin, compared to individuals of same age without sleeping difficulties [128
], but this phenomenon is not restricted to individuals of advanced age [3
]. In cases of pediatric survivors of craniopharyngioma surgery, the resulting lack of melatonin secretion was associated with inappropriate daytime sleep and nocturnal awakenings [54
]. A perturbation of the circadian system may contribute to these symptoms but does not fully explain them, since the rhythm of sleep/wakefulness was evident in the actograms [56
]. Nocturnal sleep deficits are compensated by the homeostatic drive to sleep and can lead to daytime somnolence as well. Similar changes have been observed after pinealectomy [131
], although exceptionally a lengthening of nighttime total sleep duration has also been observed, which was, however, mainly caused by an increased REM sleep duration [132
]. Other cases, in which the circadian system was predominantly affected, will be discussed in the next section.
Sleep difficulties are often accompanying symptoms of depressive disorders [133
]. Chronic insomnia has even been considered as a predictor and, possibly, a triggering factor for this group of diseases [133
]. In fact, sleep disturbances have been reported as a prodromal symptom several weeks prior to the recurrence of a depressive episode [133
]. However, the etiologic heterogeneity of depressive disorders does not allow to conclude on a general relationship between melatonin deficiency, resulting insomnia, and depression. Nevertheless, this connection may exist in some subforms. Moreover, decreased melatonin levels can be a reason for inefficient entrainment and, thus, inappropriate circadian timing, either with regard to the coupling to external time cues or to internal phase relationships within the multioscillator system [32
]. Some types of depressive disorders that are associated with or, possibly, caused by circadian dysfunction will be discussed below.
In addition to its sleep promoting properties, melatonin exhibits various other sedating, antiexcitatory, and anticonvulsant effects, which comprise different actions, such as facilitation of GABAergic transmission, modulation of glutamate receptors, secondary effects by decreases of cytosolic Ca2+
or metabotropic mGlu3
receptors, interference with neuronal NO synthase, changes in K+
currents, and potentiation of strychnine-sensitive glycine-induced currents (summarized in [6
]). To what extent these functions are impaired under conditions of melatonin deficiency remains to be studied. This may not be obvious, as long as individuals are not challenged by diseases, but can become relevant if excitotoxic and brain inflammatory processes take place, for example, in neurodegenerative disorders or brain infection. Similar considerations may be justified for antihyperalgesic, antinociceptive and anxiolytic effects, which seem to be functionally related to antiexcitatory actions [3
Numerous other consequences of melatonin deficiency may be deduced from preclinical studies, mainly conducted in nocturnally active rodents. Differences between diurnal and nocturnal species have to be considered especially in all areas concerning neuronal activities, the cardiovascular system, and physical exercise. In these cases, the applicability to humans remains to be demonstrated, especially in the following examples. MT2
knockout mice were reported to be impaired in hippocampal long-term potentiation [137
], a finding of interest in terms of neuronal plasticity and learning. MT1
knockout mice exhibited gradual sensorimotor deficits and increased times of immobility in forced swim tests, which is usually interpreted as an indication of depressed-like behavior [138
Countless publications have dealt with experimental melatonin deficiency by pinealectomy in animals. Only some studies will be considered here, which are potentially relevant to clinical medicine. In senescent rats, pinealectomy caused enhanced oxidative damage to membrane lipids, protein, and DNA in various organs, compared to controls of the same age [139
]. These data are in good agreement with the amply documented antioxidant properties of melatonin, which have been demonstrated in numerous organisms and experimental models [1
]. Pinealectomy was also reported to increase homocysteine levels, which might indicate a higher risk of cardiovascular disease, results that were in line with the homocysteine-reducing action of melatonin [142
]. In models of neurodegeneration, based on focal brain ischemia or glutamate toxicity, the damaged areas were larger in pinealectomized rats than in control animals [143
The loss of melatonin as a component of the antioxidative protection system may be also relevant during light-induced melatonin suppression in nocturnal shift work [144
], in addition to the perturbation of circadian oscillators. Similar assumptions have been made with regard to aging. However, aging is a complex phenomenon during which primary, lingering processes that include increased free-radical formation because of progressive mitochondrial impairments are superimposed by events of deterioration due to diseases, which lead to secondary impairments [19
]. Individual catastrophes such as infarction, stroke, renal failure, or cancer impair the function of organs and cells and, thereby, contribute to the acceleration of the more continual mechanisms of aging, even if treatment is successful. Less severe diseases, such as subclinical chronic inflammation, may also affect the health state and lead to a more rapidly progressing senescence. Aging itself and many age-related diseases are associated with increases in free-radical formation, along with a higher vulnerability to oxidative damage and less efficient repair mechanisms [19
]. On this background, it seems attractive to assume that melatonin, which acts as a direct and indirect antioxidant, improves mitochondrial function, and has some additional cell-protective and antiiflammatory properties, may antagonize senescence. Correspondingly, melatonin deficiency might cause an acceleration of aging and increase the likelihood of developing age-related diseases. However, the direct evidence for this relationship is still insufficient. On the one hand, the health state of experimental animals treated during aging with melatonin is usually better, as referred to as the “Methuselah syndrome” [153
]. Old melatonin-treated rodents display a higher mobility, a glossy fur, absence of skin inflammations, and low osteoporosis, compared to age-matched controls [6
]. These findings indicate that melatonin deficiency may promote age-related diseases.
On the other hand, life extension by melatonin is not that much apparent in those rodent strains which do not die from cancer [6
]. Thus, a longer lifespan observed in mice strains that predominantly die from cancer reflects chemopreventive actions of melatonin rather than a true antiaging effect [6
]. However, a prolongation of life by melatonin was demonstrated in the senescence-accelerated SAMP8 mouse strain [154
]. These mice are more vulnerable to oxidative stress, but a major question is that of whether the processes responsible for the more rapid aging are identical with the normal causes of aging. As argued elsewhere [19
], other progerias, for example, of a laminopathic type, do not reflect normal aging.
Since melatonin is multiply involved in immunodulation [1
], and since the immune system is deteriorating by age [157
], melatonin deficiency may also be assumed to contribute to immunological aging. However, the role of melatonin is highly complex in this regard. First, the methoxyindole exerts both immune stimulatory and antiinflammatory properties and can act in a pro- or antioxidant fashion, depending on leukocytes affected and conditions of infection or inflammation. Moreover, melatonin is synthesized by several types of leukocytes [1
]. Although many immune cells express melatonin receptors [3
] and can, therefore, respond to the circulating hormone, a decrease in melatonin secretion by the pineal gland does not necessarily imply losses of immune functions, as far as they are based on paracrine and autocrine actions of melatonin produced by leukocytes. Nevertheless, the relationship between melatonin and the immune system during aging remains to be an issue worth of future efforts.
Immunological aspects of melatonin extend to oncological questions. Melatonin deficiency has, in fact, been discussed in terms of the risk of developing certain types of cancer. Oncostatic actions of melatonin have been observed in various experimental models and include growth and apoptosis of malignant cells [160
]. These findings clearly exceed the immunological role and primarily concern signaling mechanisms in the respective cancer cells. Nonetheless, the development of tumors from transformed cells may be favored under conditions of melatonin deficiency, when immunomodulation by the pineal hormone has declined. In humans, melatonin deficiency has been attributed to a higher incidence of prostate [65
], endometrial [75
], and breast [65
] cancers. It has remained unclear whether the decreases in melatonin have occurred prior to the disease and are contributing factors to tumor development or represent secondary changes induced by the tumor. Moreover, it remains to be clarified whether, or to which extent, the insufficient melatonin levels and the perturbations of the circadian system are decisive.
An emerging field of melatonin research concerns metabolic disorders, obesity, prediabetic states, diabetes type 2, and general insulin resistance [3
]. Numerous data from preclinical studies have shown a regulation of insulin and glucagon release by melatonin. Direct evidence for an involvement of the methoxyindole in diabetes has been obtained in mice, in which insulin resistance is induced by knockout of the MT1
receptor gene [169
]. Corresponding data were reported for obesity and prediabetic states. Aging rodents showed increases in visceral adipose tissue that were correlated to a decline of melatonin [1
]. Weight gain induced in old- or middle-aged rats by high-fat diet, by ovariectomy, or, notably, by pinealectomy was reversed by melatonin, with concomitant normalizations of insulin and leptin levels [170
]. Similar activities were reported for the synthetic melatonergic agonists NEU-P11 [174
] and ramelteon [176
]. In humans, the main evidence was obtained in several studies which demonstrated an enhanced risk for diabetes type 2 in variants of the MT2
receptor gene (summarized in [32
]). Collectively, all pertinent findings indicate that high nocturnal melatonin and intact melatonin signaling are in favor of avoiding diabetes type 2, despite the chronobiological differences between nocturnally active rodents and humans.
With regard to the numerous sites of melatonin receptor expression within the body, many additional consequences may arise from melatonin deficiency and be clinically relevant. A high number of data, which would by far exceed the scope of this review, exist for effects of melatonin in other tissues, including the cardiovascular system, bones, other endocrine glands, and visceral organs. However, direct evidence, on a clinical basis, for a causative role of melatonin deficiency in their respective diseases would be required for definite judgments.