褪黑素与神经疾病关系的研究进展

褪黑素具有调节生物钟、促进睡眠等作用。笔者主要介绍了褪黑素与神经保护作用、癫、阿尔茨海默病、脑缺血再灌注损伤、帕金森病等的关系。     

褪黑素在胶质瘤中的抗癌作用及其机制

褪黑素(MT)是主要由松果体分泌的胺类激素,具有调节日夜规律、抗衰老、抗氧化、抗炎、调节免疫等多种生理功能。近年来对MT抗癌作用的研究逐渐成为热点。MT具有抗胶质瘤的生理特性,多种机制参与了MT在胶质瘤中的抗癌作用,主要包括抑制雌激素、抗氧化应激、促进肿瘤细胞凋亡、调节肿瘤细胞周期、抑制肿瘤细胞的转移和侵袭、克服肿瘤的多重耐药性以及神经保护等。     

促红细胞生成素对脑缺血的保护作用研究进展

体外胞培养及动物实验证明，促红细胞生成素对脑缺血损伤具有神经保护和治疗作用。其作用机制可能包括抗谷氨酸兴奋毒性、调节NO的合成、抗氧化作用、抗炎作用、抗神经元凋亡、促进血管生成、促进神经元再生和神经营养作用等。外源性促红细胞生成素可通过血脑屏障进入脑组织内而发挥神经保护作用，提示促红细胞生成素有望成为防治脑缺血的一种新药。     

褪黑素在早发性卵巢功能不全中的应用及研究进展

早发性卵巢功能不全是一种严重影响女性生育力和生活质量的疾病，多数发病原因不明，治疗手段有限。褪黑素是松果体产生的一种激素，具有调节昼夜节律、睡眠觉醒和抗氧化作用，其水平随着机体衰老而降低。外源性补充褪黑素作为助眠类保健品被广泛使用。研究发现，卵巢组织局部也可合成褪黑素，通过抗氧化应激和调节内分泌等作用保护卵巢功能，褪黑素不足是卵巢衰老的原因之一。该文就外源性补充褪黑素在早发性卵巢功能不全中的应用及研究进展进行综述，并分析了其具体作用机制，以期为早发性卵巢功能不全的治疗提供新的思路与方法。     

褪黑素的研究进展及对肾脏的保护作用

研究发现褪黑素具有广泛的生物学作用,对生物的昼夜节律、心血管循环系统、呼吸系统、泌尿系统和性成熟及生殖、免疫调节、抗氧化、抗肿瘤及衰老、眼部疾病等均具有重要调节作用。本研究对褪黑素的合成分泌、生物特性、作用机制等的研究进展以及对肾脏疾病的保护作用和临床应用前景进行逐一综述。     

褪黑素抗氧化保护作用机制及应用的研究进展

褪黑素(MT)除具有调节睡眠、生殖及昼夜节律等生理功能外，还具有抗氧化活性，是一种高效自由基清除剂。从抗氧化的化学机制方面看，MT为高选择性电子供体，不易发生氧化还原循环反应，也无促氧化副作用。从抗氧化的生物学机制方面看，MT通过保护生物大分子，抑制细胞凋亡和诱导抗氧化防御酶发挥抗氧化效应。体内外动物实验表明，MT对神经性疾病、环境化合物的靶器官毒性、自发性和诱发性肿瘤、糖尿病和胚胎发育异常等自由基损伤性疾病都有不同程度的保护作用。     

银杏叶提取物对神经退行性疾病的作用机制及研究进展

随着人口老龄化的加快,神经退行性疾病的发病率呈逐年上升的趋势。神经退行性疾病具有病因复杂、病程长、难治愈等特点,目前银杏叶提取物的神经保护作用已被广泛认可,但其有效成分及其具体作用机制尚未明确。本文将根据神经退行性疾病的发病机制来探讨银杏叶提取物对神经的保护作用,主要从其改善Aβ聚集、抗炎、抗氧化、抗凋亡、保护线粒体、调节能量代谢等角度来研究其治疗神经退行性疾病的机制。     

神经甾体——一类新的神经调节剂

神经甾体是由中枢，周围神经组织及腺体产生的对中枢神经系统具有重要调节作用的一类甾体化合物，它不同于经典的皮质激素和性激素，在体内有特定的生物合成，代谢及调节机制，具有多种生理作用，如中枢抑制，记忆增强，神经保护等，本文概述了近年关于神经甾体类化合物的生物合成，代谢，生理药理学作用及其作用机制等方面研究的一些新进展。     

褪黑素与抗氧化作用

褪黑素（ＭＴ）主要由松果体合成分泌,它是一种理想的自由基清除剂。通过抗氧化作用,ＭＴ保护了ＤＮＡ、脂质以及蛋白质免遭自由基或活性氧的损伤。内源性ＭＴ的不足可诱发疾病,给予外源性ＭＴ则能延缓疾病的发生。     

褪黑素拮抗肝氧化性损伤的研究进展

近来发现松果腺分泌的褪黑素是一种比维生素Ｅ更有效的自由基清除剂和抗氧化剂。褪黑素具有无毒、易穿透生理解剖屏障和进入亚细胞成分的特点。它可通过供电子直接灭活毒性自由基,并明显增强机体抗氧化防御系统。实验证明,褪黑素能拮抗致癌剂黄樟精、百草枯和脂多糖所致的氧化性肝损伤,有效地保护细胞核ＤＮＡ和脂质膜免受氧化性损伤,刺激谷胱甘肽过氧化物酶和谷胱甘肽还原酶等机体重要的抗氧化酶活性。此外,还发现褪黑素可在促进大鼠切除肝脏再生的同时,影响淋巴细胞亚群分布,调节肝脏药物代谢酶和防止胸腺细胞凋亡。这些研究结果提示,褪黑素的神经免疫调节作用也可能有利于机体抵抗氧化性肝损伤。     

Physiology and pharmacology of melatonin in relation to biological rhythms

Melatonin is an evolutionarily conserved molecule that serves a time-keeping function in various species. In vertebrates, melatonin is produced predominantly by the pineal gland with a marked circadian rhythm that is governed by the central circadian pacemaker (biological clock) in the suprachiasmatic nuclei of the hypothalamus. High levels of melatonin are normally found at night, and low levels are seen during daylight hours. As a consequence, melatonin has been called the “darkness hormone”. This review surveys the current state of knowledge regarding the regulation of melatonin synthesis, receptor expression, and function. In particular, it addresses the physiological, pathological, and therapeutic aspects of melatonin in humans, with an emphasis on biological rhythms.     

Melatonin and circadian rhythms

Melatonin synthesis and secretion by the pineal gland is under the control of the suprachiasmatic nucleus and consequently has a profound circadian rhythm. In this review we discuss some of the issues surrounding the measurement of melatonin rhythmicity in biological fluids and the factors that influence melatonin circadian rhythmicity, including light and drugs. We also review the role of melatonin rhythmicity in sleep timing and sleep initiation.     

Melatonin, biological rhythm disorders and phototherapy

Biological rhythms are endogenous in nature and are generated by self sustained oscillators present in the living organisms themselves. Of these, circadian rhythms are the most thoroughly studied and are driven by the suprachiasmatic (SCN) of hypothalamus. The recent discovery of high affinity melatonin receptors ML1, ML2 in SCN suggests that melatonin is involved in the control of circadian rhythm generation. The fact that biological rhythm disorders like delayed sleep phase syndrome (DSPS), Jet lag, shift-work disorders, seasonal effective disorder (SAD) respond well either to phototherapy or melatonin adds further support to the concept that melatonin is involved in the pathogenesis of these conditions. Indeed altered melatonin rhythms have bee documented in MDP, shift work disorder, endogenous depression etc. In addition to functioning as a rhythm regulator, melatonin is also involved in the control of sleep, regulation of body temperature, reproduction, and as a free radical scavanger and antioxidant protecting the cells and tissues of our body against oxidative damage. Low levels of melatonin in cancer patients and patients with coronary heart disease indicate that melatonin may be involved in these disorders also.     

Determination of melatonin in biological fluids in the presence of the melatonin agonist S 20098: comparison of immunological techniques and GC-MS methods

Immunoassays were investigated for the determination of melatonin in biological samples in the presence of a naphthalenic structural analogue S 20098, which is currently under development as a melatonin agonist. The lack of specificity of commercially available antibodies in the presence of closely related molecules led us to develop an LC-RIA procedure with a quantification limit set at 15 pg/ml(-1). Because this technique was not sensitive enough and difficult to use on a routine basis, a more sensitive GC-MS technique was developed. This method involved automated solid-phase extraction (plasma) or liquid-liquid extraction (saliva), derivatization of the indolic moiety and GC separation with an automated switching device before MS detection. The method was validated over the range 1-100 pg/ml(-1), with a quantification limit set at 1 pg/ml(-1) in human plasma and saliva. Intra-assay and inter-assay precision and accuracy were within 16% for all concentrations investigated and each biological matrix. The stability of melatonin in plasma and saliva under various storage conditions was also determined. The specificity of the assay for the analysis of melatonin in the presence of S 20098 and its metabolises was demonstrated. The method was subsequently applied for the determination of endogenous melatonin concentrations in plasma and saliva samples from clinical studies performed with S 20098 to provide pharmacodynamic data.     

Subsensitive melatonin suppression by dim white light: possible biological marker of panic disorder

Light is involved in providing entrainment of circadian rhythms and the suppression of the pineal hormone melatonin. In patients with affective disorders, there have been indications of circadian as well as seasonal variation in illness, which may be reflected in melatonin production. Varying sensitivity to light has been noted within healthy individuals as well as in some patients with affective disorders. Recent evidence suggests that patients with panic disorder may have an altered and phase-delayed melatonin rhythm. The present study examined the nocturnal plasma melatonin rhythm in patients with panic disorder, and also examined their melatonin sensitivity to dim light. The melatonin rhythm was examined in 6 patients with panic disorder and 8 controls. The melatonin sensitivity to dim white light (200 lx) was examined in 8 patients with panic disorder and 63 controls and was compared to that of a group of 7 patients with other anxiety disorders. Patients with panic disorder demonstrated a trend towards higher and delayed peak melatonin levels compared to controls. Patients with panic disorder also had a subsensitive melatonin suppression by dim white light, compared to controls and patients with other anxiety disorders (p<0.005). The phase-delayed circadian rhythm observed in patients with panic disorder may be secondary to the subsensitivity of the melatonin response to light. It is hypothesized that the subsensitivity may be due to abnormal neurotransmitter/receptor systems involved in regulation of melatonin suppression and circadian rhythmicity, and may lead to phase- delayed circadian rhythms. The melatonin subsensitivity to light may be used as a biological marker of panic disorder.     

Kinetic radical-scavenging activity of melatonin

Carbon-centred free radicals can be involved in damage to biological systems under hypoxiclanoxic conditions as well as in ischaemia/reperfusion injury. The antioxidant activities of melatonin against carbon-centred radicals are poorly understood. The aim of this study was to investigate the antioxidant properties of melatonin against carbon-centred radicals in a biomimetic model system consisting of growing methyl methacrylate (MMA) radicals (poly-MMA radicals, PMMA*). The kinetics of the polymerization of MMA initiated by thermal decomposition of 2,2'-azobis(isobutyronitrile) (AIBN; R* radical) or benzoyl peroxide (BPO; PhCOO* radical) in the presence of melatonin were investigated by the induction period method under nearly anaerobic conditions. As melatonin concentrations increased, the length of the induction period (IP) increased, but for the BPO system the IP reached a plateau at a molar ratio of BPO to melatonin of 5:1, indicating that the oxidation of melatonin by PhCOO* was limited. At low concentrations of melatonin, the stoichiometric factor (n, the number of free radicals trapped by the antioxidant moiety) for melatonin was approximately 2, but as the melatonin concentration increased the n value decreased markedly to 0.1. These observations suggest that melatonin may possess catalytic activity contributing to radical avoidance. The initial rate of polymerization (Rp) in the BPO system was markedly suppressed by high concentrations of melatonin, suggesting a strong interaction between oxidative end-products formed from melatonin and PMMA*. Under conditions where n was about 2, the kinh values for melatonin in the BPO system and the AIBN system were 6.58 x 10(4) M(-1)S(-1) and 2.49 x 10(3) M(-1)s(-1), respectively. In the BPO system, the kinh of melatonin was of a similar magnitude to that of a-tocopherol, whereas in the AIBN system the kinh of melatonin was 100-fold greater than that of tocopherol. The present findings suggest that melatonin may be able to scavenge harmful carbon-centred radicals in vivo.     

The effect of age and pre-light melatonin concentration on the melatonin sensitivity to dim light.

The hormone melatonin is secreted at night from the pineal gland, with light being a potent inhibitor of its secretion. Age related decreases in plasma melatonin concentrations have indicated that this may be related to pineal calcification with aging. Recently, it was shown that the melatonin sensitivity to light may be a biological marker of bipolar disorder. However, on average, patients were older than the control group in most studies, and it is not known if age has an effect on the melatonin suppression by light. To test this hypothesis, the present study investigated the effect of age on the melatonin sensitivity to dim light (200 lux). Participants were grouped into three age groups. On the testing night, they were placed in a dark room from 21.00 h to 02.30 h. Light exposure was for an hour from midnight to 01.00 h. Blood samples were collected at regular intervals for measurement of plasma melatonin. No significant differences were found in the percentage suppression of melatonin within the age groups defined in the present study (P > 0.5). No correlation was also found between age and percentage suppression of melatonin (r2 = 0.007; P > 0.1). Our results suggest that the melatonin suppression by light (200 lux) is not affected by age.     

Arylalkylamine N-acetyltransferase (AANAT) genotype as a personal trait in melatonin synthesis

The melatonin rhythm is arguably the best marker for the phase of the endogenous "biological clock." Arylalkylamine N-acetyltransferase (AANAT) is known to catalyze the acetylation of serotonin, a rate-limiting process in melatonin synthesis. Different single-nucleotide polymorphisms (SNPs) in the AANAT gene were identified recently in the Japanese population, and one of the genes was significantly associated with the delayed sleep phase syndrome. Thus, 54 healthy Caucasian males were genotyped to investigate whether these SNPs in the AANAT gene affected melatonin levels. The endogenous melatonin levels were analyzed in saliva under standardized experimental conditions ("constant routines") by radioimmunoassay. Despite the broad temporal variation of the human nocturnal melatonin profiles, none of the investigated SNPs were found in the AANAT gene in this study. These findings point to ethnic differences with respect to these SNPs, rather than time of day termed "morningness." In summary, SNPs in the AANAT gene identified thus far cannot explain the observed interindividual differences for nocturnal melatonin profiles in the subjects investigated.     

New issues about melatonin and its effects on the digestive system

In human beings, melatonin is secreted in a cyclic way by the pineal gland, although it has been detected in other tissues. Synthesis of melatonin takes place in the pinealocyte. It depends on adrenergic stimulation, and its secretion is related to the photoperiod in a circadian model of low activity during light phase and high activity at night time. Former studies aimed to establish the mechanisms by which melatonin carries out its biological function, proved the existance of high affinity binding sites. However, melatonin can pass through the plasmatic membrane; this property suggested a possible activity of the hormone inside the cell trough activation of nuclear receptors. Moreover, melatonin can act by itself as a potent oxygen-free-radical scavenger, which renders it a very strong antioxidant. It is currently accepted that melatonin plays an important role in numerous physiological processes. The gastrointestinal tract of numerous animal species contains melatonin, which is synthesized essentially by intestinal enterochrommaffin cells. Some investigations have revealed that its liberation follows also a circadian rhythm, although its secretion pattern might be influenced by nutritional factors. Receptors for melatonin have been identified in the digestive system, therefore the indolamine might play a leading role in different aspects of the vast digestive physiopathology. The hormone may interact with receptors and subsequently stimulate the synthesis of gastroprotective hormones and also exerts a direct defense on the epithelium, enhances submucosal blood flow and prevents the damage induced by ischemia followed by reperfusion. Moreover, studies have shown that treatment with melatonin reduces the severity of the lesions induced by NSAIDs on gastric mucosa suggesting a beneficial role of melatonin in preventing this gastropathy related to antiinflammatories.     

Analogues of diverse structure are unable to differentiate native melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores.

1. The pineal hormone melatonin exerts its biological effects through specific, high affinity G-protein coupled receptors. Recently, three melatonin receptor subtypes (Mel1a, Mel1b and Mel1c) have been cloned. Neither the cloned subtypes, nor the native receptors have yet been compared in a detailed pharmacological analysis. 2. The present study examined the structure-activity relationships of a series of 21 melatonin analogues, by comparing their potency on the pigment aggregation response in Xenopus laevis melanophores with their affinity in radioligand binding competition studies in chicken retina and sheep pars tuberalis (PT), two tissues in which melatonin is known to mediate a biological response. 3. All but four of the analogues were full melatonin receptor agonists producing a concentration-related redistribution of pigment granules in cultured Xenopus melanophores. The remaining analogues produced little pigment aggregation at 10 microM. 4. Saturation studies with 2-[125I]-iodomelatonin identified a single binding site in the chicken retina and sheep PT membranes, with a KD of 36.6 +/- 2.8 and 37.3 +/- 4.3 pM, and a maximal number of binding sites (Bmax) of 16.6 +/- 0.5, and 40.1 +/- 1.7 fmol mg-1 protein, respectively. 5. Comparison of the potency/affinity of the analogues for the binding sites gave a highly significant correlation in each case, retina/melanophore, r = 0.97 (P < 0.001, n = 17), PT/melanophore, r = 0.97 (P < 0.001, n = 17) and PT/retina, r = 0.98 (P < 0.001, n = 21). 6. Despite their large range in affinity and structural diversity these melatonin agonists were unable to distinguish between melatonin receptors in the chicken retina, sheep pars tuberalis and Xenopus melanophores.