Assessment of the Potential Role of Tryptophan as the Precursor of Serotonin and Melatonin for the Aged Sleep-wake Cycle and Immune Function: Streptopelia Risoria as a Model

Paredes, Sergio D. 1 Barriga, Carmen 1 Reiter, Russel J. 2 Rodríguez, Ana B. 1

[1 ] Department of Physiology (Neuroimmunophysiology Research Group), Faculty of Science, University of Extremadura, Badajoz, Spain

[2 ] Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, U.S.A

Abstract

In the present review we summarize the relationship between the amino acid, tryptophan, the neurotransmitter, serotonin, and the indole, melatonin, with the rhythms of sleep/wake and the immune response along with the possible connections between the alterations in these rhythms due to aging and the so-called “serotonin and melatonin deficiency state.” The decrease associated with aging of the brain and circulating levels of serotonin and melatonin seemingly contributes to the alterations of both the sleep/wake cycle and the immune response that typically accompany old age. The supplemental administration of tryptophan, e.g. the inclusion of tryptophan-enriched food in the diet, might help to remediate these age-related alterations due to its capacity of raise the serotonin and melatonin levels in the brain and blood. Herein, we also summarize a set of studies related to the potential role that tryptophan, and its derived product melatonin, may play in the restoration of the aged circadian rhythms of sleep/wake and immune response, taking the ringdove ( Streptopelia risoria) as a suitable model.

Introduction

Tryptophan is a polar, hydrophobic amino acid indispensable for protein synthesis. It is classified as an “essential” amino acid, i.e. it cannot be synthesized by the human organism and must therefore be ingested in the diet. Once tryptophan is consumed, it is readily absorbed into the capillaries in the intestinal wall. A small amount of the amino acid remains free while the majority of it (roughly 80%–90%) is transported bound to albumin through the blood and into the brain. This transport may be altered by the competition exerted by other free, neutral amino acids of high molecular weight, branched-chain amino acids, including valine, leucine and isoleucine, as well as phenylalanine and tyrosine, which bind to the same transporters. 1, 2

The metabolism of tryptophan is complex. It is involved in a variety of metabolic pathways and requires a suitable quantity of biopterin, magnesium or vitamin B6, which is involved in the conversion of the amino acid into serotonin and in the metabolism of other by-products, such as kynurenine. The main precursor of tryptophan is the anthralinic acid or anthranilate, a compound that after a series of chemical reactions is transformed into indole-3-glycerolphosphate. The enzyme tryptophan synthase converts this latter compound into glyceraldehyde 3-phosphate in a two-step reaction with the intermediary indole bound to the active site of the enzyme and with the intervention of serine ( Fig. 1). The contribution of tryptophan to energetic metabolism is double since on one hand it is ketogenic, i.e. it forms acetyl coenzyme A, and on the other it is glucogenic, as it produces alanine. 3

Tryptophan is transported to the liver where it is metabolized. Thereafter, in consecutive reactions it is transformed into nicotinic acid and other subproducts that either are stored or serve as a basis for important substances including quinolinate, picolinate or glutarate. 4

The amino acid tryptophan is the precursor of several important products including serotonin or melatonin ( Fig. 2). These molecules are biogenic amines of low molecular weight that belong to the indole group. It has been observed that the synthesis of melatonin in the pineal gland diminishes with aging. 57 This is believed to be due to degenerative changes in the neural structures (postganglionic neurons) innervating the pineal gland and central nervous system, rather than to the degeneration of the pineal tissue per se, 8 as well as to a reduction in the quantity of the necessary precursor, serotonin. 7, 9, 10 However, the number or sensitivity of melatonin receptors throughout the organism may decline with age as a result of the usual degenerative processes. 11 The result is the development of the so-called “serotonin and melatonin deficiency state.” 1214 This age-related state seemingly contributes to the alterations of both the sleep-wake cycle and the immune responsivity that characterizes aging. Thus, the consumption of tryptophan as a pharmacological agent or as part of a diet rich in this amino acid may attenuate age-related changes in circadian organization, the immune system, sleep, and other disorders, due to its ability to elevate circulating levels of serotonin and melatonin. 1518

This review is constructed to provide a concise view of the effects of tryptophan, serotonin and melatonin on the sleep-wake cycle and the immune system responses, to identify possible links between the impairment of these rhythms and the reduction in serotonin and melatonin levels in the aging organism, and to illustrate the potential restorative role that tryptophan may play against the age-related afore-mentioned circadian alterations. Finally, we present the ring dove ( Streptopelia risoria) as a suitable model for the study of the aged sleep-wake or activity-rest rhythms and immunosenescence and summarize the results obtained in this animal species in the circadian rhythm research field over the last decade.

Tryptophan, Serotonin, Melatonin, and the Sleep-wake Cycle

The initiation of investigations related to the hypnotic effects that tryptophan exerts on the human sleep dates back to the 70s and 80s, 19, 20 when it was observed that this amino acid augmented the propensity to sleep. During this interval tryptophan was used as a successful therapeutic agent to combat chronic insomnia. 21 More recently, the consolidation properties of tryptophan for the sleep-wake rhythm of newborns have been tested. It has been shown that being fed with nutritionally dissociated milk formulas, i.e. a diurnal formula with low content of tryptophan and carbohydrates and a high amount of protein, supplemented with the nucleotides cytidine 5-monophosphate, guanosine 5-monophosphate and inosine 5-monophosphate, and a nocturnal formula that contains high levels of tryptophan and carbohydrates, a low level of protein, with the nucleotides adenosine 5-monophosphate and uridine 5-monophosphate, improved the total hours of sleep, the efficiency of sleep, the minutes of nocturnal immobility, and reduced both the number of nocturnal awakenings and the sleep latency of newborns. 22, 23 This is of special importance at a stage of life where an appropriate rest period is directly related to an optimal development of both the nervous and immune systems.

The first studies showing a relationship between serotonin and sleep appeared in the middle of the 50s. It was observed that reserpine, an antipsychotic, antihypertensive indole alkaloid dimin ished the concentration of serotonin in the brain and induced a sedative state analogous to sleep. 24 It was also reported that the parenteral injection of L-5-hydroxytryptamine caused cortical synchronization and that inhibitors of the enzyme monoamine oxidase selectively suppressed paradoxical sleep or REM for long periods of time that could persist for days or even weeks. 25 Serotonin subsequently appeared as a key factor in understanding some of the mechanisms involved in the sleep-wake cycle. In fact, subsequent investigations documented that the destruction of the raphe nuclei, an area with an abundance of serotonin-containing neurons, by means of coagulation, produced insomnia for lengthy periods of time (10–15 days). Thus, a relationship among insomnia intensity, the magnitude of the injury in the raphe nuclei and the amount of brain serotonin that remained in the telencephalon after the degeneration of the serotoninergic terminals was established. Particularly, a correlation between the destruction of the rostral raphe and the slow-wake sleep and the telencephalic serotonin, which decreased, and between paradoxical sleep and damage to the nucleus raphe magnus was identified. 26, 27 It was additionally pointed out that p-chlorophenylalanine inhibited the enzyme tryptophan hydroxylase, which in turn impaired the biosynthesis of serotonin and secondarily led to states of total insomnia. 28

These experiments led to the elaboration of the so-called “monoaminergic theory of sleep.” This established that serotonin, or somnotonin as it was named by Koella, 29 was the neurotransmitter or “neurohormone” of sleep, since it produced sleep by the inhibition of the reticular formation and locus ceruleus, the putative centers of wakefulness. Conversely, catecholamines were found to be responsible for awakening. The demonstration, however, that the electric activity of serotoninergic neurons as well as the release of serotonin increased during wakefulness and decreased with sleep was seemingly in clear contradiction with the afore-mentioned theory. In the late 80s, however, a relationship between the sleep/wake cycle and serotonin was again considered. More recent experiments suggest that during wakefulness, serotonin is responsible for initiating a cascade of post-synaptic genomic processes in hypnogenic neurons located in the pre-optic area. 30 Through these processes, the release of the neurotransmitter during wakefulness leads to a homeostatic regulation of slow wave sleep, 30 also acting as a positive modulator of melatonin synthesis. 31

Among the diverse physiological functions in which melatonin has been involved, its role as regulator of the sleep/wake rhythms has attracted the attention of a number of sleep researchers in the last decade. The discovery that melatonin was mainly secreted at night and the tight relationship between the nocturnal increase of endogenous melatonin and the existing co-ordination of sleep as well as the pro-somnogenic effects that the pineal indole seemingly possessed, led many investigators to suggest that melatonin was likely implicated in the physiological regulation of sleep. With regard to this presumption, it was observed that the suppression of the production of melatonin using β-blockers correlated with insomnia, 3234 while the increase of the plasma levels of melatonin by reducing the activity of the enzymes that metabolize the indole in the liver resulted in an augmentation of the somnolence state. 35

It was reported that during the wake period immediately prior to sleep, known as the wake-maintenance zone or “forbidden zone” for sleep, 36 the propensity for sleep is reduced to a minimum and, at the same time, the activity of the neurons of the central nervous system is elevated. 37, 38 Thus, the transition from the wake stage to a period of high propensity for sleep coincides with the nocturnal elevation of the endogenous rhythm of melatonin. 39 This increase seems to be temporally related to the opening of the so-called sleep gate. 40, 41

Taking into account the relationship between the endogenous secretion of melatonin and the opening of the entry into nocturnal sleep, it has been proposed that the role of the pineal indole does not involve an active induction of sleep, rather it consists of the inhibition of the mechanisms that generate the circadian period of wakefulness, 42 presumably through the MT1 melatonin receptor 43, 44 and GABAergic activation 45, 46 at the central nervous system level.

Regarding the effects of the exogenous administration of melatonin on sleep and the circadian clock, there are a number of studies reporting that diurnal treatment with the indole produces drowsiness, 4751 as well as raising the circulating levels of melatonin to values normally observed at night. 52

For these reasons, melatonin, through its actions in the central nervous system, is seemingly a crucial substance for the co-ordination of the circadian mechanism of sleep. However, the recent discovery of melatonin receptors in other brain areas such as the hippocampus 53 makes necessary further investigation to elucidate the exact role of melatonin on sleep in the different brain structures. Moreover, considering the rather high levels of melatonin in certain plant foodstuffs ( Table 1), 54 the consumption of melatonin through the diet may have significant benefits to human and animal health.

Tryptophan, Serotonin, Melatonin, and the Immune System

The concentration of the amino acid tryptophan is lower in psychologically depressed patients with respect to control individuals. 55 This consequently produces a decrease in the levels of serotonin, a neurotransmitter that has frequently been implicated in depressive syndromes. 56 Moreover, it has been observed that when depressive disorders appear, they are accompanied by an inflammatory response involving the immune system, which is inversely proportional to the concentration of tryptophan in plasma. 57 This is also negatively correlated to the number of leukocytes and other components of the immune system including interleukin 6 (IL-6) and IL-8. 58 It has been reported that individuals with sleep disturbances experience the same symptoms as patients suffering from depression, i.e. a diminution of the tryptophan levels in plasma and an augmentation of both IL-6 and IL-8, compared to healthy individuals. 56, 57 They also experience a decrease in the levels of IL-2. 59 On the other hand, when interruption of sleep for 5 hours during the nocturnal period occurs, the levels of IL-1 and IL-2 are elevated. When somnolence is produced in excess, IL-6 and tumor necrosis factor α (TNF-α) are elevated, 60 with a subsequent rise in the number of monocytes and neutorphils. 61

Regarding the effect that the amino acid exerts on the phagocytic function, recent studies suggest an enhancement of phagocytosis after the oral administration of tryptophan. Particularly, it has been observed that administering the amino acid to rats causes incremental changes in circulating levels of melatonin as well as stimulating the antigenic capacity of ingestion of peritoneal macrophages obtained during the nocturnal period. 15, 62 An elevation of the phagocytic capacity at night has also been observed in otherwise untreated rats and mice. 6366 This suggests that the activation of the innate immune response after tryptophan consumption may be due to its conversion into the pineal indole. In fact, it has been shown that macrophages obtained from the peritoneal cavity of normal rats when incubated with tryptophan show an increase in arylalkylamine N-acetyltransferase activity which corresponds to a rise in melatonin production. 67 Nevertheless, tryptophan is also the precursor of serotonin, a compound that may also play a role in the function of the innate immune system. Owing to the fact that receptors for serotonin exist in leukocytes and a transporter for this amine has been found in macrophages, mononuclear leukocytes, and B cells, this neurotransmitter may be a critical element for the connection between the nervous and immune systems. 68, 69 Some studies have shown that serotonin may also possess an antioxidative role. 7072 Serotonin has also been reported to inhibit leukocyte phagocytosis, 73, 74 especially when the concentrations of neurotransmitter used are in the pharmacological range. 71 Since circadian variations of serotonin in plasma and different brain regions have been observed, 75 this may somehow influence the circadian daily variations of the immune system.

A substantial body of research has defined melatonin as a remarkable molecule with pleiotropic effects both of an endocrine and a non-endocrine nature on the immune system. 7678 The abolition of the daily rhythm of melatonin via either surgical or functional pinealectomy has been shown to directly correlate to weight loss of the thymus as well as to the abnormal involution of this immune organ; this is also accompanied by a depletion of lymphoblasts and an almost total absence of lymphocytes. 79 A reduction in the size of lymph nodes associated with follicular loss in the outer cortex 80 together with an alteration of the activities of thymic polyamine biosynthetic amines have also been noted. 8183 Other immune organs such as the spleen or the bursa of Fabricius in birds are impaired following pinealectomy. In this respect, Brainard et al. 79 showed a lack of evident germinal centers and an apparent inactivity of the red pulp in the Syrian hamster spleen, while Jankovic et al. 84 found a delayed development not only in the bursa but also in the thymus and spleen of pinealectomized chicks. The absence of the pineal gland has also been reported to significantly reduce IL-2 production and NK activity 85, 86 and decrease the cellular and humoral immune response of both mammals and birds. 8790 When melatonin is administered to pinealectomized animals, the effects on immune system are typically reversed.

In vivo models have shown melatonin to be considered as a positive regulator of immune responses. The administration of melatonin results in the enhancement of antigen presentation by splenic macrophages in major histocompatibility complex II, IL-1 and TNF-α production, 91 the increase in the generation of thymosin α1 through a rise in prothymosin α gene expression 92 as well as the production of IL-10. 93 In mice, treatment with melatonin also upregulates macrophage-colony stimulating factor, TNF-α, transforming growth factor β and stem cell factor gene expression in peritoneal macrophages and the levels of IL-1β, interferon γ, macrophage-colony stimulating factor, TNF-α and stem cell factor in splenocytes. 94

The pineal indole also possesses potential positive effects on several immune system pathologies including acute and chronic inflammation 95, 96 and syndromes provoked by certain viruses such as the encephalomyocarditis virus, 97 lethal Semliki Forest virus and the attenuated non-invasive West Nile virus 98 as well as the Venezuelan equine encephalomyelitis virus. 99101

The Serotonin and Melatonin Deficiency State Due to Ageing: Effects and Consequences on the Sleep/wake Cycle and the Immune System

Aging is associated with a reduction in the size of the brain. These changes are generally attributed to a loss of neurons in specific layers and regions of the brain, although there exists considerable interindividual variation. 102 The loss of neurons has been shown to occur in the locus ceruleus, the main source of catecholaminergic neurons, and in the substantia nigra, where dopaminergic neurons are most abundant. This may contribute to age-related changes in homeostasis, sleep alterations, stability, movement, and cognitive function. 103 Alterations tend to affect the myelinated axons (the white matter) at a much greater degree when compared to the neuron cell bodies in the grey matter. 104 Aging has also been proposed to modify the permeability of the blood-brain barrier, which may have consequences in terms of porosity of this structure to different drugs or molecules and to cause a decline in the brain metabolism and blood flow. 105

Neurotransmitter functions of serotonin are widely distributed in the central nervous system and are related to the regulation of a variety of behaviors. Serotonin is seemingly involved in the regulation of humor, anxiety, sleep, appetite, sexual function, brain blood flow and many other functions. The serotoninergic neurons are located in the raphe nuclei of the brain stem and their axons project to all brain areas, including the cerebral cortex, thalamus, the limbic system and the hypo-thalamus. In regard to this, any change in the number of serotonin receptors or in the endogenous levels of the neurotransmitter due to aging may have consequences on behaviour or cognitive function. Diverse studies have shown that alterations in serotinergic neurotransmission cause age-related alterations. Particularly, a reduction in the density of the serotonin type 2 receptor (5HT2A) has been described. 106

The injection of altanserin, a high affinity ligand to 5HT2A receptor union sites, to young and old subjects showed that the specific union for this receptor was significantly reduced in old individuals compared to the young, as well as the number of receptors, whose loss was marked in certain brain regions. 106 Since many antidepressant drugs typically relieve the symptoms of depression by blocking serotonin reuptake in order to facilitate an increase in serotonin activity, it is speculated that the high incidence of depression in the elderly may be attributed to the reduction in serotonin receptors. Moreover, it has been reported that serotonin receptors and transporters are less sensitive to hormone regulation, which responds to the deficiency associated to aging of the regulation of the hippocampal serotoningeric system exerted by corticosterone. 107 This suggests that the age-related changes in the neurochemistry of serotonin may be a cause of the increased rates of depression and hypercortisolemia observed in the aged populations. In parallel, serotonin is known to increase the quality of slow wave sleep, 30 as well as being a waking neurotransmitter. 108 In addition, the close relationship between serotonergic activity and the adjustments of circadian phase has suggested that serotonin also plays a role in the endogenous regulation of the circadian clock. 109 These findings point to the participation of serotonin neurotransmission in the behavioral alterations commonly observed in aged individuals and may have potential therapeutic implications.

Blood melatonin levels show a clear circadian rhythm, with low levels during the day and high values at night, with these values being 10/15-fold greater that those measured in the diurnal period. 110, 111 In humans, the indole has been shown to gradually decrease during the increased life span, with the day/night rhythm being practically absent in individuals over 65-yr old ( Fig. 3). 112 This observation has also been reported when melatonin levels in young and old rats, gerbils, hamsters or ringdoves are compared. 113, 114 It is believed that the amplitude of the nocturnal melatonin rhythm is genetically determined as it shows important interindividual differences, 115 even though in a given individual it exhibits a high degree of fidelity over time. 116 Hence, some subjects produce significantly less melatonin in their life than others, which may be of importance for aging. 13

Aging is a crucial factor in terms of sleep characteristics. The structure, depth, and continuity of sleep tend to change over the life span. 117 Some reports have shown that more than a third of the elderly experience recurrent difficulty to maintain sleep 118 due to impairment in both the quality and the quantity of sleep. 119 Sleep onset latency usually increases together with the number and duration of awakenings, while sleep stability declines, and sleep consolidation is altered. 117 It is therefore not surprising that the information provided by epidemiologic studies reveals that up to 40% of individuals over 65-yr old complain about sleep problems and 12%–25% suffer from persistent insomnia. 120 The number of elderly people that have been prescribed sleep drugs or that use aids to facilitate nocturnal rest is estimated to be around 14%. 121

Aging also causes alterations in the amplitude of the sleep/wake circadian rhythm. 122 The temporal organization of sleep is impaired and the regulatory mechanisms of the sleep processes are attenuated. 123 Several reasons suggested for these age-related changes are a reduction in the number of pinealocytes, changes in retina and in the suprachiasmatic nuclei or alterations in melatonin secretion. 124

The effectiveness of the immune system decreases during aging. The lymphoid tissues of the spleen, bone marrow and thymus are progressively lost; this increases the incidence of infections, autoimmune diseases and cancer. 125 With advancing age, the number and proliferative capacity in response to mitogen-stimulation of the diverse subpopulations of T-lymphocytes is reduced 126, 127 while apoptosis is elevated. 128 Moreover, the synthesis and secretion of immunoglobulins is delayed, presumably due to a lack of appropriate levels of cytokines; 129 this decreases the competence of antibodies in immunization against infectious agents. 130 Antigen-presenting cells or accessory cells and phagocytes experience an age-related rise in the oxidative state, 131 resulting in a reduced capability to adapt to environmental stress and in a reduction of the phagocytic parameters. 114

It is known that the pineal gland influences the function of the neuroendocrine system and the efficacy of the immune system to recognize and react to any endogenous or exogenous factor. 132 For this reason, it has been suggested that aging is a result of the deterioration of this key factor of the pineal gland due to a deficient melatonin secretion and a decline in the melatonin/serotonin ratio. This may impair several aspects of an individual’s neurophysiology. 48 It has been observed that early extirpation of the pineal gland produces substantial accumulations of lipid peroxidation products, oxidized DNA, reduced fluidity of cell membranes and elevated protein damage in many organs. 133 These changes are a consequence of the loss of the endogenous melatonin rhythm. Impairment in melatonin synthesis is thought to likely play a role in the aging process since this indole participates in vital defence mechanisms including free radical scavenging and indirect antioxidative actions. 134, 135 Thus, melatonin is estimated to be responsible for the scavenging of ten or more reactive damaging agents. 136 Furthermore, its initial, secondary, tertiary and quaternary derivatives are all potent scavengers that, together with melatonin, form a remarkable cascade of reactions referred to as melatonin’s antioxidative cascade. 136, 137 The detoxification of radical and radical products by melatonin and its derivatives are receptor-independent actions and only require that the scavenger be at the site where the radical product is generated. 138 This is essential since highly reactive agents mediate damage in the immediate vicinity of where they are produced, i.e. the damage is site specific. 138 Melatonin also has receptor-mediated actions which adds to the capability of this molecule in eradicating radicals and reducing oxidative stress. 139, 140 Thus, melatonin stimulates a number of antioxidative enzymes which metabolize reactive products to innocuous agents. The enzymes whose activities have been shown to be promoted by melatonin include both Cu/Zn and Mn superoxide dismutases, glutathione peroxidases and glutathione reductase. 139, 141, 142 The effects of melatonin on the activities of the antioxidative enzymes are likely receptor-mediated and involve receptors on the plasma membrane and also presumably receptors/binding sites in the nucleus. 140

The efficiency of sleep is also reduced as a result of low circulating levels of the pineal indole. These phenomena typically accompany advancing age. Melatonin may thus protect against the oxidation of essential molecules, 143, 144 which appear in significant numbers in aged organisms, 145 and resist neurodegenerative disorders associated with the impairment produced in particular brain areas by free radicals. 146 In fact, melatonin may possess benefits in Parkinson and Alzheimer diseases. 147, 148

Pinealectomy is believed to accelerate the aging process, causing high blood pressure, elevated alkaline phosphatase activity, modification in the synthesis of prostaglandins, and induction of REM. These alterations are seemingly counteracted by the administration of melatonin. 149 Many studies support the idea that melatonin may be considered as an anti-aging and rejuvenating product. The evidence accumulated to date supports the hypothesis that the supplemental treatment with melatonin may be of benefit during aging. 150, 151

The Potential Restorative Role of Tryptophan of the Impaired in the Sleep/wake Cycle and Immune System that Accompany Aging: Streptopelia Risoria as a model

The ringdove ( Sterptopelia risoria) is a species characterized by being diurnal and monophasic with sleep-wake cycles similar to those of human beings and, therefore, it represents a good model to investigate impairments in the circadian system due to age, including immune alterations.

The first study performed in the ringdove that showed a relationship between the pineal gland, melatonin and the immune system was that of Rodríguez and Lea. 87 Pinealectomy produced a significant increase in the number of total white blood cells and total protein concentration in plasma in addition to altering different stages of the phagocytic process. Also, during an immunization study, a reduction in the percentage of leukocytes and lymphocytes and an increase in the percentage of heterophils accompanied by a rise in the concentration of serum corticosterone were observed 3 hr following treatment. For the immunological parameters, adherence capacity and latex bead ingestion were increased 3 hr after normal sleep serum injection and the nitroblue tetrazolium reduction test 3 and 24 hr after normal sleep serum treatment. In addition, the administration of normal sleep serum produced a significant increase in serum T3 and T4 concentrations 4 days following injection. These results indicate that the loss of melatonin due to pinealectomy has a marked effect on both the number and function of immune cells.

In reference to in vivo experiments with melatonin, a correlation between the circadian rhythm of the indole, phagocytosis, and superoxide anion levels has been reported. 152 Thus, the elevated melatonin serum levels during the dark period coincide with an enhanced phagocytosis of inert particles and lower superoxide anion levels derived from the immune system. These effects where reinforced when the animals received melatonin orally, which also elevated circulating levels of the indole. 153, 154 Similar results were observed when the phagocytosed particle was a living organism ( Candida albicans) with the effect being dose-dependent. 153, 155 In vitro experiments have reported similar results, with the chemoattractant ability for heterophils being significantly enhanced by the pineal indole 156 as well as an augmentation of the phagocytic function and a decline in the free radical production. 65 Melatonin also decreased the superoxide dismutase activity (an indicator of the metabolic burst) in heterophils after the ingestion of latex beads. 157

The concentration of malonaldehyde in cells is an index of induced oxidative damage to membrane lipids. The co-incubation of a heterophil suspension with or without inert particles (latex beads), as material to be phagocytosed, in combination with melatonin has been shown to clearly reduce the production of malonaldehyde. The enhancement of malonaldehyde levels produced by latex beads was also annulled in the samples incubated with melatonin. 158

In stressful situations, an alteration in the endogenous circadian rhythm of melatonin in the ringdove has been described. 159 This has also been reported in mammals, where a decreased MESOR and amplitude of the melatonin rhythm, and a significantly elevated MESOR of the corticosterone rhythm have been observed. 66, 160

Streptopelia risoria also experiences a “serotonin and melatonin deficiency state” during aging; 7, 10 this is associated with increased nocturnal activity and depressed immune function. 7, 154, 161, 162 Under these conditions, orally administered melatonin has been reported to improve nocturnal rest not only in old ringdoves, but also in young birds. 161, 162 This is likely to be a result of a decrease in the core temperature and an increase in the peripheral temperature observed after the oral administration of the indole in this species. 162 Thus, melatonin may be used to palliate the reduction in the thermoregulatory responses and the capacity for thermal comfort reported in the elderly. 163 This is of importance since sleep disorders are believed to be caused, at least partly, by changes in the circadian rhythms of temperature and melatonin. 164

The oral administration of the indole restores some of the changes that aging produces in the innate immune response, with an enhancement in the phagocytic processes and a decrease in the production of free radicals, reflecting the scavenging properties of melatonin; this is most probably due to the restoration of the nocturnal rise of circulating melatonin due to its administration. 153, 154, 161, 165 This hypothesis is corroborated by previous findings showing that the incubation of ringdove heterophils obtained from old animals with the physiological concentrations of serum melatonin typical of young and mature birds induced a dose-dependent rise in both the phagocytic index and the candidicide capacity, together with a decline in superoxide anion levels. 166 Furthermore, the incubation of old heterophils with the physiological concentrations of melatonin characteristic of young animals (50 and 300 pg/ml, diurnal and nocturnal, respectively) counteracted the enhancement of malonaldehyde levels caused by latex beads, with the effect being greater at the longer incubation time tested. 167

Once the potential role of the pineal indole to reverse the age-related alteration in the activity/rest rhythms and immune impairment in the ringdove was documented, the next step was to test whether tryptophan, the precursor of melatonin and also of the neurotransmitter serotonin would have similar effects. Tryptophan administered in the diet is known to increase the availability of serotonin in the brain, improve the EEG delta potential, and elevate the amount of NREM. 168 It has also been observed in mammals that orally ingested tryptophan increases brain levels of serotonin during the day and the circulating levels of melatonin during the immediately subsequent night. 62 Likewise, tryptophan administration raised the circulating levels of both serotonin and melatonin in rats. 15, 18 In sexually immature ringdoves, the administration of the amino acid increased nocturnal rest, which seemingly correlated with the augmented circulating levels of melatonin caused by tryptophan treatment. 169 Tryptophan significantly increases the hippocampal, striatal, and hypothalamic serotonin contents, 10 and reduces the expression of c-fos in the suprachiasmatic nucleus. 170 C-fos levels are high in several cerebral regions during spontaneous waking or sleep deprivation and fall after a few hours of sleep. 171

In old ringdoves, the treatment with 300 mg of tryptophan per kg b.w. reduces nocturnal activity without affecting their diurnal activity, an effect accompanied by a general increase of serum serotonin levels 16 This increase of serum serotonin indicates a higher availability of tryptophan which, after passing the blood–brain barrier, would be converted into serotonin. 10, 15, 18, 31, 62 The elevated serotonin in the pineal gland serves as a substrate for melatonin synthesis, and increases in the levels of this molecule would reduce nocturnal activity of old ringdoves, 16 improving their aging-impaired nocturnal rest. 7 Tryptophan administered at the same dose and time also provoked an improvement of the circadian rhythm of temperature in this species. 162

Regarding the innate immune response in old birds, treatment with tryptophan produced a significant diurnal and nocturnal augmentation in phagocytic parameters; the values reached during the night were significantly higher that those measured during the day. 17 This is consistent with earlier findings demonstrating that giving the amino acid to mammals 15, 62 or birds, 172 or melatonin itself to these species 14, 154, 165, 173, 174 has a general immuno-enhancing effect. Moreover, a reduced production of superoxide anion radicals in old ringdoves was observed after tryptophan treatment. 17 This change was presumably due to the rise of the circulating serum levels of melatonin produced by the exogenous administration of its precursor. 16, 17 This indicates that rising serum levels of melatonin are accompanied by a decline in the levels of superoxide anion radicals produced by heterophils, as reported previously. Also, tryptophan significantly limits the reduction in cell viability of heterophils exposed to hydrogen peroxide. 17 A similar effect was obtained when the cells are incubated with melatonin. 154 Furthermore, both the oral administration of the amino acid and the indole lowered cytokine levels in aged birds. 162

Concluding Remarks

A variety of studies on serotonin neurotransmission indicate that, as a consequence of aging, a reduction in the density of serotonin receptors and marked disturbance in the 5-hydroxindole acetic/serotonin turnover and in the responses of the receptors/transporters to the hormonal regulation occur. 106, 107 Many of these alterations result in a decreased serotonin binding. Furthermore, the production of melatonin suffers a dramatic decline with age. 13 These neurochemical changes may have etiologic implications in the altered behavior observed in old individuals and an underlying cause of several geriatric conditions, including the impaired sleep/wake cycle and immunosenescence. The evidence obtained in the ringdove and other animal models suggests that the supplemental administration of tryptophan, e.g. the inclusion of tryptophan-enriched food in the diet, might help to remediate the reduction in serotonin and melatonin that normally occurs as animals age, and be consequently beneficial in the treatment of sleep problems and alterations in the innate immune response.

Acknowledgements

This investigation was supported by a research grant from Consejería de Infraestructuras y Desarrollo Tecnológico (Junta de Extremadura, 3PR05A053). S.D. Paredes was the beneficiary of a grant from Consejería de Economía, Comercio e Innovación—Fondo Social Europeo (Junta de Extremadura, POS07012).

Notes

[1] Disclosure

The authors report no conflicts of interest.

References

1. 

Steinberg LA, O’Connell NC, Hatch TFTryptophan intake influences infants’ sleep latencyJ Nutr(1992) 122: 178191 Pubmed ID: 1512627

2. 

Jansman AJM, Kemp GWP, van Cauwenberghe SEffect of the level of branch chain amino acids (BCAA) and tryptophan in the diet of performance of pigletsBook of Abstracts of the 51st EAAP congressThe Hague, The Nethelands(2000) 396

3. 

Gómez G, Llorca RAminoácidosBiopsicología(2000) 3: 54876

4. 

Cooper JR, Bloom FE, Roth RHThe biochemical basis of neuropharmacology6th edNew YorkOxford University Press(1991)

5. 

Reiter RJ, Richardson BA, Johnson LYPineal melatonin rhythm: reduction in aging Syrian hamstersScience(1980) 210: 13723 Pubmed ID: 7434032

6. 

Reiter RJ, Craft CM, Johnson JEJrAge-associated reduction in nocturnal melatonin levels in female ratsEndocrinology(1981) 109: 12957 Pubmed ID: 7285872

7. 

Paredes SD, Terrón MP, Cubero JComparative study of the activity/rest rhythms in young and old ringdove ( Streptopelia risoria): correlation with serum levels of melatonin and serotoninChronobiol Int(2006) 23: 77993 Pubmed ID: 16887748

8. 

Ruzsas C, Mess BMelatonin and aging. A brief surveyNeuro Endocrinol Lett(2000) 21: 1723 Pubmed ID: 11455324

9. 

Pietraszek MH, Urano T, Serizawa SCircadian rhythm of serotonin: influence of ageThromb Res(1990) 60: 2537 Pubmed ID: 2084955

10. 

Garau C, Aparicio S, Rial RVAge-related changes in circadian rhythm of serotonin synthesis in ring doves: effects of increased tryptophan ingestionExp Gerontol(2006a) 41: 408 Pubmed ID: 16271444

11. 

Zhdanova IVMelatonin as a hypnotic: proSleep Med Rev(2005) 9: 5165 Pubmed ID: 15649738

12. 

Wurtman RJAge-related decreases in melatonin secretion—clinical consequencesJ Clin Endocrinol Metab(2000) 85: 21356 Pubmed ID: 10852441

13. 

Karasek M, Reiter RJMelatonin and agingNeuro Endocrinol Lett(2002) 23: Suppl1416 Pubmed ID: 12019345

14. 

Paredes SD, Barriga C, Rodríguez ABMelatonin and tryptophan as therapeutic agents against the impairment of the sleep-wake cycle and immunosenescence due to aging in Streptopelia risoriaNeuro Endocrinol Lett(2007a) 28: 75760 Pubmed ID: 18063930

15. 

Sánchez S, Paredes SD, Martín MIEffect of tryptophan administration on circulating levels of melatonin and phagocytic activityJ Appl Biomed(2004) 2: 169177

16. 

Paredes SD, Terrón MP, Cubero JTryptophan increases nocturnal rest and affects melatonin and serotonin serum levels in old ringdovePhysiol Behav(2007b) 90: 57682 Pubmed ID: 17222434

17. 

Paredes SD, Terrón MP, Marchena AMTryptophan modulates cell viability, phagocytosis and oxidative metabolism in old ringdovesBasic Clin Pharmacol Toxicol(2007c) 101: 5662 Pubmed ID: 17577317

18. 

Mateos SS, Sánchez CL, Paredes SDCircadian levels of serotonina in plasma and brain after oral administration of tryptophan in ratsBasic Clin Pharmacol Toxicol(2009) 104: 5259 Pubmed ID: 19152552

19. 

Wyatt RJ, Engelman K, Kupfer DJEffects of L-tryptophan (a natural sedative) on human sleepLancet(1970) 2: 842846 Pubmed ID: 4097755

20. 

Spinweber CLL-tryptophan administered to chronic sleep-onset insomniacs: late-appearing reduction of sleep latencyPsychopharmacology (Berl)(1986) 90: 1515 Pubmed ID: 3097693

21. 

Demisch K, Bauer J, Georgi KTreatment of severe chronic insomnia with L-tryptophan and varying sleeping timesPharmacopsychiatry(1987) 20: 2458 Pubmed ID: 3432358

22. 

Cubero J, Narciso D, Aparicio SImproved circadian sleep-wake cycle in infants fed a day/night dissociated formula milkNeuro Endocrinol Lett(2006a) 27: 37380 Pubmed ID: 16816833

23. 

Cubero J, Narciso D, Terrón PChrononutrition applied to formula milks to consolidate infants’ sleep/wake cycleNeuro Endocrinol Lett(2007) 28: 3606 Pubmed ID: 17693960

24. 

Brodie BB, Pletscher A, Shore PAEvidence that serotonin has a role in brain functionScience(1955) 122: 968 Pubmed ID: 13274056

25. 

Jouvet M, Vimont P, Delorme F[Elective suppression of paradoxal sleep in the cat by monoamine oxidase inhibitors]C R Seances Soc Biol Fil(1965) 159: 15959 Pubmed ID: 4221672

26. 

Dahlstroem A, Fuxe KEvidence for the existence of monoamine-containing neurons in the central nervous system I. Demonstration of monoamines in the cell bodies of brain stem neuronsActa Physiol Scand Suppl(1964) 232: 155 Pubmed ID: 14229500

27. 

Jouvet MBiogenic amines and the states of sleepScience(1969) 163: 3241 Pubmed ID: 4303225

28. 

Koe BK, Weissman Ap-Chlorophenylalanine: a specific depletor of brain serotoninJ Pharmacol Exp Ther(1966) 154: 499516 Pubmed ID: 5297133

29. 

Koella WPSerotonin and sleepExp Med Surg(1969) 27: 15768 Pubmed ID: 4903796

30. 

Jouvet MSleep and serotonin: an unfinished storyNeuropsychopharmacology(1999) 21: 24S7S Pubmed ID: 10432485

31. 

Huether G, Poeggeler B, Adler LEffects of indirectly acting 5-HT receptor agonists on circulating melatonin levels in ratsEur J Pharmacol(1993) 283: 24954 Pubmed ID: 8405095

32. 

Brismar K, Mogensen L, Wetterberg LDepressed melatonin secretion in patients with nightmares due to beta-adrenoceptor blocking drugsActa Med Scand(1987) 221: 1558 Pubmed ID: 2884812

33. 

Brismar K, Hylander B, Eliasson KMelatonin secretion related to side-effects of beta-blockers from the central nervous systemActa Med Scand(1988) 223: 52530 Pubmed ID: 3291558

34. 

Van Den Heuvel CJ, Reid KJ, Dawson DEffect of atenolol on nocturnal sleep and temperature in young men: reversal by pharmacological doses of melatoninPhysiol Behav(1997) 61: 795802 Pubmed ID: 9177549

35. 

Hartter S, Wang X, Weigmann HDifferential effects of fluvoxamine and other antidepressants on the biotransformation of melatoninJ Clin Psychopharmacol(2001) 21: 16774 Pubmed ID: 11270913

36. 

Lavie PUltrashort sleep-waking schedule. III. ‘Gates’ and ‘forbidden zones’ for sleepElectroencephalogr Clin Neurophysiol(1986) 63: 41425 Pubmed ID: 2420557

37. 

Buysse DJ, Nofzinger EA, Germain ARegional brain glucose metabolism during morning and evening wakefulness in humans: preliminary findingsSleep(2004) 27: 124554 Pubmed ID: 15586778

38. 

Long MA, Jutras MJ, Connors BWElectrical synapses coordinate activity in the suprachiasmatic nucleusNat Neurosci(2005) 8: 616 Pubmed ID: 15580271

39. 

Dijk DJ, Cajochen CMelatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEGJ Biol Rhythms(1997) 12: 62735 Pubmed ID: 9406038

40. 

Tzischinsky O, Shlitner A, Lavie PThe association between the nocturnal sleep gate and nocturnal onset of urinary 6-sulfatoxymelatoninJ Biol Rhythms(1993) 8: 199209 Pubmed ID: 8280909

41. 

Shochat T, Luboshitzky R, Lavie PNocturnal melatonin onset is phase locked to the primary sleep gateAm J Physiol(1997) 273: R36470 Pubmed ID: 9249573

42. 

Lavie PMelatonin: role in gating nocturnal rise in sleep propensityJ Biol Rhythms(1997) 12: 65765 Pubmed ID: 9406042

43. 

Liu C, Weaver DR, Jin XMolecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clockNeuron(1997) 19: 91102 Pubmed ID: 9247266

44. 

Hunt AE, Al-Ghoul WM, Gillette MUActivation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clockAm J Physiol Cell Physiol(2001) 280: C1108 Pubmed ID: 11121382

45. 

Golombek DA, Pevet P, Cardinali DPMelatonin effects on behavior: possible mediation by the central GABAergic systemNeurosci Biobehav Rev(1996) 20: 40312 Pubmed ID: 8880732

46. 

Tenn CC, Niles LPThe antidopaminergic action of S-20098 is mediated by benzodiazepine/GABA(A) receptors in the striatumBrain Res(1997) 756: 2936 Pubmed ID: 9187346

47. 

Waldhauser F, Saletu B, Trinchard-Lugan ISleep laboratory investigations on hypnotic properties of melatoninPsychopharmacology (Berl)(1990) 100: 2226 Pubmed ID: 2305009

48. 

Grad BR, Rozencwaig RThe role of melatonin and serotonin in aging: updatePsychoneuroendocrinology(1993) 14: 28395 Pubmed ID: 8292130

49. 

Nave R, Peled R, Lavie PMelatonin improves evening nappingEur J Pharmacol(1995) 275: 2136 Pubmed ID: 7796857

50. 

Hughes RJ, Badia PSleep-promoting and hypothermic effects of daytime melatonin administration in humansSleep(1997) 20: 12431 Pubmed ID: 9143072

51. 

Satomura T, Sakamoto T, Shirakawa SHypnotic action of melatonin during daytime administration and its comparison with triazolamPsychiatry Clin Neurosci(2001) 55: 3034 Pubmed ID: 11422884

52. 

Dollins AB, Zhdanova IV, Wurtman RJEffect of inducing nocturnal serum melatonin concentrations in daytime on sleep, mood, body temperature, and performanceProc Natl Acad Sci U S A(1994) 91: 18248 Pubmed ID: 8127888

53. 

Savaskan E, Ayoub MA, Ravid RReduced hippocampal MT2 melatonin receptor expression in Alzheimer’s diseaseJ Pineal Res(2005) 38: 1016 Pubmed ID: 15617532

54. 

Paredes SD, Korkmaz A, Manchester LCPhytomelatonin: A reviewJ Exp Bot(2009a) 10.1093/jxb/ern284

55. 

Yatham LN, Liddle PF, Shiah ISEffects of rapid tryptophan depletion on brain 5-HT(2) receptors: a PET studyBr J Psychiatry(2001) 178: 44853 Pubmed ID: 11331561

56. 

Maes M, Bosmans E, De Jongh RIncreased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depressionCytokine(1997) 9: 8538 Pubmed ID: 9367546

57. 

Song C, Lin A, Bonaccorso SThe inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depressionJ Affect Disord(1998) 49: 2119 Pubmed ID: 9629951

58. 

Maes M, Lin A, Bosmans ESerotonin-immune interactions in detoxified chronic alcoholic patients without apparent liver disease: activation of the inflammatory response system and lower plasma total tryptophanPsychiatry Res(1998) 78: 15161 Pubmed ID: 9657419

59. 

Uthgenannt D, Schoolmann D, Pietrowsky REffects of sleep on the production of cytokines in humansPsychosom Med(1995) 57: 97104 Pubmed ID: 7792381

60. 

Vgontzas AN, Papanicolaou DA, Bixler EOElevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesityJ Clin Endocrinol Metab(1997) 82: 13136 Pubmed ID: 9141509

61. 

Dinges DF, Douglas SD, Zaugg LLeukocytosis and natural killer cell function parallel neurobehavioral fatigue induced by 64 hours of sleep deprivationJ Clin Invest(1994) 93: 19309 Pubmed ID: 7910171

62. 

Esteban S, Nicolaus C, Garmundi AEffect of orally administered L-tryptophan on serotonin, melatonin, and the innate immune response in the ratMol Cell Biochem(2004) 267: 3946 Pubmed ID: 15663184

63. 

Barriga C, Martín MI, Tabla RCircadian rhythm of melatonin, corticosterone and phagocytosis: effect of stressJ Pineal Res(2001) 30: 1807 Pubmed ID: 11316329

64. 

Barriga C, Martín MI, Ortega EPhysiological concentrations of melatonin and corticosterone in stress and their relationship with phagocytic activityJ Neuroendocrinol(2002a) 14: 6915 Pubmed ID: 12213130

65. 

Rodríguez AB, Terrón MP, Duran JPhysiological concentrations of melatonin and corticosterone affect phagocytosis and oxidative metabolism of ring dove heterophilsJ Pineal Res(2001) 31: 3138 Pubmed ID: 11485002

66. 

Paredes SD, Sánchez S, Parvez HAltered circadian rhythms of corticosterone, melatonin, and phagocytic activity in response to stress in ratsNeuro Endocrinol Lett(2007d) 28: 48995 Pubmed ID: 17693961

67. 

Martins EJr, Ferreira AC, Skorupa ALTryptophan consumption and indoleamines production by peritoneal cavity macrophagesJ Leukocyte Biol(2004) 75: 11161121 Pubmed ID: 14982948

68. 

Mossner R, Lesch KPRole of serotonin in the immune system and in neuroimmune interactionsBrain Behav Immun(1998) 12: 24971 Pubmed ID: 10080856

69. 

Hofstetter HH, Mossner R, Lesch KPAbsence of reuptake of serotonin influences susceptibility to clinical autoimmune disease and neuroantigen-specific interferon-gamma production in mouse EAEClin Exp Immunol(2005) 142: 3944 Pubmed ID: 16178854

70. 

Schuff-Werner P, Splettstosser W, Schmidt FSerotonin acts as a radical scavenger and is oxidized to a dimer during the respiratory burst of human mononuclear and polymorphonuclear phagocytesEur J Clin Invest(1995) 25: 47784 Pubmed ID: 7556365

71. 

Schuff-Werner P, Splettstoesser WAntioxidative properties of serotonin and the bactericidal function of polymorphonuclear phagocytesAdv Exp Med Biol(1999) 467: 3215 Pubmed ID: 10721072

72. 

Betten A, Dahlgren C, Hermodsson SSerotonin protects NK cells against oxidatively induced functional inhibition and apoptosisJ Leukoc Biol(2001) 70: 6572 Pubmed ID: 11435487

73. 

Nannmark U, Sennerby L, Bjursten LMInhibition of leukocyte phagocytosis by serotonin and its possible role in tumor cell destructionCancer Lett(1992) 62: 836 Pubmed ID: 1540935

74. 

Salman-Tabcheh S, Guerin MC, Torreilles JPotential role of the peroxidase-dependent metabolism of serotonin in lowering the polymorphonuclear leukocyte bactericidal functionFree Radic Res(1996) 24: 618 Pubmed ID: 8747893

75. 

Sánchez S, Sánchez C, Paredes SDCircadian variations of serotonin in plasma and different brain regions of ratsMol Cell Biochem(2008) 317: 105111 Pubmed ID: 18563534

76. 

Carrillo-Vico A, Guerrero JM, Lardone PJA review of the multiple actions of melatonin on the immune systemEndocrine(2005) 27: 189200 Pubmed ID: 16217132

77. 

Carrillo-Vico A, Reiter RJ, Lardone PJThe modulatory role of melatonin on immune responsivenessCurr Opin Investig Drugs(2006) 7: 42331

78. 

Berger JA two-clock model of circadian timing in the immune system of mammalsPathol Biol (Paris)(2008) 56: 28691 Pubmed ID: 18289800

79. 

Brainard GC, Watson-Whitmeyer M, Knobler RLNeuroendocrine regulation of immune parameters. Photoperiod control of the spleen in Syrian hamstersAnn N Y Acad Sci(1988) 540: 7046 Pubmed ID: 3207300

80. 

Maestroni GJ, Hertens E, Galli PMelatonin-induced T-helper cell hematopoietic cytokines resembling both interleukin-4 and dynorphinJ Pineal Res(1996) 21: 1319 Pubmed ID: 8981257

81. 

Scalabrino G, Ferioli ME, Nebuloni REffects of pinealectomy on the circadian rhythms of the activities of polyamine biosynthetic decarboxylases and tyrosine adminotransferase in different organs of the ratEndocrinology(1979a) 104: 37784 Pubmed ID: 36272

82. 

Scalabrino G, Ferioli ME, Basagri MEndocrine regulation of thymic biosynthetic polyamine decarboxylases in adult ratAm J Physiol(1979b) 237: E610 Pubmed ID: 223448

83. 

Fraschini F, Ferioli ME, Nebuloni RPineal gland and polyaminesJ Neural Transm(1980) 48: 20921 Pubmed ID: 7400810

84. 

Jankovic BD, Knezevic Z, Kojic LPineal gland and immune system. Immune functions in the chick embryo pinealectomized at 96 hours of incubationAnn N Y Acad Sci(1994) 719: 398409 Pubmed ID: 8010609

85. 

del Gobbo V, Libri V, Villani NPinealectomy inhibits interleukin-2 production and natural killer activity in miceInt J Immunopharmacol(1989) 11: 56773 Pubmed ID: 2807631

86. 

Libri V, Del Gobbo V, Villani NInfluence of pineal gland lesion on interleukin-2 production and natural killer activity in C57BL/6 micePharmacol Res(1990) 22: Suppl 352 Pubmed ID: 2097643

87. 

Rodríguez AB, Lea RWEffect of pinealectomy upon the nonspecific immune response of the ring-dove ( Streptopelia risoria)J Pineal Res(1994) 16: 15966 Pubmed ID: 7932039

88. 

Yellon SMDaily melatonin treatments regulate the circadian melatonin rhythm in the adult Djungarian hamsterJ Biol Rhythms(1996) 11: 413 Pubmed ID: 8695891

89. 

Haldar C, Singh R, Guchhait PRelationship between the annual rhythms in melatonin and immune system status in the tropical palm squirrel Funambulus pennantiChronobiol Int(2001) 18: 6169 Pubmed ID: 11247114

90. 

Moore CB, Siopes TD, Steele CTPineal melatonin secretion, but not ocular melatonin secretion, is sufficient to maintain normal immune responses in Japanese quail ( Coturnix coturnix japonica)Gen Comp Endocrinol(2002) 126: 3528 Pubmed ID: 12093123

91. 

Pioli C, Caroleo MC, Nistico GMelatonin increases antigen presentation and amplifies specific and non specific signals for T-cell proliferationInt J Immunopharmacol(1993) 15: 4638 Pubmed ID: 8365822

92. 

Molinero P, Soutto M, Benot SMelatonin is responsible for the nocturnal increase observed in serum and thymus of thymosin alpha1 and thymulin concentrations: observations in rats and humansJ Neuroimmunol(2000) 103: 1808 Pubmed ID: 10696913

93. 

Raghavendra V, Singh V, Kulkarni SKMelatonin enhances Th2 cell mediated immune responses: lack of sensitivity to reversal by naltrexone or benzodiazepine receptor antagonistsMol Cell Biochem(2001) 221: 5762 Pubmed ID: 11506187

94. 

Liu F, Ng TB, Fung MCPineal indoles stimulate the gene expression of immunomodulating cytokinesJ Neural Transm(2001) 108: 397405 Pubmed ID: 11475007

95. 

Reiter RJ, Tan DX, Osuna CActions of melatonin in the reduction of oxidative stress: A reviewJ Biomed Sci(2000) 7: 44458 Pubmed ID: 11060493

96. 

d’Emmanuele di Villa Bianca R, Marzocco S, Di Paola RMelatonin prevents lipopolysaccharide-induced hyporeactivity in ratJ Pineal Res(2004) 36: 14654 Pubmed ID: 15009504

97. 

Maestroni GJ, Conti A, Pierpaoli WRole of the pineal gland in immunity. III. Melatonin antagonizes the immunosuppressive effect of acute stress via an opiatergic mechanismImmunology(1988) 63: 4659 Pubmed ID: 3350581

98. 

Ben-Nathan D, Maestroni GJ, Lustig SProtective effects of melatonin in mice infected with encephalitis virusesArch Virol(1995) 140: 22330 Pubmed ID: 7710351

99. 

Bonilla E, Valero-Fuenmayor N, Pons HMelatonin protects mice infected with Venezuelan equine encephalomyelitis virusCell Mol Life Sci(1997) 53: 43034 Pubmed ID: 9176561

100. 

Bonilla E, Rodon C, Valero NMelatonin prolongs survival of immunodepressed mice infected with the Venezuelan equine encephalomyelitis virusTrans R Soc Trop Med Hyg(2001) 95: 20710 Pubmed ID: 11355563

101. 

Bonilla E, Valero N, Chacín-Bonilla LMelatonin increases interleukin-1beta and decreases tumor necrosis factor alpha in the brain of mice infected with the Venezuelan equine encephalomyelitis virusNeurochem Res(2003) 28: 6816 Pubmed ID: 12716016

102. 

Timiras PPhysiological basis of aging and geriatrics2nd edBoca RatonCRC Press(1994)

103. 

Reeves S, Bench C, Howard RAgeing and the nigrostriatal dopaminergic systemInt J Geriatr Psychiatry(2002) 17: 35970 Pubmed ID: 11994891

104. 

Mrak RE, Griffin ST, Graham DIAging-associated changes in human brainJ Neuropathol Exp Neurol(1997) 56: 126975 Pubmed ID: 9413275

105. 

Mattson MPCellular and neurochemical aspects of aging human brainHazzard WR, Blass JP, Ettinger WH, Halter JB, Ouslander JGPrinciples of geriatric medicine and gerontology5th edNew YorkMcGraw-Hill(1999) 11931208

106. 

Meltzer CC, Smith G, Price JCReduced binding of [18F]altanserin to serotonin type 2A receptors in aging: persistence of effect after partial volume correctionBrain Res(1998) 813: 16771 Pubmed ID: 9824691

107. 

Maines LW, Keck BJ, Smith JECorticosterone regulation of serotonin transporter and 5-HT1A receptor expression in the aging brainSynapse(1999) 32: 5866 Pubmed ID: 10188639

108. 

Ursin RSerotonin and sleepSleep Med Rev(2002) 6: 5569 Pubmed ID: 12531142

109. 

Glass JD, DiNardo LA, Ehlen JCDorsal raphe nuclear stimulation of SCN serotonin and circadian phase-resettingBrain Res(2000) 859: 22432 Pubmed ID: 10719068

110. 

Arendt JMelatonin and the mammalian pineal glandLondonChapman and Hall(1995)

111. 

Karasek MMelatonin in humans—where we are 40 years after its discoveryNeuro Endocrinol Lett(1999) 20: 17988 Pubmed ID: 11462112

112. 

Karasek M, Reiter RJ, Cardinali DPFuture of melatonin as a therapeutic agentNeuro Endocrinol Lett(2002) 23: Suppl 1118121 Pubmed ID: 12019364

113. 

Myers BL, Badia PChanges in circadian rhythms and sleep quality with aging: mechanisms and interventionsNeurosci Biobehav Rev(1995) 19: 55371 Pubmed ID: 8684716

114. 

Rodríguez AB, Barriga C, Paredes SDAge, melatonin and the immune systemPandalai SGRecent Research Developments in Molecular and Cellular Biochemistry. Vol. 2, Part IITrivandrumResearch Sign Post(2005) 25587

115. 

Bergiannaki JD, Soldatos CR, Paparrigopoulos TJLow and high melatonin excretors among healthy individualsJ Pineal Res(1995) 18: 15964 Pubmed ID: 7562374

116. 

Arendt JMelatoninClin Endocrinol (Oxf)(1988) 29: 20529 Pubmed ID: 3073883

117. 

Pandi-Perumal SR, Seils LK, Kayumov LSenescence, sleep, and circadian rhythmsAgeing Res Rev(2002) 1: 559604 Pubmed ID: 12067601

118. 

Foley DJ, Monjan AA, Brown SLSleep complaints among elderly persons: an epidemiologic study of three communitiesSleep(1995) 18: 42532 Pubmed ID: 7481413

119. 

Pandi-Perumal SR, Zisapel N, Srinivasan VMelatonin and sleep in aging populationExp Gerontol(2005) 40: 91125 Pubmed ID: 16183237

120. 

Blanco M, Kriber N, Cardinali DP[A survey of sleeping difficulties in an urban Latin American population]Rev Neurol(2004) 39: 11519 Pubmed ID: 15264159

121. 

Blanco M, Kriguer N, Lloret SPAttitudes towards treatment among patients suffering from sleep disorders. A Latin American surveyBMC Fam Pract(2003) 4: 17 Pubmed ID: 14629777

122. 

Duffy JF, Czeisler CAAge-related change in the relationship between circadian period, circadian phase, and diurnal preference in humansNeurosci Lett(2002) 318: 11720 Pubmed ID: 11803113

123. 

Daan S, Beersma DG, Borbely AATiming of human sleep: recovery process gated by a circadian pacemakerAm J Physiol(1984) 246: R16183 Pubmed ID: 6696142

124. 

Swaab DF, Dubelaar EJ, Hofman MABrain aging and Alzheimer’s disease; use it or lose itProg Brain Res(2002) 138: 34373 Pubmed ID: 12432778

125. 

Ginaldi L, De Martinis M, D’Ostilio AThe immune system in the elderly: I. Specific humoral immunityImmunol Res(1999a) 20: 1018 Pubmed ID: 10580635

126. 

Rea IM, Stewart M, Campbell PChanges in lymphocyte subsets, interleukin 2, and soluble interleukin 2 receptor in old and very old ageGerontology(1996) 42: 6978 Pubmed ID: 9138976

127. 

Pawelec GImmunosenescence: impact in the young as well as the oldMech Ageing Dev(1999) 108: 17 Pubmed ID: 10366035

128. 

McLeod JDApoptotic capability in ageing T cellsMech Ageing Dev(2000) 121: 1519 Pubmed ID: 11164469

129. 

Richter M, Jodouin CAThe delay in the synthesis and secretion of immunoglobulins by the B cells of healthy ambulatory elderly is due to subtle defects in the null cells and the B cellsAging Immunol Infect Dis(1993) 4: 116

130. 

Song H, Price PW, Cerny JAge-related changes in antibody repertoire: contribution from T cellsImmunol Rev(1997) 160: 5562 Pubmed ID: 9476665

131. 

McArthur WPEffect of aging on immunocompetent and inflammatory cellsPeriodontol(2000) (1998) 16: 5379

132. 

Pierpaoli W, Lesnikov VTheoretical considerations on the nature of the pineal ‘ageing clock.’Gerontology(1997) 43: 205 Pubmed ID: 8996827

133. 

Reiter RJ, Tan D, Kim SJAugmentation of indices of oxidative damage in life-long melatonin-deficient ratsMech Ageing Dev(1999) 110: 15773 Pubmed ID: 10576246

134. 

Reiter RJMelatonin: Lowering the high price of free radicalsNews Physiol Sci(2000a) 15: 246250 Pubmed ID: 11390919

135. 

Reiter RJMelatonin and agingMosley JE, Armbrecht HJ, Coe RM, Vellas BThe Science of Geriatrics. Vol INew YorkSpringer(2000b) 232333

136. 

Tan DX, Manchester LC, Terron MPOne molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and reactive nitrogen speciesJ Pineal Res(2007) 42: 2842 Pubmed ID: 17198536

137. 

Tan DX, Reiter RJ, Manchester LCChemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavengerCurr Top Med Chem(2002) 2: 18197 Pubmed ID: 11899100

138. 

Reiter RJ, Tan DX, Jou MJBiogenic amines in the reduction of oxidative stress: Melatonin and its metabolitesBiogenic Amines(2008) 22: 115

139. 

Rodriguez C, Mayo JC, Sainz RMRegulation of antioxidant enzymes: a significant role for melatoninJ Pineal Res(2004) 36: 19 Pubmed ID: 14675124

140. 

Tomas-Zapico C, Coto-Montes AA proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymesJ Pineal Res(2005) 39: 99104 Pubmed ID: 16098085

141. 

Pablos MI, Agapito MT, Guiterrez RMelatonin stimulates the activity of the detoxifying enzyme glutathione peroxidase in several tissues of chicksJ Pineal Res(1995) 19: 1115 Pubmed ID: 8750343

142. 

Barlow-Walden LR, Reiter RJ, Abe MMelatonin stimulates glutathione peroxidase activityNeurochem Int(1995) 26: 497502 Pubmed ID: 7492947

143. 

Tan DX, Chen LD, Poeggeler BMelatonin: a potent, endogenous hydroxyl radical scavengerEndocr J(1993) 1: 5760

144. 

Tan D, Reiter RJ, Chen LDBoth physiological and pharmacological levels of melatonin reduce DNA adduct formation induced by the carcinogen safroleCarcinogenesis(1994) 15: 2158 Pubmed ID: 8313511

145. 

Rao KS, Loeb LADNA damage and repair in brain: relationship to agingMutat Res(1992) 275: 31729 Pubmed ID: 1383773

146. 

Strong R, Mattamal MB, Andor ACFree radicals, the aging brain, and age-related neurodegeerative disordersYu BPFree Radicals in AgingBoca RatonCRC Press(1993)

147. 

Acuña-Castroviejo D, Coto-Montes A, Gaia Monti MMelatonin is protective against MPTP-induced striatal and hippocampal lesionsLife Sci(1997) 60: PL239 Pubmed ID: 9000122

148. 

Mayo JC, Sainz RM, Tan DXMelatonin and Parkinson’s diseaseEndocrine(2005) 27: 16978 Pubmed ID: 16217130

149. 

van Rensburg SJ, Daniels WM, van Zyl JMA comparative study of the effects of cholesterol, beta-sitosterol, beta-sitosterol glucoside, dehydroepiandrosterone sulphate and melatonin on in vitro lipid peroxidationMetab Brain Dis(2000) 15: 25765 Pubmed ID: 11383550

150. 

Ferrari CKFunctional foods, herbs and nutraceuticals: towards biochemical mechanisms of healthy agingBiogerontology(2004) 5: 27589 Pubmed ID: 15547316

151. 

Bondy SC, Sharman EHMelatonin and the aging brainNeurochem Int(2007) 50: 57180 Pubmed ID: 17276551

152. 

Rodríguez AB, Marchena JM, Nogales GCorrelation between the circadian rhythm of melatonin, phagocytosis, and superoxide anion levels in ring dove heterophilsJ Pineal Res(1999a) 26: 3542

153. 

Terron M, del P, Paredes SD, Barriga COral administration of melatonin to old ring doves ( Streptopelia risoria) increases plasma levels of melatonin and heterophil phagocytic activityJ Gerontol A Bio Sci Med Sci(2005a) 60: 4450

154. 

Paredes SD, Terrón MP, Marchena AMEffect of exogenous melatonin on viability, ingestion capacity, and free-radical scavenging in heterophils from young and old ringdoves ( Streptopelia risoria)Mol Cell Biochem(2007e) 304: 30514 Pubmed ID: 17557194

155. 

Terrón MP, Cubero J, Barriga CPhagocytosis of Candida albicans and superoxide anion Levels in ring dove ( Streptopelia risoria) heterophils: effect of melatoninJ Neuroendocrinol(2003) 15: 11115 Pubmed ID: 14636172

156. 

Rodríguez AB, Ortega E, Lea RWMelatonin and the phagocytic process of heterophils from the ring dove ( Streptopelia risoria)Mol Cell Biochem(1997) 168: 18590 Pubmed ID: 9062908

157. 

Rodríguez AB, Nogales G, Ortega EMelatonin controls superoxide anion level: modulation of superoxide dismutase activity in ring dove heterophilsJ Pineal Res(1998) 24: 914 Pubmed ID: 9468113

158. 

Rodríguez AB, Nogales G, Marchena JMSuppression of both basal and antigen-induced lipid peroxidation in ring dove heterophils by melatoninBiochem Pharmacol(1999b) 58: 13016

159. 

Barriga C, Marchena JM, Lea RWEffect of stress and dexamethasone treatment on circadian rhythms of melatonin and corticosterone in ring dove ( Streptopelia risoria)Mol Cell Biochem(2002b) 232: 2731 Pubmed ID: 12030377

160. 

Paredes SD, Sánchez S, Rial RVChanges in behaviour and in the circadian rhythms of melatonin and corticosterone in rats subjected to a forced-swimming testJ Appl Biomed(2005) 3: 4756

161. 

Paredes SD, Terrón MP, Valero VOrally administered melatonin improves nocturnal rest in young and old ringdoves ( Streptopelia risoria)Basic Clin Pharmacol Toxicol(2007f) 100: 25868 Pubmed ID: 17371530

162. 

Paredes SD, Marchena AM, Bejarano IMelatonin and tryptophan affect the activity-rest rhythm, core and peripheral temperatures, and interleukin levels in the ringdove: Changes with ageJ Gerontol A Biol Sci Med Sci(2009b) 10.1093/gerona/gln054

163. 

Campbell SS, Murphy PJRelationships between sleep and body temperature in middle-aged and older subjectsJ Am Geriatr Soc(1998) 46: 45862 Pubmed ID: 9560068

164. 

Barriga-Ibars C, Rodríguez-Moratinos AB, Esteban S[Inter-relations between sleep and the immune status]Rev Neurol(2005) 40: 54856 Pubmed ID: 15898017

165. 

Terrón MP, Paredes SD, Barriga CComparative study of the heterophil phagocytic function in young and old ring doves ( Streptopelia risoria) and its relationship with melatonin levelsJ Comp Physiol [B](2004) 174: 4217

166. 

Terrón MP, Cubero J, Marchena JMMelatonin and aging: in vitro effect of young and mature ring dove physiological concentrations of melatonin on the phagocytic function of heterophils from old ring doveExp Gerontol(2002) 37: 4216 Pubmed ID: 11772529

167. 

Terrón MP, Paredes SD, Barriga CMelatonin, lipid peroxidation, and age in heterophils from the ring dove ( Streptopelia risoria)Free Radic Res(2005b) 39: 6139

168. 

Ouichou A, Pevet PImplication of tryptophan in the stimulatory effect of delta-sleep-inducing peptide on indole secretion from perifused rat pineal glandsBiol Signals(1992) 1: 7887 Pubmed ID: 1307916

169. 

Cubero J, Narciso D, Valero VThe oral administration of tryptophan improves nocturnal rest in young animals: Correlation with melatoninBiogenic Amines(2006b) 20: 5362

170. 

Garau C, Aparicio S, Rial RVAge related changes in the activity-rest circadian rhythms and c-fos expression of ring doves with aging. Effects of tryptophan intakeExp Gerontol(2006b) 41: 43038 Pubmed ID: 16564149

171. 

Cirelli C, Tononi GOn the functional significance of c-fos induction during the sleep-waking cycleSleep(2000) 23: 45369 Pubmed ID: 10875553

172. 

Cubero J, Narciso D, Valero VOral administration of L-tryptophan in the morning affects phagocytosis and oxidative metabolism in heterophils of Streptopelia roseogriseaBiogenic Amines(2005) 19: 20921

173. 

Maestroni GJThe immunotherapeutic potential of melatoninExpert Opin Investig Drugs(2001) 10: 46776

174. 

Guerrero JM, Reiter RJMelatonin-immune system relationshipsCurr Top Med Chem(2002) 2: 16779 Pubmed ID: 11899099

175. 

Dubbels R, Reiter RJ, Klenke EMelatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometryJ Pineal Res(1995) 18: 2831 Pubmed ID: 7776176

176. 

Hattori A, Migitaka H, Iigo MIdentification of melatonin in plants and its effects on plasma melatonin levels and binding to melatonin receptors in vertebratesBiochem Mol Biol Int(1995) 35: 62734 Pubmed ID: 7773197

177. 

Badria FAMelatonin, serotonin, and tryptamine in some egyptian food and medicinal plantsJ Med Food(2002) 5: 1537 Pubmed ID: 12495587

178. 

Paredes SD[Effect of the administration of melatonin and tryptophan on the activity-rest rhythms, phagocytic function and oxidative metabolism in Streptopelia risoria Modifications with age]CáceresServicio de Publicaciones de la Universidad de Extremadura(2007)

Figures and Tables

Figure 1.

Scheme of the conversion of anthranilic acid to tryptophan. PRPP, phosphoribosylpyrophosphate; PP 3, pyrophosphate; PRA, N-(5’Phosphoribosyl)-anthranilate; CDRP, 1-(o-Carboxyphenylamino)-1-deoxyribulose-5-phosphate; InGP, indole-3-glycerolphosphate.

Scheme of the conversion of anthranilic acid to tryptophan. PRPP, phosphoribosylpyrophosphate; PP3, pyrophosphate; PRA, N-(5’Phosphoribosyl)-anthranilate; CDRP, 1-(o-Carboxyphenylamino)-1-deoxyribulose-5-phosphate; InGP, indole-3-glycerolphosphate.
Figure 2.

Pathways of indole metabolism in photosensitive pineal cells. Enzymes: AADA, aromatic L-amino acid decarboxylase; AA-NAT, aralkylamine N-acetyltransferase; DeAc, deacetylase; HIOMT, hydroxyindole-O-methyltransferase; MAO, monoamine oxidase; TPH, tryptophan hydroxylase. Indoles: N-acetyl-serotonin; 5-HIAA, 5-Hydroxyindoleacetic acid; 5-HTL, 5-hydroxytryptophol; 5-MIAA, 5-methoxyindole-3-acetic. Chemical structure of melatonin is shown at the bottom of the figure (taken from Paredes, 2007, 178 modified).

Pathways of indole metabolism in photosensitive pineal cells. Enzymes: AADA, aromatic L-amino acid decarboxylase; AA-NAT, aralkylamine N-acetyltransferase; DeAc, deacetylase; HIOMT, hydroxyindole-O-methyltransferase; MAO, monoamine oxidase; TPH, tryptophan hydroxylase. Indoles: N-acetyl-serotonin; 5-HIAA, 5-Hydroxyindoleacetic acid; 5-HTL, 5-hydroxytryptophol; 5-MIAA, 5-methoxyindole-3-acetic. Chemical structure of melatonin is shown at the bottom of the figure (taken from Paredes, 2007,178 modified).
Figure 3.

Diagrammatic representation of daily profiles of serum melatonin levels throughout lifespan (taken from Karasek and Reiter, 13 modified).

Diagrammatic representation of daily profiles of serum melatonin levels throughout lifespan (taken from Karasek and Reiter,13 modified).
Table 1.

Levels of melatonin in representative common vegetables and fruits measured using different methods by Dubbels et al. 175 (1), Hattori et al. 176 (2), and Badria 177 (3).

Common name Scientific name Melatonin (1) a Melatonin (2) b Melatonin (3) c
Apple Malus domestica 47.6 ± 3.1 16.1
Asparagus Asparagus officinalis 9.5 ± 3.2
Banana Musa ensete 65.5
Banana Musa sapientum 46.6
Beetroot Beta vulgaris 0.2
Cabbage Brassica oleracea var. capitata 107.4 ± 7.3 30.9
Carrot Daucus carota 55.3 ± 11.9 49.4
Corn Zea mays 1366.1 ± 465.1 187.8
Cucumber Cucumis sativus 8.6 24.6 ± 3.5 59.2
Garlic Allium sativum 58.7
Ginger Zingiber officinale 583.7 ± 50.3 142.3
Kiwi fruit Actinidia chinensis 24.4 ± 1.7
Onion Allium cepa 31.5 ± 4.8 29.9
Pineapple Ananas comosus 36.2 ± 8.4 27.8
Pomegranate Punica granatum 16.8
Radish Raphanus sativus 75.8
Rice Oryza sativa 1006.0 ± 58.5 149.8
Strawberry Fragaria magna 12.4 ± 3.1 13.6
Tomato Lycopersicon esculentum 50.6 32.2 ± 2.4
Tomato Lycopersicon pimpinellifolium 11.2 30.2

a ng/100 g edible plant material (without peel). Levels measured by RIA and HPLC-MS.

b pg/g tissue. Levels quantified by RIA.

c ng/100 g. Levels measured by GC/MS analysis.