Schoenenberger G A
Eur Neurol. 1984;23(5):321-45. doi: 10.1159/000115711.
From 1963 to 1970 the possibility of humoral transmission of delta (SWS)-EEG sleep in rabbits by, i.c.v. infusion of extracorporal dialysate from blood of the sinus confluens of donors kept asleep by electrical stimulation of the ventromedian intralaminar thalamus, has been established. From 1970 to 1977 we isolated, characterized and synthesized a nonapeptide called delta-sleep-inducing peptide (DSIP) responsible for this effect. Subsequently, intravenous administration of DSIP was shown to produce, in different animals, sleep lasting for hours. Analogs with exchanged amino acids in the sequence or shortening the peptide by one or two amino acids decreased or abolished the effect, as did breakdown products, suggesting a close structure-specificity. In contrast sleep-induction per se was found to be species specific, i.e. in cats REM-sleep was predominantly produced. I.c.v., i.v. and s.c. administration yielded, in contrast to pharmaka, a parabolic dose-response curve with different effective optima. Additionally to sleep-induction, DSIP acts upon the circadian rhythmicity of the locomotor activity and transmitter concentrations in the brain and on that of plasma proteins and cortisol levels. We then synthesized a manyfold more powerful derivative by phosphorylation of the serine in position 7 (DSIP-P). Both forms, DSIP and DSIP-P occur in human CSF. Immunoreactive DSIP-like material was found in plasma of several mammals and humans, in human urine, CSF and milk. The penetration of the blood-brain barrier by the peptide has been proven and it was shown that unweaned rats are able to take up DSIP by the intestinal tract. The half-life time for proteolytic split-off of tryptophan by brain slices and homogenates is 15 min. Endogenous immunoreactive DSIP-like material in plasma, urine and CSF was found to be bound to a larger protein (carrier ?) and thus protected from proteolysis. Immunohistochemically DSIP was shown to occur in different regions of the rat brain. The multivariate activity of the peptide was then suggested by its interaction with acute and chronic stress and with drug-effects such as morphine, d-amphetamine and barbiturates. An induction of MAO-A and RNA synthesis in the brain was observed and the brain concentration of DSIP increased during progressed hibernation. Finally, alcohol addictism produced a substantial decrease of the DSIP-concentration in the rat brain and a specific electrophysiological effect on isolated neurons of rats and rabbits was established.(ABSTRACT TRUNCATED AT 400 WORDS)
1963年至1970年期间，通过向家兔脑室内注入来自供体窦汇血液的体外透析液，证实了δ（慢波睡眠）-脑电图睡眠在家兔中通过体液传播的可能性，供体通过电刺激丘脑腹内侧板内核而保持睡眠状态。1970年至1977年，我们分离、鉴定并合成了一种名为δ-睡眠诱导肽（DSIP）的九肽，它负责产生这种效应。随后发现，静脉注射DSIP在不同动物中可产生持续数小时的睡眠。序列中氨基酸交换或肽链缩短一两个氨基酸的类似物，以及降解产物，都可降低或消除这种效应，这表明存在紧密的结构特异性。相比之下，睡眠诱导本身具有物种特异性，即猫主要产生快速眼动睡眠。与药物不同，脑室内、静脉内和皮下给药产生的剂量-反应曲线呈抛物线形，具有不同的有效最佳值。除了诱导睡眠外，DSIP还作用于运动活动的昼夜节律、大脑中的递质浓度以及血浆蛋白和皮质醇水平。然后，我们通过对第7位丝氨酸进行磷酸化合成了一种效力强得多的衍生物（DSIP-P）。DSIP和DSIP-P两种形式都存在于人类脑脊液中。在几种哺乳动物和人类的血浆、人类尿液、脑脊液和乳汁中发现了免疫反应性DSIP样物质。已证实该肽可穿透血脑屏障，并且未断奶的大鼠能够通过肠道摄取DSIP。脑切片和匀浆对色氨酸进行蛋白水解分裂的半衰期为15分钟。发现血浆、尿液和脑脊液中的内源性免疫反应性DSIP样物质与一种更大的蛋白质（载体？）结合，从而免受蛋白水解。免疫组织化学显示DSIP存在于大鼠脑的不同区域。该肽的多方面活性随后通过其与急性和慢性应激以及与吗啡、右旋苯丙胺和巴比妥类药物等药物效应的相互作用得到提示。观察到脑内单胺氧化酶A（MAO-A）和RNA合成的诱导，并且在深度冬眠期间脑内DSIP浓度增加。最后，酒精成瘾导致大鼠脑内DSIP浓度大幅降低，并确定了对大鼠和家兔离体神经元的特定电生理效应。（摘要截断于400字）
