DSIP

The hypothesis for this therapeutic use of delta sleep-inducing peptide (DSIP) was based on several animal studies conducted by Tissot. He showed that morphine, alcohol, pentobarbital as well as DSIP, when injected directly into the bulbo-mesencephalo-thalamic recruiting system, induced slow-wave sleep with numerous spindles. In all cases, this effect was reversed by Naloxone. Thus, it has been postulated that DSIP possesses an agonistic activity on opiate receptors and might be of value in the treatment of withdrawal syndromes. Therefore, DSIP was administered intravenously to 107 inpatients presenting with symptoms of alcohol (n = 47) or opiate (n = 60) withdrawal. The assessment of effect was based on the clinical evaluation by the physician and the nursing staff. Approximately 13% of the patients from the first and 22% from the second group did not fulfil the requirements for the evaluation of treatment. In, respectively, 97 and 87% of opiate and alcohol addicts, the clinical symptoms and signs disappeared after DSIP administration or improved markedly and rapidly. Anxiety, however, was slower to decrease. On the average, the clinical symptomatology had a more prolonged course and a higher number of DSIP injections were required for opiate addicts than for alcoholics. Tolerance to the DSIP treatment was good, aside from headaches reported by a few patients.

The effects of acute intravenous administration of synthetic DSIP, 25 nmoles/kg b.wt, on disturbed human sleep were tested in 6 middle-aged chronic insomniacs. The results were: longer sleep duration and a higher quality of sleep with fewer interruptions; slightly more REM-sleep, but no day-time sedation or other side effects though the sleep enhancing capacity was seen for up to 6 h of night sleep. Sleep-promoting effects occurred only in the second hour after injection, in the first hour a slight arousing effect was indicated. The study corroborates the findings of previous investigations in healthy subjects and shows that DSIP has a normalizing influence on human sleep regulation.

A first study of DSIP (= synthetic delta sleep-inducing peptide) application to humans was carried out in six normal volunteers (four males and two females) under extensive psychophysiologic observations and measurements in a double-blind cross-over design. DSIP was applied as slow intravenous infusions at a dosage of 25 nmol/kg in the morning. The subjects immediately reported a feeling of sleep pressure, and sleep increased by 59% (median of total sleep time) within a 130-min interval after the treatment as compared with placebo. Delayed effects on subsequent night sleep were shorter sleep onset, reduced percentage of stage 1, and better sleep efficiency. Nevertheless, sophisticated behavioral and EEG analyses revealed no sedation in the classic pharmacologic way. The results suggest that DSIP in humans is also efficacious by sustaining natural sleep functions. The compound was well-tolerated and no psychologic, physiologic, or biochemical side effects were observed.

Experimental results suggested a modulation or 'programming' interaction of delta sleep-inducing peptide (DSIP) with endogenous opioid-peptidergic systems and exogenous intracerebrally or systemically administered morphine and amphetamine. The induction of cerebral MAO-A activity, a pronounced influence on the circadian rhythms of locomotion and intracerebral neurotransmitter as well as plasma protein and cortisol concentrations has been reported. DSIP was also shown to counteract experimentally induced stress situations in animals. An improvement of the psychomotor performance and the concentration capacity in humans beside sleep normalization and pronounced effects on withdrawal symptoms including pain states in alcoholics and opiate addicts was discovered. This encouraged a pilot study for a possible action of the peptide in humans suffering from chronic pronounced pain episodes. We investigated the therapeutic effect in 7 patients with migraine episodes and vasomotor headaches, chronic tinnitus and psychogenic pain attacks. The anamnestic (baseline) values were statistically compared with the katamnestic control period. DSIP lowered significantly the pain levels of 6 out of 7 patients after intravenous administration on 5 consecutive days followed by 5 injections every 48-72 h. Remarkably, a simultaneous significant reduction of the concomitantly occurring depressive states was observed.

A peptide which induces slow-wave EEG (sleep) after intraventricular infusion into the brain has been isolated from the extracorporeal dialysate of cerebral venous blood in rabbits submitted to hypnogenic electrical stimulation of the intralaminar thalamic area. It was shown by amino-acid analysis and sequence determination to be Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu and named "Delta Sleep-Inducing Peptide" (DSIP). This compound was synthesized as well as 5 possible metabolic products (1--8, 2--9, 2--8, 1--4 and 5--9), 2 nonapeptide analogues (with one and two amino-acids exchanged) and a related tripeptide (Trp-Ser-Glu). All 9 synthetic peptides were infused intraventricularly in rabbits (6 nmol/kg in 0.05 ml of CSF-like solution over 3.5 min) and tested under double-blind conditions. A total of 61 rabbits including controls were used. The EEG from the frontal neocortex and the limbic archicortex were subjected to direct fast-Fourier transformation and analyzed by an 1108 computer system. A highly specific delta and spindle EEG-enhancing effect of the synthetic DSIP could be demonstrated. The mean increase of EEG delta activity reached 35% in the neocortex and limbic cortex as compared to control animals receiving CSF-like solution or any of the other 8 peptides. The final chemical characterization of the synthetic DSIP revealed that only the pure alpha-aspartyl peptide is highly active in contrast to its beta-Asp isomer. A neurohumoral modulating and programming activity was suggested.

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.