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。     

褪黑素对下丘脑氨基酸神经递质的影响

应用纸电泳一双波长薄层扫描法测定了雄性小鼠下丘脑天冬氨酸（Ａｓｐ）．谷氨酸（Ｇｉｎ），及γ－氨基丁酸（ＧＡＢＡ）３种神经递质的含量和褪黑素（ＭＴ）对其影响。结果发现；下丘脑内３种氨基酸神经递质含量均呈明显的昼夜节律性变化，ＭＴ使Ａｓｐ、ＧＡＢＡ的昼夜节律曲线上移，在１２：００及２０：００ｈ升高Ａｓｐ、ＧＡＢＡ作用明显。不同剂量的ＭＴ腹腔注射能够升高Ａｓｐ．ＧＡＢＡ含量，以５μｇ·ｋｇ－１剂量为强，脑室注射ＭＴ的效果更佳。然而，不同浓度，不同时ＩＭＭＴ给药均不影响下丘脑Ｇｌｕ水平。利血平化小鼠的Ａｓｐ、ＧＡＢＡ含量升高，Ｇｌｎ含量则下降、给利血平化动物注射ＭＴ，则ＭＴ对Ａｓｐ，ＧＡ－ＢＡ的影响消失，而使Ｇｌｎ含量进一步下降。提示：ＭＴ对Ａｓｐ、ＧＡＢＡ昼夜节律产生影响，这种影响可能通过单胺神经递质介导。     

褪黑素对老年人睡眠障碍的调节作用

目的研究褪黑素(MT,改善睡眠药)对有睡眠障碍及患有非急性期心脑血管病的老年人睡眠状态的影响。方法用多中心随机双盲和安慰剂平行对照试验设计,224例60岁以上亚健康和非急性期心脑血管病患者随机分为2组,试验组口服MT3~6 mg;对照组口服安慰剂,均连服6个月。用匹兹堡睡眠质量指数(PSQI)进行评分。结果服用MT1-6月后,除第6项(催眠药物)外,PSQI总分均值显著下降,表明睡眠质量显著改善,较对照组均有显著改善。服用1月时,睡眠质量改善的有效率为69.3%;服用2,3,4,5,6月后,试验组睡眠质量指数总分持续稳步改善,有效率继续升高,显著优于对照组;6月时,达到睡眠质量改善的最佳效果,有效率为91.2%。结论MT有显著改善老年人睡眠质量的生理作用。     

L-苹果酸对褪黑素催眠作用的影响

目的考察γ 氨基丁酸合成酶抑制剂L 苹果酸对褪黑素催眠作用的影响。方法采用褪黑素协同戊巴比妥钠睡眠及脑电图描记方法。结果L 苹果酸 ( 6 0 0mg/kg)连续灌胃 5d具有明显抑制褪黑素延长小鼠戊巴比妥钠睡眠时间的作用。脑电图分析表明 ,L 苹果酸 ( 4 2 0mg/kg)还能明显抑制褪黑素引起的大鼠总睡眠时间和慢波睡眠时间的增加 ,及抑制褪黑素引起的觉醒时间的减少 ,但对睡眠潜伏期和快波睡眠时间无明显影响。结论首次发现褪黑素的催眠作用能被γ 氨基丁酸合成酶抑制剂L 苹果酸拮抗。褪黑素催眠作用的机制可能由GABA能神经系统介导     

脑内氨基酸水平与学习记忆能力的相关性

学习记忆能力下降是阿尔茨海默病(AD)等痴呆性疾病的主要表现,其与脑内氨基酸关系密切。谷氨酸(Glu)介导兴奋性信号传导,突触间隙中的Glu会激活N-甲基-D-天冬氨酸受体,诱导产生长时程增强效应,实现学习记忆过程,但若其浓度过高则产生神经毒性作用;γ-氨基丁酸(GABA)介导抑制性信号传导,AD小鼠脑组织样品中的GABA显著降低;自噬系统产生游离氨基酸作为终产物,其途径受Glu和GABA等氨基酸水平的控制,神经元自噬能力的缺乏导致了明显的神经退行性表现;Glu/GABA比值在一定范围内的升高可提高学习记忆能力,比值过高则产生抑制作用;牛磺酸(Tau)在大脑中分布广泛,其浓度随老化而降低,可调节大脑兴奋性和抑制性之间的平衡,增强大脑海马对依赖性记忆的保留,促进衰老小鼠海马齿状回干细胞的增殖,调节脑中谷氨酰胺酶、谷氨酸脱羧酶和谷氨酰胺合成酶的活性,抑制过氧化反应进而提高学习记忆能力,其对星形胶质细胞的激活作用可促进学习记忆能力的发挥。姜黄提取物作用于血管性痴呆小鼠,降低脑内的Glu含量而改善学习记忆能力;艾烟能使快速老化模型小鼠Glu和天冬氨酸降低,升高GABA而抗衰老,提高认知功能;AD模型大鼠兴奋性神经递质Glu和天冬氨酸升高,抑制性神经递质GABA和甘氨酸降低,补肾益智方通过改变这种变化发挥改善学习记忆的作用,而蛇床子素可降低AD大鼠Glu和Glu/GABA比值,这可能是其改善认知的机制。氨基酸的测定方法包括分光光度法、离子色谱法、高效液相法、液质联用法和氨基酸分析仪法,我们基于前期的研究,利用全自动氨基酸分析仪A300建立一种氨基酸自动测定方法,经过方法学考察,具有良好的分离度、线性关系、重复性以及回收率,适用于脑内游离氨基酸含量的批量测定,以期进一步研究脑内氨基酸水平与学习记忆能力的相关性。     

头孢曲松对甲基苯丙胺致大鼠行为及纹状体氨基酸等递质含量改变的影响

目的观察甲基苯丙胺(METH)急性处理时致神经损伤情况,以及纹状体中氨基酸类神经递质谷氨酸(glutamate,Glu)、单胺类神经递质多巴胺(dopamine,DA)及其代谢产物DOPAC的变化。方法建立METH急性毒性模型,同时利用药物头孢曲松进行干预,利用清醒动物脑微透析技术检测神经递质含量的变化。结果 METH急性给药组与盐水对照组相比,刻板行为明显增加(P<0.01);急性给予METH后,胞外Glu浓度持续增加,在本试验检测时间(0～6 h)范围内,与基础平衡值相比,在给药5.5 h时Glu浓度已增加450%。胞外DA水平在1 h达峰值,与基础平衡值相比,浓度增加1248.6%。与METH组相比,头孢曲松预防给药可明显降低大鼠纹状体胞外Glu浓度(P<0.05)。结论 METH急性处理能引起纹状体中胞外谷氨酸的含量明显增加,导致神经损伤;METH的神经毒性与兴奋性氨基酸的过度释放密切相关。     

藏药七十味珍珠丸对惊厥小鼠脑内氨基酸含量的影响

目的　观察七十味珍珠丸的抗惊厥作用及作用机制。方法　七十味珍珠丸ig给药,使用硫代氨基脲制成惊厥小鼠模型,测定惊厥开始时间、致死率;采用高压液相色谱仪测定小鼠脑内抑制性氨基酸γ氨基丁酸(GABA)、甘氨酸(Gly)和兴奋性氨基酸谷氨酸(Glu)、天门冬氨酸(Asp)的含量。结果　七十味珍珠丸对硫代氨基脲所致惊厥的开始时间,具有显著延迟作用,可明显减少小鼠致死率。有升高惊厥小鼠脑内GABA ,降低脑内Glu含量的作用趋势,但无显著差异(P>0.05) ,而对Glu/GABA的比值,却有明显的降低作用(P<0.05、P<0.01) ,使Glu/GABA保持正常动物的水平,即维持中枢神经系统兴奋和抑制状态平衡的作用,阻止惊厥发生。结论　该药具有抗惊厥作用,其作用机制可能是通过调节脑内兴奋性和抑制性氨基酸的平衡来实现的     

藏药七十味珍珠丸对惊厥小鼠脑内氨基酸含量的影响

目的　观察七十味珍珠丸的抗惊厥作用及作用机制。方法　七十味珍珠丸ig给药 ,使用硫代氨基脲制成惊厥小鼠模型 ,测定惊厥开始时间、致死率 ;采用高压液相色谱仪测定小鼠脑内抑制性氨基酸γ 氨基丁酸 (GABA)、甘氨酸 (Gly)和兴奋性氨基酸谷氨酸 (Glu)、天门冬氨酸 (Asp)的含量。 结果　七十味珍珠丸对硫代氨基脲所致惊厥的开始时间 ,具有显著延迟作用 ,可明显减少小鼠致死率。有升高惊厥小鼠脑内GABA ,降低脑内Glu含量的作用趋势 ,但无显著差异 (P >0 .0 5 ) ,而对Glu/GABA的比值 ,却有明显的降低作用 (P <0 .0 5、P <0 .0 1) ,使Glu/GABA保持正常动物的水平 ,即维持中枢神经系统兴奋和抑制状态平衡的作用 ,阻止惊厥发生。结论　该药具有抗惊厥作用 ,其作用机制可能是通过调节脑内兴奋性和抑制性氨基酸的平衡来实现的     

褪黑素对谷氨酸所致动物脑内MDA生成的抑制作用

用体内及体外两种实验方法 ,研究了谷氨酸对鼠脑组织中过氧化脂质及还原型谷胱甘肽含量的影响 ,以及施用褪黑素 (MT)后对谷氨酸的对抗作用 .结果表明 ,在体外 ,不同浓度的谷氨酸(2 9～ 11 7mmol/L )均能显著提高大鼠脑匀浆中丙二醛 (MDA )的含量 ;而加入MT(1～ 10mmol/L) ,可显著的对抗这种升高 .体内实验 ,小鼠侧脑室给予不同浓度的谷氨酸可显著升高全脑组织中丙二醛 (MDA)的含量及降低还原型谷胱甘肽的含量 ;如预先腹腔注射MT(1～ 10mg·kg-1) ,可显著对抗谷氨酸的影响 .MT的这种作用可能是其抗衰老的机制之一 .     

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.     

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.     

GABA合成酶抑制剂盐酸氨基脲对褪黑激素催眠作用的影响

目的:观察GABA合成酶抑制剂盐酸氨基脲对褪黑激素催眠作用的影响.方法:采用小鼠协同戊巴比妥钠睡眠法和大鼠脑电图描记法测定盐酸氨基脲对睡眠和褪黑激素催眠作用的影响.结果:褪黑激素对小鼠和大鼠均具有明显的催眠作用.盐酸氨基脲单独使用对小鼠和大鼠的睡眠无影响,但能明显阻断褪黑激素对戊巴比妥钠引起的小鼠睡眠时间的延长,并且明显抑制褪黑激素引起的大鼠总睡眠时间,慢波睡眠时间,快波睡眠时间的增加和觉醒时间的减少.结论:盐酸氨基脲能明显拮抗褪黑激素的催眠作用,提示褪黑素的催眠作用由GABA能系统介导.     

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.     

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.     

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