Melatonin and Melatonergic Drugs on Sleep: Possible Mechanisms of Action

被引:182
作者
Srinivasan, Venkataramanujan [2 ,3 ]
Pandi-Perumal, Seithikurippu R. [4 ]
Trahkt, Ilya [4 ]
Spence, D. Warren [5 ]
Poeggeler, Burkhard [6 ]
Hardeland, Ruediger [6 ]
Cardinali, Daniel P. [1 ]
机构
[1] Univ Buenos Aires, Fac Med, Dept Fisiol, RA-1121 Buenos Aires, DF, Argentina
[2] SRM Univ, SRM Med Coll Hosp, Kattankulathoor, India
[3] SRM Univ, Res Ctr, Kattankulathoor, India
[4] Columbia Univ, Coll Phys & Surg, Dept Med, Div Clin Pharmacol & Expt Therapeut, New York, NY USA
[5] Univ Hlth Network, Sleep & Alertness Clin, Toronto, ON, Canada
[6] Univ Gottingen, Johann Friedrich Blumenbach Inst Zool & Anthropol, Gottingen, Germany
关键词
Agomelatine; Circadin; hypnotics; insomnia; melatonin; ramelteon; sleep; suprachiasmatic nucleus; SUPRACHIASMATIC NUCLEUS; CIRCADIAN-RHYTHMS; RAMELTEON TAK-375; N-ACETYLTRANSFERASE; PINEAL-GLAND; EXOGENOUS MELATONIN; SIGNAL-TRANSDUCTION; ELDERLY-PATIENTS; NOCTURNAL SLEEP; REM-SLEEP;
D O I
10.1080/00207450802328607
中图分类号
Q189 [神经科学];
学科分类号
071006 [神经生物学];
摘要
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.
引用
收藏
页码:821 / 846
页数:26
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