Effect of melatonin on endogenous circadian rhythm

Objective To further authenticate the role of melatonin on endogenous biologic clock system.Methods Pinealectomized mice were used in the experiments,a series of circadian rhythm of physiology index,such as glucocorticoid,amino acid neurotransmitter,immune function,sensitivity of algesia and body temperature were measured.Results Effects of melatonin on endogenous circadian rhythm roughly appeared four forms:1)The model of inherent rhythm was invariant,but midvalue was removed.2)Pacing function:pinealectomy and melatonin administration changed amplitude of the circadian vibration of aspartate,peripheral blood WBC and serum hemolysin.3)Phase of rhythm changed,such as the effects on percentage of lymphocyte and sensitivity of algesia.4)No effect,the circadian rhythm of body temperature belong to this form.Conclusions Melatonin has effects some circadian rhythm,and it can adjust endogenous inherent rhythm and make the rhythm keep step with environmental cycle.Melatonin may be a kind of Zeitgeber,Pineal gland might being a rhythm bearing organ to some circadian rhythm.     

Recent developments in melatonin receptor ligands

In recent years, many physiological properties of melatonin have been described resulting in much interest in the development of synthetic compounds possessing agonist or antagonist properties for melatonin receptors. These compounds have structural similarity to melatonin, being derivatives of either substituted tryptamines or of bioisosteric moieties of the indole ring such as benzothiophene, indene and naphthalene. Research to determine the structural parameters of the melatonergic pharmacophore led to the synthesis of potent constrained, polycyclic compounds. The important roles of substitutions on the 2 position of the indole ring and of the alkyl chain of the acyl group have been highlighted. The ethylamido chain seems to prefer the flexible conformation and a folded conformer has been shown to be the active conformation. Almost all of the compounds described have been patented. They have been claimed to be useful for the treatment of depression, sleep disorders and disturbances of circadian rhythm. Some patents have claimed also anti-ovulatory or antiproliferative properties. No compounds developed so far discriminate between the different melatonin receptor subtypes and few compounds have been described as antagonists for melatonin receptors.     

Alterations in circadian rhythms of melatonin and cortisol in patients with bronchial asthma

INTRODUCTIONBronchial asthma is a characteristic circadianrhythm disease in many aspects. Patients with asthmaoften experience a nocturnal worsening of pulmonaryfunction[1], asthmatic symptoms[2,3], and sleep quality[4].Asthma patients also show a diurnal variation in deathwith the peak occurring during the early morning hours[5].The mechanisms involved in circadian rhythms ofasthma are multiple, interactive, and presently not fullyunderstood[6].Cortisol exhibits a circadian rhythm, reac…     

Potential therapeutic use of melatonin in migraine and other headache disorders

There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Some headaches have a clearcut seasonal and circadian pattern, such as cluster and hypnic headaches. Melatonin levels have been found to be decreased in both migraine and cluster headaches. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of pro-inflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilisation, GABA and opioid analgesia potentitation, glutamate neurotoxicity protection, neurovascular regulation, 5-HT modulation and the similarity in chemical structure to indometacin. The treatment of headache disorders with melatonin and other chronobiotic agents, such as melatonin agonists (ramelteon and agomelatin), is promising and there is a great potential for their use in headache treatment.     

褪黑素对睡眠的调节作用及与脑内氨基酸递质的关系

目的：研究褪黑素促眠、昼夜节律作用有 与脑内氨基酸递质的关系。方法：以翻正反射为指标研究褪黑素对小鼠睡眠及其昼夜节律的影响。采用纸电泳－双波长扫描法,测定褪黑素对小鼠不同脑区中γ-氨基丁酸（GABA）和谷氨酸（Glu)含量的影响。结果：褪黑素能明显促进小鼠睡眠,其药效强度依赖于给药的时辰。褪黑素可使小鼠下丘脑内γ-氨基丁酸含量明显升高。但对谷氨酸水平无明显影响。结论：褪黑素促眠作用可能与小鼠下丘脑中γ-氨基丁酸含量升高有关。     

褪黑素对睡眠的调节作用及与脑内氨基酸递质的关系

目的 :研究褪黑素促眠、昼夜节律作用及其与脑内氨基酸递质的关系。方法 :以翻正反射为指标研究褪黑素对小鼠睡眠及其昼夜节律的影响。采用纸电泳 双波长扫描法 ,测定褪黑素对小鼠不同脑区中γ 氨基丁酸 (GABA)和谷氨酸 (Glu)含量的影响。结果 :褪黑素能明显促进小鼠睡眠 ,其药效强度依赖于给药的时辰。褪黑素可使小鼠下丘脑内γ 氨基丁酸含量明显升高。但对谷氨酸水平无明显影响。结论 :褪黑素促眠作用可能与小鼠下丘脑中γ 氨基丁酸含量升高有关     

The effect of clonidine and bright light on plasma melatonin

We studied the effect of the α₂-adrenoceptor agonist, clonidine, and bright artificial light (>2500 lux) on the nocturnal increase in plasma melatonin in normal subjects. Clonidine (1.5 μg/kg, intravenously) was without effect on plasma melatonin concentration. In contrast, bright light treatment abolished the increase in night-time melatonin. Bright light is a simple and effective means of altering melatonin secretion in humans.     

Effect of isoproterenol upon serotonin N-acetyltransferase (SNAT) activity and melatonin production in the chick pineal gland

The administration of isoproterenol to chicks (5 days after hatching) resulted in a modest increase in pineal serotonin N-acetyltransferase (SNAT) activity and a decrease in pineal melatonin levels. The changes observed following isoproterenol administration did not occur consistently in a dose-related or time-course related manner, nor were these changes of the magnitude seen in endogenous nocturnal melatonin levels. Therefore, interpretation of the physiological significance of the isoproterenol-induced changes in melatonin and SNAT must be carefully evaluated.     

唾液中游离皮质醇和松果体素水平昼夜节律性变化与夜间哮喘相关性研究

目的　探讨唾液中游离皮质醇和松果体素水平昼夜节律性变化与夜间哮喘发病机制和昼夜肺功能变化的关系。方法　采用放射免疫分析方法测定 15例正常人和 15例夜间哮喘病人唾液中游离皮质醇和松果体素水平 ,哮喘病人中急性发作期 8例 ,缓解期 7例。 2 4h内按 12个时间点采集唾液样本 ,夜间取样时光照强度控制在 5 0lx之内。结果　 3组间游离皮质醇水平差异具有显著性 (P <0 0 1)。与对照组比较 ,急性发作期和缓解期病人游离皮质醇 2 4h平均水平均降低 (P <0 0 1) ;振幅减小 (P <0 0 5 ) ;峰值相位(acrophase)延迟 (P <0 0 1,P <0 0 5 )。 3组间游离松果体素水平差异亦具有显著性 (P <0 0 1)。与对照组比较 ,急性发作期和缓解期病人松果体素水平基线值 ,振幅和峰值皆降低(P <0 0 5orP <0 0 1) ;急性发作期峰值相位延迟 (P <0 0 5 )。凌晨 4点游离皮质醇水平分别与占FEV1预计值 %和占PEF预计值 %正相关 (r =0 5 3 ,P <0 0 5 ;r =0 5 5 ,P<0 0 5 ) ,游离松果体素水平与占PEF预计值 %呈正相关 (r=0 5 2 ,P <0 0 5 )。昼夜占PEF预计值 %差值和夜间出现症状或憋醒次数呈正相关 (r =0 62 5 ,P <0 0 5 )。结论　唾液中游离皮质醇和松果体素水平的昼夜节律性改变参与夜间哮喘的发病过程 ,且与病人     

褪黑素抗氧化作用研究进展

褪黑素（MT）由松果腺分泌,具有明显的生物节律性,包括昼夜节律、季节节律和生命周期节律。MT分泌减少与机体衰老关系密切,有松果体钙化、生物钟、神经内分泌-免疫系统及自由基损伤等多种学说,尤其神经系统退变与自由基累积性损伤密切相关。MT是一强大的内源性自由基清除剂,可以对抗羟自由基对机体的攻击以及谷氨酸兴奋毒性作用,对中枢神经系统有保护作用。体内研究证明,遏制老化期MT的下降,保护MT生成的内源性节律或外源性使用MT能够明显地延长寿命,减少老年相关性疾病的发生。MT抗衰老研究具有广阔前景。     

松果腺及褪黑素与衰老

衰老是机体随年龄的增长逐渐丧失对环境的适应能力。这个过程伴有行为、内分泌及其他生理功能的改变，使得机体抵抗损伤性刺激的能力降低，对疾病的易感性增加。松果腺的功能随年龄的增加而变化，并与衰老的进程平行。年龄增加松果腺钙化率增高，其生物合成和分泌功能降低，松果腺移植可延缓动物的衰老。褪黑素是吲哚类物质，主要来源于松果腺细胞，血中水平与年龄有关，衰老可导致褪黑素水平下降。外源性褪黑素能延长大鼠的生存期，并能推迟家兔老年性疾病的发生时间。进一步研究发现松果腺和褪黑素延缓衰老与其具有抗自由基作用，调节炎症免疫反应，调节生物钟，影响激素分泌和参与应激等功能有关。而老年期体内自由基清除能力降低、激素分泌紊乱、生物钟衰退、肿瘤及其他疾病的易感性增加正是衰老的重要特征。因此，对褪黑素的深入研究将为抗衰老药的开发开辟新的途径     

Effects of An-Shen-Bu-Nao Syrup on the inducible nitric-oxide synthase activity and melatonin in brain of sleep deprivation rats

Objective： To study the effects of An-Shen-Bu-Nao Syrup （AS） on the inducible nitricoxide synthase （iNOS） activity and melatonin content in brain of sleep deprivation （SD） rats. Methods： Rats were divided into groups of control, SD model, SD＋AS （0.02ml/kg）, and SD＋ AS （0.06ml/kg） . The rats were fed with AS for 2 weeks and were subjected to sleep deprivation for 4 days, and then the iNOS activity in the front cortex was analyzed, and melatonin in the pineal gland was analyzed with HPLC. Results： Compared with the control rats, SD rats had the significantly elevated iNOS activity in the front cortex. Rats treated with AS （0. 06ml/kg） showed significantly decreased iNOS activity than SD rats.     

Recent advances in the development of melatonin MT1 and MT2 receptor agonists

Importance of the field: Increasing clinical evidences suggest that melatonin receptor agonists can represent a novel therapeutic approach for the treatment of sleep disturbances and depression. A variety of studies also revealed a role of melatonin and its receptors in different patho-physiological conditions. Due to the multiple effects of this hormone, the design of new agents able to interact selectively with melatonin receptors has become an area of great interest during the last decade.

Areas covered in this review: An extensive inspection of patents and scientific literature about MT₁ and MT₂ melatonin receptor agonists reported from 1999 to early 2010.

What the reader will gain: A comprehensive review of structures recently claimed as melatonin receptor agonists and a broad overview of structure–activity relationships for these ligands.

Take home message: After 5 decades of research, the field of melatonin receptor agonists comprises a variety of chemical entities, belonging to structurally different classes. Patents filed since 1999 claim new melatonin receptor agonists, characterized either by improved pharmacokinetic or pharmacodynamic properties, compared to those of melatonin receptor agonists already approved for clinical uses. The results of preclinical studies on animal models show that melatonin receptor agonists can be considered promising agents for the treatment of CNS-related pathologies.     

松果腺褪黑素对大鼠腹腔巨噬细胞化学发光和脾、下丘脑PGE_2含量的影响

采用松果腺切除术、酵母多糖调理的鲁米诺依赖的化学发光法及前列腺素E_2(PGE_2)放射免疫测定方法观察了松果腺和褪黑索(MT)对大鼠腹腔巨噬细胞化学发光及脾、下丘脑PGE_2含量的影响。结果表明:松果腺切除后大鼠腹腔巨噬细胞化学发光值降低,脾及下丘脑PGE_2含量升高,10～1000 μg·kg~(-1)MT分别恢复之。其中以10μg·kg~(-1)MT作用最强;10μg·kg~(-1)MT还抑制正常大鼠脾及下丘脑PGE_2含量。上述作用可能是松果腺MT对炎症免疫调节作用的部分机制。     

Ramelteon for Insomnia Related to Attention-Deficit/Hyperactivity Disorder (ADHD)

Objectives

This study evaluated the efficacy of ramelteon for insomnia in adult subjects with ADHD.

Experimental Design

For this randomized, double-blind, placebo-controlled crossover trial, 8 mg of ramelteon was given nightly, within three hours of bedtime, to ADHD-insomnia subjects confirmed by DSM-IV-TR, ADHD-RS, MINI, and clinical interview. All subjects underwent two weeks each of ramelteon and placebo. Objective sleep measures were obtained by actigraphy. Subjective measures included: the Epworth Sleepiness Scale (ESS) and ADHD-RS.

Principal observations

Of 36 subjects entering the study, 58% met criteria for circadian rhythm sleep disorder (CRSD), delayed sleep phase type. During ramelteon period, mid-sleep time, an indicator of circadian phase, occurred significantly earlier, by ~45 minutes compared to placebo period. An association was noted between the magnitude of the sleep phase advance and the timing of ramelteon administration in relationship to sleep start time, but did not reach statistical significance; maximal efficacy was noted 1.5 hours before bedtime. Paradoxically, ramelteon marginally, but significantly increased sleep fragmentation and ESS scores compared to the placebo state.

Conclusions

Ramelteon is efficacious in maintaining an earlier sleep/wake cycle in adults with ADHD and CRSD but can have paradoxical fragmenting effects on sleep and exacerbate daytime sleepiness. In the presence of a circadian rhythm disorder, the usual dosing and timing parameters for ramelteon need to be carefully considered.     

An investigation of the effect of immediate and extended release venlafaxine on nocturnal melatonin and cortisol release in healthy adult volunteers

The secretion of the hormone melatonin is particularly robust to the effect of pharmacological agents. Medications may alter melatonin levels through either altering adrenergic activity or affecting liver enzymes involved in melatonin metabolism. The aim of this study was to investigate the effect of venlafaxine, a third generation antidepressant with known adrenergic properties on melatonin secretion. A further aim of the study was to investigate the correlation between plasma and salivary measures on this medication. Eight healthy adult participants (four males, four females) took part in this double blind placebo controlled randomised trial. Participants were tested on 3 nights after taking venlafaxine XR (75 mg), venlafaxine IR (75 mg) or placebo. Participants were placed in a darkened room between 1900 and 0300 h and regular temperature readings, blood and saliva samples were drawn to assess melatonin and cortisol secretion in each condition. There was no significant effect of venlafaxine IR or XR on melatonin concentrations in plasma or saliva and no effects on other circadian parameters including cortisol and temperature. It was notable that the correlation between plasma and salivary melatonin levels became poor after drug treatment. These results indicate that at low doses the mixed serotonergic and noradrenergic drug venlafaxine has no effect on nocturnal melatonin concentrations.     

松果腺在衰老过程中的地位与褪黑素的作用

目的论述松果腺及褪黑素与机体衰老的因果关系 ,进而提出衰老的松果腺学说。方法 1 本学说提出的背景 ;2 松果腺学说的实验依据 ;3 褪黑素的机能调节作用与抗衰老机理。结果与结论 1 松果腺学说的内容 :衰老源于松果腺形态和功能的变化 ,然后扩展到全身组织细胞 ,呈现多种退行性体征。补充外源性褪黑素或移植松果腺 ,可以延缓老化 ,增长动物寿命。 2 松果腺和褪黑素是年龄变化的函数。随着松果腺钙化 ,褪黑素合成与分泌减少 ,生物节律变得不稳定 ,适应内外环境能力降低。褪黑素在生物界分布极为广泛 ,它作为进化保留分子使机体与环境保持协调统一。褪黑素可在多方面发挥作用 ,通过矫正生物钟功能、调节神经内分泌活动、清除自由基、增强免疫、抗应激、保护遗传物质和促进衰老相关基因表达等 ,起到抗衰老作用。 3 最后阐述松果腺学说的理论意义和应用前景。     

昼夜节律睡眠-觉醒障碍与恶性肿瘤发生发展的关系

昼夜节律睡眠-觉醒障碍是指睡眠-觉醒周期与人体24 h生物节律失调所致的一类睡眠疾病,它可以影响人体的认知功能和代谢等过程,还能促进恶性肿瘤的发生发展——通过改变时钟基因表达直接促进肿瘤增殖,并通过抑制褪黑素的分泌等内分泌机制间接加速肿瘤发展。本文阐述了昼夜节律睡眠-觉醒障碍的定义、它导致的病理状态以及它对恶性肿瘤发生发展的影响,以期为昼夜节律性睡眠-觉醒障碍影响的肿瘤发生发展的防治提供可能的治疗措施。     

Role of melatonin in mood disorders and the antidepressant effects of agomelatine

Introduction: Disturbances of circadian rhythms and sleep play an important role in various types of mood disorders like major depressive disorder (MDD), bipolar depressive disorder (BPD) and seasonal affective disorder (SAD). Malfunctioning of the SCN–pineal–melatonin link has been suggested as the main cause for these disorders. As a rhythm-regulating factor and as a hormone involved in the regulation of sleep, melatonin is essential for the control of mood and behavior.

Areas covered: Melatonin's involvement in various mood disorders is reviewed based on studies undertaken in patients with MDD, BPD and SAD. The chemistry and metabolism of the newly introduced antidepressant, agomelatine, a MT1/MT2 melatonin receptor agonist and 5-HT2c antagonist in brain areas involved in mood regulation are also discussed. Its clinical role in mood regulation, agomelatine's efficacy, safety and tolerability are also reviewed.

Expert opinion: Agomelatine, a melatonergic antidepressant with a rapid onset of action, has been shown effective in various types of mood disorders (e.g., MDD, BPD, SAD). Some studies find it superior to other common antidepressants (SSRIs, SNRIs) that are in clinical use today. Agomelatine's efficacy, good tolerability and safety profile suggest that it may become a preferred antidepressant in the near future.