DSIP Research & Studies

The research aims to elucidate the sleep-promoting mechanism of DSIP-CBBBP, exploring its impact on neurotransmitter levels and sleep regulation, and to analyze its composition and structure.

Delta sleep-inducing peptide (DSIP) was isolated from rabbit cerebral venous blood by Schoenenberger-Monnier group from Basel in 1977 and initially regarded as a candidate sleep-promoting factor. However, the link between DSIP and sleep has never been further characterized, in part because of the lack of isolation of the DSIP gene, protein and possible related receptor. Thus the hypothesis regarding DSIP as a sleep factor is extremely poorly documented and still weak. Although DSIP itself presented a focus of study for a number of researchers, its natural occurrence and biological activity still remains obscure. DSIP structure is different from any other known representative of the various peptide families. In this mini-review we hypothesize the existence of a DSIP-like peptide(s) that is responsible (at least partly) for DSIP-like immunoreactivity and DSIP biological activity. This assumption is based on: (i) a highly specific distribution of DSIP-like immunoreactivity in the neurosecretory hypothalamic nuclei of various vertebrate species that are not particularly relevant for sleep regulation, as revealed by the histochemical studies of the Geneva group (Charnay et al.); (ii) a large spectrum of DSIP biological activity revealed by biochemical and physiological studies in vitro; (iii) significant slow-wave sleep (SWS) promoting activity of certain artificial DSIP structural analogues (but not DSIP itself!) in rabbits and rats revealed by our early studies; and (iv) significant SWS-promoting activity of a naturally occurring dermorphin-decapeptide that is structurally similar to DSIP (in five of the nine positions) and the sleep-suppressing effect of its optical isomer, as revealed in rabbits. Potential future studies are outlined, including natural synthesis and release of this DSIP-like peptide and its role in neuroendocrine regulation.

Delta sleep-inducing peptide (DSIP) and P-DSIP, phosphorylated analogue, were found to have enhancing effects on hypothermia induced by i.p. injection of apomorphine (2 mg/kg), a dopamine agonist. Further, the action of P-DSIP appeared and diminished more quickly than that of DSIP. A minimal effective dose of these peptides was 10 ng and the dose-response relationship exhibited an inverted bell-shape with a maximal effective dose of 1 microgram. By the pretreatment of anti-DSIP the enhancing effect of DSIP but not P-DSIP, was totally abolished and the action of both peptides was antagonized by haloperidol. These findings suggest that DSIP and P-DSIP have a close relation to the dopaminergic system on the thermoregulatory mechanisms.

Delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) has previously been demonstrated in brain neurons and in endocrine cells of the pituitary and the adrenal medulla. By means of three different antisera against synthetic DSIP we now describe the occurrence and distribution of DSIP-LI in several gut endocrine cells. The human gut was the richest source, where DSIP-LI was located in gastrin/CCK, secretin and PYY/glicentin cells. The rat and pig gut harbour a moderate number of immunoreactive cells in the antral mucosa but in the intestines DSIP-LI-containing cells were very few. By radioimmunoassay, the concentration of DSIP-LI was determined in extracts of various gut regions from man, pig and rat. The highest concentrations were found in all human specimens compared with corresponding samples in the pig and rat. In all three species, high-performance liquid chromatography revealed a single peak of DSIP-like material with approximately the same retention time as DSIP 3-9. Taken together, the present results provide evidence for the presence of DSIP-LI in gut endocrine cells in man, pig and rat; the human gut seems to be the richest source of DSIP-like peptides.

The nonapeptide delta-sleep-inducing peptide (DSIP) has been isolated from venous blood of rabbits induced to sleep. Numerous reports have described sleep as well as extra-sleep effects. Radiochemical and immunochemical data suggest a relationship of DSIP with the pineal gland supported by interactions of this peptide with pineal functions such as the serotonin N-acetyltransferase activity. In order to demonstrate the natural occurrence of DSIP-like material associated with high Mr proteins in the ovine pineal, organs were water-extracted and fractionated by ultrafiltration and gel filtration. Radioimmunoassay (RIA) for DSIP-like fragments of the fractions revealed considerable amounts of pineal DSIP-like immunoreactivity (DSIP-LI) apparently existing in small as well as large molecular forms. Acidification of large DSIP-LI forms resulted in the elution from Sephadex G-50 of Mr less than or equal to 1,000 DSIP-like material. This free DSIP-LI form coeluted with the synthetic DSIP nonapeptide from microBondapak C18 on high-performance liquid chromatography. The results, therefore, appear to indicate the presence of a (biospecific) noncovalent intermolecular interaction of DSIP (1-9) with proteins (Mr greater than or equal to 10,000) of the ovine pineal gland.

Delta-Sleep-Inducing Peptide (DSIP) has several physiological effects in addition to its ability to promote sleep in animals under certain conditions. These effects include modification in thermoregulation, heart rate, blood pressure, pain threshold, and in the lymphokine system. DSIP effects are circadian cycle-dependent. Moreover, some of DSIP effects appear before neurological or behavioral signs of sleep. DSIP may promote peripheral preparatory physiological mechanisms associated with sleep onset.

The concentrations of delta sleep-inducing peptide (DSIP)-like (DSIP-LI) and P-DSIP-like (phosphorylated, Ser7) immunoreactivity (P-DSIP-LI) were measured by specific radioimmunoassay in the cerebrospinal fluid (CSF) of patients with senile dementia of the Alzheimer type [SDAT, subdivided into early (S1), middle (S2) and late dementia (S3)], multi-infarct dementia (MD), Parkinson's disease (PD), vascular disease (VD) and communicating hydrocephalus (H), as well as in control patients (C1, C2). Mean DSIP-LI and P-DSIP-LI concentrations were found to be significantly higher in the elderly control group (C1, mean age 83 +/- 5 years) than in the middle-aged control group (C2, mean age 40 +/- 16 years). DSIP-LI and P-DSIP-LI were positively correlated with age in both control groups. Significant decreases of DSIP-LI compared with age-matched controls (C1) were observed for S2, S3, MD, PD, VD and H. In contrast, no significant differences corresponding to pathology were found for P-DSIP-LI.

The effects of DSIP on night sleep and on waking functions are demonstrated in double-blind studies in insomniacs, presenting influences of single dose treatments as well as of repeated injections. Moreover, a single case study describes the efficiency of DSIP on narcolepsy.

The isolation and characterization of delta-sleep-inducing peptide (DSIP) achieved from 1963 to 1977 were reviewed in 1984. The first reports describing sleep as well as extra-sleep effects of DSIP also were included in that work. Only two years later, much additional literature concerning DSIP has accumulated. Besides further sleep-inducing and/or -supporting effects of DSIP in animals, considerable work has been carried out to evaluate the potential use of the peptide for therapeutic purposes such as treatment of insomnia, pain, and withdrawal. Immunohistochemical as well as radioimmunochemical studies provided further insights into the natural occurrence of the nonpeptide and the distribution of DSIP-like material in the body, suggesting possible relations of the peptide to certain diseases. Various physiological functions of DSIP and a possible mechanism of action involving the modulation of adrenergic transmission remain to be established.

The brain and plasma levels of immunoactive delta sleep-inducing peptide (DSIP) as well as the permeability of the blood-brain barrier (BBB) to radioiodinated N-Tyr-DSIP (125I-DSIP) were measured at 0400, 0800, 1200, 1600, 2000, and 2400 hr in rats in a normal 12-hr-light/12-hr-dark cycle and at 0800 in rats in constant light or constant dark. Both brain and blood levels of immunoactivity showed statistically significant diurnal changes, whereas the measurement of BBB permeability varied in a regular fashion over time without the changes reaching statistical significance. Immunoactive levels of DSIP in both the plasma and the brain were higher and permeability of the BBB to 125I-DSIP increased in both the constant light and especially the constant dark groups in comparison with the cycled 0800 group. Diurnal variations continued to occur in the blood levels of immunoactive DSIP in the constant dark animals. Studies with radioiodinated serum albumin (RISA) showed that these findings did not result from a change in brain hemodynamics. Immunoactive levels of DSIP in the plasma correlated with brain immunoactive levels and with BBB permeability to 125I-DSIP. The increase in penetration of 125I-DSIP into the brain that occurred with changes in the lighting cycle appeared to be magnified by pre-treatment with aluminum. The results show interrelationships among various aspects of the neuroendocrine axis for DSIP and their modulation by physiological factors.

This paper summarizes different investigations into effects of delta sleep-inducing peptide (DSIP) injections on insomnia. Two different studies showed improvement of sleep following single injections of 25 nmol/kg b.w. before sleep. Repeated administrations indicated a buildup with normalization of sleep structure after four administrations. Repeated injections in the morning - besides increasing daytime activity - still had a strong positive effect on night sleep, but not so two doses daily. A case of insomnia in organic brain disease responded well to higher doses. The results are discussed as to the mode of action of DSIP and its possible therapeutic use in insomnia.

Repeated injections of delta sleep-inducing peptide (DSIP) were given to a 35-year-old male narcoleptic. Effects on wakefulness and sleep were evaluated by self-reports, performance tests, multiple sleep latency test and all-night polysomnography. DSIP reduced the frequency of sleep attacks and increased activity, alertness and performance during day-time. The sleep period was compressed by DSIP with enhancement of REM sleep. The results suggest that the effects are due to an accentuation of circadian and ultradian rhythms by DSIP.

Although delta-sleep inducing peptide was isolated and characterized several years ago, no definitive evidence has been presented for the natural existence of the free peptide. Several attempts at the partial characterization of DSIP-like immunoreactivity (DSIP-LI) have indicated that a small part of the total immunoreactivity is probably present as the free nonapeptide. Using gel chromatography (Sephadex G-100) and subsequent high performance liquid chromatography on rabbit, human, rat and dog plasma, we now show a distinct peak of DSIP-LI that has the same elution position as synthetic DSIP. Free DSIP was also found in human CSF, whereas in human urine most of the small molecular weight DSIP-LI eluted at a position corresponding to DSIP-P, the phosphorylated analog of DSIP. A newly developed antibody recognizing primarily small molecular weight DSIP-LI was used in a modified, rapid assay to facilitate demonstration of the natural occurrence of free DSIP.

The effects of delta sleep-inducing peptide (DSIP) have not been fully determined. Besides sleep-inducing activities, effects on locomotor behavior, stress-reduction, and temperature-regulation have been published. It was reported that DSIP reversed the increase in temperature of rats injected at room temperature with 15 mg d-amphetamine per kg body weight. We examined this effect in mice with 9 different concentrations of DSIP in addition to D-Ala4-DSIP and an analog, DSIP-P, phosphorylated at the serine in position 7. A reduction of the increased temperature was observed in mice but not in rats. This effect was only significant after pretreatment with 0.1 and 150 nmol DSIP/kg, but not the other doses. D-Ala4-DSIP decreased the rise in temperature between 50-150 nmol/kg, but DSIP-P showed no such effect nor was DSIP able to significantly reduce the increase of temperature induced by the larger dose of 30 mg/kg d-amphetamine. A bell-shaped dose-response curve was found for D-Ala4-DSIP; for DSIP two active dose ranges were observed. Thus, complex dose-effect relationships seem to exist for DSIP (and perhaps its analogs) in thermoregulation.

In an open study 7 patients with severe insomnia were treated by a series of 10 injections with the delta-sleep-inducing peptide (DSIP). In all but 1 case sleep was normalized for follow-up periods of 3-7 months. The mood and performance during the daytime improved as well. A problem may be a long-standing habit of drug addiction.

Since the turn of the century, it has been postulated that humoral factors induce sleep. Many compounds were proposed as sleep-factors, but only two of the sleep-peptides have been purified to homogeneity and characterized, so far. One of them, DSIP, was shown to be a nonapeptide of MW 849 and to induce mainly delta-sleep in rabbits, rats, mice, and humans, whereas in cats, the effect on REM sleep was more pronounced. A U-shaped activity curve was determined for the dose as well as for the time of infusion. DSIP-like material was found by RIA and immunohistochemistry in brain and by RIA in peripheral organs of the rat as well as in plasma of several mammals. In addition to sleep, the peptide also has been observed to affect electrophysiological activity, neurotransmitter levels in the brain, circadian and locomotor patterns, hormonal levels, psychological performance, and the activity of neuropharmacological drugs including their withdrawal.

Animal experiments confirmed the neuropeptide nature of delta-sleep-inducing-peptide (DSIP) and a species-specific sleep promotion. Five different human studies were carried out with single and repeated intravenous injections of DSIP under double-blind conditions, and with assessing treatment effects by psychophysiological tests and polygraphic recordings. Compatibility of DSIP was good. Slow injection proved essential. A latency of sleep induction of 1 h, but a duration of up to 20 h was found. The somnogenic properties, initially proven in animal studies, were confirmed. Indications of specific effects on chronobiological regulations were found. A complete normalization of disturbed sleep was achieved by four consecutive injections to insomniacs. During the active awake state, DSIP induced higher alertness and better performance. Psychological tests and evaluation by psychotherapists indicated modulation of ego functions by DSIP in the direction of improved stress tolerance and coping ability. The various actions of DSIP might be conceptualized neurophysiologically on the level of 'programming' behavior by means of changing 'local vigilances'. Whereas the somnogenic actions of DSIP appear promising for treating insomnia, other therapeutic perspectives in the field of psychiatry have to be explored.

An improved radioimmunoassay (RIA) for delta sleep-inducing peptide (DSIP) was used to study the permeability of the blood-brain barrier (BBB) to DSIP peptides. Although the synthetic analog [D-Ala3]-DSIP reacts fully in the assay, at least 8 of the 9 amino acids of the naturally occurring DSIP sequence are required for recognition by the antibody. A significant increase in DSIP-like immunoreactivity found in rat brain in one part of the study after peripheral injection of DSIP indicated, therefore, that some peptide crossed the BBB. The much higher levels found in brain tissue after intracarotid administration of [D-Ala3]-DSIP as compared with DSIP made it unlikely that non-specific leakage of peptide across the BBB was the only explanation. Furthermore, the findings after infusion with saline for one minute tended to rule out contamination of brain tissue by peptide remaining in blood. Thus, the results provide additional evidence that one of the ways peptides administered peripherally can influence the brain is by transport across the BBB essentially intact.

A low dose (0.1 mg/kg) of peripherally administered delta sleep-inducing peptide (DSIP) caused hypothermia in rats maintained at 4 degrees C but larger doses (1.0 or 3.0 mg/kg) did not. At 22 degrees C all 3 doses of DSIP caused hyperthermia. The interaction of d-amphetamine with DSIP was dependent on ambient temperature; at 4 degrees C DSIP had no effect on d-amphetamine-induced hypothermia, but at 22 degrees C DSIP reversed the usual d-amphetamine-induced effect of hyperthermia to hypothermia. At 4 degrees C, DSIP also potentiated the hypermotility effects of d-amphetamine but blocked it at 22 degrees C. Many rats receiving DSIP (0.1 mg/kg) and d-amphetamine (15.0 mg/kg) at 22 degrees C paradoxically exhibited what appeared to be sleep. This sleep-like effect was not found after several other doses of DSIP and d-amphetamine, chlorpromazine, or at a cold ambient temperature. Sodium methohexital caused apparent sleep in animals treated with DSIP alone or with DSIP and d-amphetamine, but was unable to induce this effect in rats receiving d-amphetamine alone. The results suggest that the effects of peripherally injected DSIP on body temperature are independent from its effects on locomotion and that both effects are dependent upon ambient temperature.