R. Hardeland
University of Göttingen
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Featured researches published by R. Hardeland.
FEBS Journal | 2006
Seithikurippu R. Pandi-Perumal; V. Srinivasan; Georges J.M. Maestroni; Daniel P. Cardinali; Burkhard Poeggeler; R. Hardeland
Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as ‘neuroendocrine transducers’ to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the ‘hormone of darkness’. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the ‘time of day’ and ‘time of year’ (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the bodys chronological pacemaker or ‘Zeitgeber’. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night‐time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up‐regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonins cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune‐enhancing and oncostatic properties. Its ‘chronobiotic’ properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift‐work sleep disorder. Melatonin acting as an ‘internal sleep facilitator’ promotes sleep, and melatonins sleep‐facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonins role as a ‘photoperiodic molecule’ in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the bodys physiological functions.
Journal of Pineal Research | 1995
R. Hardeland; Ivonne Balzer; Burkhard Poeggeler; Birgit Fuhrberg; Higinio Una; Gudrun Behrmann; Rupert Wolf; Torsten J. Meyer; Russel J. Reiter
Abstract: Melatonin is widely abundant in many eukaryotic taxa, including vari‐ous animal phyla, angiosperms, and unicells. In the bioluminescent dinoflagellate Gonyaulax polyedra, melatonin is produced in concentrations sometimes exceed‐ing those found in the pineal gland, exhibits a circadian rhythm with a pro‐nounced nocturnal maximum, and mimics the short‐day response of asexual encystment. Even more efficient as a cyst inducer is 5‐methoxytryptamine (5MT), which is also periodically formed in Gonyaulax. In this unicell, the photoperiodic signal‐transduction pathway presumably involves melatonin formation, its deace‐tylation to 5MT, 5MT‐dependent transfer of protons from an acidic vacuole, and cytoplasmic acidification. According to this concept, we observe that cyst forma‐tion can be induced by various monoamine oxidase inhibitors and protonophores, that 5MT dramatically stimulates H+‐dependent bioluminescence and leads to a decrease of cytoplasmic pH, as shown by measurements of dicyanohydroquinone fluorescence. Cellular components from Gonyaulax catalyze the photooxidation of melatonin. Its property of being easily destroyed by light in the presence of cel‐lular catalysts may have been the reason that many organisms have developed mechanisms utilizing this indoleamine as a mediator of darkness. Photooxidative reactions of melatonin, as studied with crude Gonyaulax extracts and, more in de‐tail, with protoporphyrin IX as a catalyst, lead to the formation of N1 ‐acetyl‐N ‐formyl‐5‐methoxykynuramine (AFMK) as one of the main products. Photochemical mechanisms involve interactions with a photooxidant cation radi‐cal leading to the formation of a melatonyl cation radical, which subsequently combines with a superoxide anion. Photooxidation of melatonin represents one of several possibilities of a more general, biologically highly important property of this indoleamine to act as an extremely efficient radical scavenger, including its feature of terminating radical reaction chains by a final combination with the su‐peroxide anion. Trapping of free radicals may reflect the primary and evolutionar‐ily most ancient role of melatonin in living beings.
Behavioral and Brain Functions | 2006
V. Srinivasan; Seithikurippu R. Pandi-Perumal; Daniel P. Cardinali; Burkhard Poeggeler; R. Hardeland
Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimers disease (AD), Parkinsons disease (PD) and Huntingtons disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.
Neurotoxicity Research | 2005
V. Srinivasan; Seithikurippu R. Pandi-Perumal; Georges J.M. Maestroni; Ana I. Esquifino; R. Hardeland; Daniel P. Cardinali
The pineal product melatonin has remarkable antioxidant properties. It scavenges hydroxyl, carbonate and various organic radicals, peroxynitrite and other reactive nitrogen species. Melatonyl radicals formed by scavenging combine with and, thereby, detoxify superoxide anions in processes terminating the radical reaction chains. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes like superoxide dismutase, glutathione peroxidase and glutathione reductase, and by augmenting glutathione levels. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases,e.g., Alzheimer’s disease. Melatonin has been shown to be effective in arresting neurodegenerative phenomena seen in experimental models of Alzheimer’s disease, Parkinsonism and ischemic stroke. Melatonin preserves mitochondrial homeostasis, reduces free radical generation, e.g., by enhancing mitochondrial glutathione levels, and safeguards proton potential and ATP synthesis by stimulating complex I and IV activities. Therapeutic trials with melatonin have been effective in slowing the progression of Alzheimer’s disease but not of Parkinson’s disease. Melatonin’s efficacy in combating free radical damage in the brain suggests that it may be a valuable therapeutic agent in the treatment of cerebral edema after traumatic brain injury.
Psychiatry Research-neuroimaging | 2009
Venkataramanujan Srinivasan; Seithikurippu R. Pandi-Perumal; Ilya Trakht; D. Warren Spence; R. Hardeland; Burkhard Poeggeler; Daniel P. Cardinali
Profound disturbances in sleep architecture occur in major depressive disorders (MDD) and in bipolar affective disorders. Reduction in slow wave sleep, decreased latency of rapid eye movement (REM) sleep and abnormalities in the timing of REM/non-REM sleep cycles have all been documented in patients with MDD. It is thus evident that an understanding of the basic mechanisms of sleep regulation is essential for an analysis of the pathophysiology of depressive disorders. The suprachiasmatic nucleus (SCN), which functions as the bodys master circadian clock, plays a major role in the regulation of the sleep/wakefulness rhythm and interacts actively with the homeostatic processes that regulate sleep. The control of melatonin secretion by the SCN, the occurrence of high concentrations of melatonin receptors in the SCN, and the suppression of electrical activity in the SCN by melatonin all underscore the major influence which this neurohormone has in regulating the sleep/wake cycle. The transition from wakefulness to high sleep propensity is associated with the nocturnal rise of endogenous melatonin secretion. Various lines of evidence show that depressed patients exhibit disturbances in both the amplitude and shape of the melatonin secretion rhythm and that melatonin can improve the quality of sleep in these patients. The choice of a suitable antidepressant that improves sleep quality is thus important while treating a depressive disorder. The novel antidepressant agomelatine, which combines the properties of a 5-HT(2C) antagonist and a melatonergic MT(1)/MT(2) receptor agonist, has been found very effective for resetting the disturbed sleep/wake cycle and in improving the clinical status of MDD. Agomelatine has also been found useful in treating sleep problems and improving the clinical status of patients suffering from seasonal affective disorder.
International Journal of Neuroscience | 2009
Venkataramanujan Srinivasan; Seithikurippu R. Pandi-Perumal; Ilya Trahkt; D. Warren Spence; Burkhard Poeggeler; R. Hardeland; Daniel P. Cardinali
Pineal melatonin is synthesized and secreted in close association with the light/dark cycle. The temporal relationship between the nocturnal rise in melatonin secretion and the “opening of the sleep gate” (i.e., the increase in sleep propensity at the beginning of the night), coupled with the sleep-promoting effects of exogenous melatonin, suggest that melatonin is involved in the regulation of sleep. The sleep-promoting and sleep/wake rhythm regulating effects of melatonin are attributed to its action on MT1 and MT2 melatonin receptors present in the suprachiasmatic nucleus (SCN) of the hypothalamus. Animal experiments carried out in rats, cats, and monkeys have revealed that melatonin has the ability to reduce sleep onset time and increase sleep duration. However, clinical studies reveal inconsistent findings, with some of them reporting beneficial effects of melatonin on sleep, whereas in others only marginal effects are documented. Recently a prolonged-release 2-mg melatonin preparation (CircadinTM) was approved by the European Medicines Agency as a monotherapy for the short-term treatment of primary insomnia in patients who are aged 55 or above. Several melatonin derivatives have been shown to increase nonrapid eye movement (NREM) in rats and are of potential pharmacological importance. So far only one of these melatonin derivatives, ramelteon, has received approval from the U.S. Food and Drug Administration to be used as a sleep promoter. Ramelteon is a novel MT1 and MT2 melatonergic agonist that has specific effects on melatonin receptors in the SCN and is effective in promoting sleep in experimental animals such as cats and monkeys. In clinical trials, ramelteon reduced sleep onset latency and promoted sleep in patients with chronic insomnia, including an older adult population. Both melatonin and ramelteon promote sleep by regulating the sleep/wake rhythm through their actions on melatonin receptors in the SCN, a unique mechanism of action not shared by any other hypnotics. Moreover, unlike benzodiazepines, ramelteon causes neither withdrawal effects nor dependence. Agomelatine, another novel melatonergic antidepressant in its final phase of approval for clinical use, has been shown to improve sleep in depressed patients and to have an antidepressant efficacy that is partially attributed to its effects on sleep-regulating mechanisms.
Neuropsychiatric Disease and Treatment | 2009
R. Hardeland
Hypnotic effects of melatonin and melatoninergic drugs are mediated via MT1 and MT2 receptors, especially those in the circadian pacemaker, the suprachiasmatic nucleus, which acts on the hypothalamic sleep switch. Therefore, they differ fundamentally from GABAergic hypnotics. Melatoninergic agonists primarily favor sleep initiation and reset the circadian clock to phases allowing persistent sleep, as required in circadian rhythm sleep disorders. A major obstacle for the use of melatonin to support sleep maintenance in primary insomnia results from its short half-life in the circulation. Solutions to this problem have been sought by developing prolonged-release formulations of the natural hormone, or melatoninergic drugs of longer half-life, such as ramelteon, tasimelteon and agomelatine. With all these drugs, improvements of sleep are statistically demonstrable, but remain limited, especially in primary chronic insomnia, so that GABAergic drugs may be indicated. Melatoninergic agonists do not cause next-day hangover and withdrawal effects, or dependence. They do not induce behavioral changes, as sometimes observed with z-drugs. Despite otherwise good tolerability, the use of melatoninergic drugs in children, adolescents, and during pregnancy has been a matter of concern, and should be avoided in autoimmune diseases and Parkinsonism. Problems and limits of melatoninergic hypnotics are compared.
Journal of Pineal Research | 1994
Burkhard Poeggeler; R. Hardeland
Poeggeler B, Hardeland R. Detection and quantification of melatonin in a dinoflagellate, Gonyaulax polyedra: Solutions to the problem of methoxyindole destruction in non‐vertebrate material. J. Pineal Res. 1994: 17: 1–10.
International Journal of Molecular Sciences | 2014
Dun Xian Tan; Xiaodong Zheng; Jin Kong; Lucien C. Manchester; R. Hardeland; Seok Joong Kim; Xiaoying Xu; Russel J. Reiter
Melatonin and melatonin isomers exist and/or coexist in living organisms including yeasts, bacteria and plants. The levels of melatonin isomers are significantly higher than that of melatonin in some plants and in several fermented products such as in wine and bread. Currently, there are no reports documenting the presence of melatonin isomers in vertebrates. From an evolutionary point of view, it is unlikely that melatonin isomers do not exist in vertebrates. On the other hand, large quantities of the microbial flora exist in the gut of the vertebrates. These microorganisms frequently exchange materials with the host. Melatonin isomers, which are produced by these organisms inevitably enter the host’s system. The origins of melatonin and its isomers can be traced back to photosynthetic bacteria and other primitive unicellular organisms. Since some of these bacteria are believed to be the precursors of mitochondria and chloroplasts these cellular organelles may be the primary sites of melatonin production in animals or in plants, respectively. Phylogenic analysis based on its rate-limiting synthetic enzyme, serotonin N-acetyltransferase (SNAT), indicates its multiple origins during evolution. Therefore, it is likely that melatonin and its isomer are also present in the domain of archaea, which perhaps require these molecules to protect them against hostile environments including extremely high or low temperature. Evidence indicates that the initial and primary function of melatonin and its isomers was to serve as the first-line of defence against oxidative stress and all other functions were acquired during evolution either by the process of adoption or by the extension of its antioxidative capacity.
Drug Research | 2011
R. Hardeland; Burkhard Poeggeler; Venkataramanujan Srinivasan; Ilya Trakht; Seithikurippu R. Pandi-Perumal; Daniel P. Cardinali
Melatonin (CAS 73-31-4) has both hypnotic and sleep/wake rhythm regulating properties. These sleep promoting actions, which are already demonstrable in healthy humans, have been found useful in subjects suffering from circadian rhythm sleep disorders (CRSD) like delayed sleep phase syndrome (DSPS), jet lag and shift-work sleep disorder. Low nocturnal melatonin production and secretion have been documented in elderly insomniacs, and exogenous melatonin has been shown to be beneficial in treating sleep disturbances of these patients. In comparison to a number of sleep-promoting compounds that are usually prescribed, such as benzodiazepines and z-drugs (zolpidem and zopiclon belonging to the latter ones), melatonin has several advantages of clinical value: it does not cause hangover nor withdrawal effects and is devoid of any addictive potential. However, recent meta-analyses revealed that melatonin is not sufficiently effective in treating most primary sleep disorders. Some of the reasons for a limited efficacy of this natural hormone are related to its extremely short half-life in the circulation, and to the fact that sleep maintenance is also regulated by mechanisms downstream of primary melatonergic actions. Hence, there is an urgent need for the development of melatonin receptor agonists with a longer half-life, which could be suitable for a successful treatment of insomnia. Such requirements are fulfilled by ramelteon (CAS 196597-26-9), which possesses a high affinity for the melatonin receptors MT1 and MT2 present in the circadian pacemaker, the suprachiasmatic nucleus (SCN). Ramelteon also has a substantially longer half-life than melatonin. This new drug has been successfully used in treating elderly insomniacs without any adverse effects reported, and is promising for treating patients with primary insomnia and also those suffering from CRSD. Since sleep disturbances constitute the most prevalent symptoms of various forms of depression, the need for the development of an ideal antidepressant was felt, which would both improve sleep and mitigate depressive symptoms. Since most of the currently used antidepressants, including the selective serotonin re-uptake inhibitors worsen the sleep disturbances of depressive patients, another novel melatonergic drug, agomelatine (CAS 138112-76-2), holds some promise because of its particular combination of actions: it has a high affinity for MT1 and MT2 receptors in the SCN, but it acts additionally as a 5-HT(2C) antagonist [5-hydroxytryptamine (serotonin) receptor 2C antagonist]. The latter property, which is decisive for the antidepressive action, would not favor but potentially antagonize sleep, but this is overcome during night by the melatonergic, sleep-promoting effect. This drug has been found beneficial in treating patients with major depressive and seasonal affective disorders. Unlike the other antidepressants, agomelatine improves both sleep and clinical symptoms of depressive illness and does not have any of the side effects on sleep seen with other compounds in use. This property seems to be of particular value because of the aggravating effects of disturbed sleep in the development of depressive symptoms. Based on these facts, agomelatine seems to be a drug of superior efficacy with a promising future in the treatment of depressive disorders. However, long-term safety studies are required for both ramelteon and agomelatine, with a consideration of the pharmacology of their metabolites, their effects on redox metabolism, and of eventual undesired melatonergic effects, e. g., on reproductive functions. According to current data, both compounds seem to be safe during short-term treatment
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University of Texas Health Science Center at San Antonio
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