Glucocorticoid replacement is permissive for rapid eye movement sleep and sleep consolidation in patients with adrenal insufficiency.

There is a well described temporal relation between hormonal secretion and sleep phase, with hormones of the hypothalamic-pituitary-adrenal (HPA) axis possibly playing a role in determining entry into and duration of different sleep stages. In this study sleep features were studied in primary Addison's patients with undetectable levels of cortisol treated in a double blind, randomized, cross-over fashion with either hydrocortisone or placebo supplementation. We found that REM latency was significantly decreased in Addison's patients when receiving hydrocortisone at bedtime, whereas REM sleep time was increased. There was a trend toward an increase in the percentage of time in REM sleep and the number of REM sleep episodes. Waking time after sleep onset was increased, whereas no differences were observed between the two conditions when total sleep time or specific non-REM sleep parameters were evaluated. Our results suggest that in Addison's patients, cortisol plays a positive, permissive role in REM sleep regulation and may help to consolidate sleep. These effects may be mediated either directly by the central effects of glucocorticoids and/or indirectly through CRH and/or ACTH.

High delta sleep-inducing peptide-like immunoreactivity in plasma in suicidal patients with major depressive disorder.

BACKGROUND: Delta sleep-inducing peptide (DSIP) supposedly involves the hypothalamus-pituitary-adrenal (HPA) axis. Previous studies have shown deviated plasma DSIP-like immunoreactivity (DSIP-LI) levels, as well as abnormal DSIP-LI responses to corticotropin-releasing hormone in patients with major depressive disorder (MDD). This study was performed to investigate plasma-DSIP-LI and its association with the dexamethasone suppression test (DST) in suicide attempters. METHODS: Plasma-DSIP and serum cortisol were measured before and after dexamethasone intake in 34 suicide attempters and in healthy age- and sex-matched controls. RESULTS: We found significantly elevated DSIP-LI levels in MDD patients (p < .005), and a significant correlation between predexamethasone cortisol and predexamethasone DSIP-LI levels in healthy controls. Postdexamethasone DSIP-LI levels increased in subjects with low predexamethasone DSIP-LI levels, whereas they decreased in subjects with high predexamethasone DSIP-LI levels. CONCLUSIONS: Results give some support to the theory of glucocorticoid involvement in the regulation of DSIP, and suggest altered DSIP-LI levels in suicidal MDD patients.

Correlations between plasma-neuropeptides and temperament dimensions differ between suicidal patients and healthy controls.

BACKGROUND: Decreased plasma levels of plasma-neuropeptide Y (NPY) and plasma-corticotropin releasing hormone (CRH), and increased levels of plasma delta-sleep inducing peptide (DSIP) in suicide attempters with mood disorders have previously been observed. This study was performed in order to further understand the clinical relevance of these findings. METHODS: Examination of correlates between temperament dimensions (Karolinska Scales of Personality (KSP), the Eysenck Personality Questionnaire together with the IVE- impulsiveness scale (EPQI), and the Marke-Nyman Temperament (MNT)) and NPY, CRH and DSIP and serum-cortisol in the dexamethasone suppression test (DST) in 38 suicidal patients and matched controls. RESULTS: NPY correlated significantly and positively with psychasthenia, irritability, and stability and significantly and negatively with validity in patients, but significantly and negatively with muscular tension, psychasthenia, verbal aggression and irritability in controls. DSIP correlated significantly and positively with impulsiveness (EPQI) in controls. CRH correlated negatively with lie in controls. Cortisol correlated significantly and positively with validity, extraversion and verbal aggression and significantly and negatively with inhibition of aggression in controls. CONCLUSION: NPY may be related to stress tolerance. DSIP seems to be associated with impulsivity/antisocial traits. LIMITATIONS: Non-suicidal patients were not included in the examination. CLINICAL RELEVANCE: The state of depression or stress seems to influence the correlations studied.

Delta sleep-inducing peptide in normal humans and in patients with sleep apnea and narcolepsy.

We measured morning plasma concentrations of delta sleep-inducing-peptide-like-immunoreactivity (DSIP-LI) in 9 sleep apnea patients, 10 narcolepsy patients, and 11 normal controls. Comparisons between the three groups showed no significant differences, although there was a trend toward association with low levels of DSIP-LI in the narcoleptic group, particularly in patients not using medications. No differences were found in the morning or evening plasma DSIP-LI levels in a second group of 11 normal controls and 8 sleep apneics. Our findings do not appear to support a biological marker role of disease activity for single measures of plasma DSIP in sleep apnea.

Human plasma DSIP decreases at the initiation of sleep at different circadian times.

Nocturnal plasma delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) was determined serially in seven healthy male subjects. Time courses during nocturnal sleep (2300-0800 h), nocturnal sleep deprivation (2300-0500 h), and morning recovery sleep (0500-0800 h) after sleep deprivation were compared. A significant decrease in plasma DSIP-LI was found at the transition from wakefulness to sleep in both evening sleep (2300 h) and morning recovery sleep (0500 h). Time courses were accompanied by physiological changes in sleep electroencephalographic slow-wave activity, and in plasma concentrations of cortisol and human growth hormone. No sleep stage specificity was found. It is concluded that DSIP is influenced by the initiation of sleep.

Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome.

To evaluate the sleep disturbances of patients with Cushing syndrome and to examine the relationship between the sleep disturbances and plasma levels of delta-sleep-inducing peptide-like immunoreactivity (DSIP-LI), we performed three polysomnographic/endocrinological studies in patients with Cushing syndrome. In study 1, polysomnography was studied in 12 patients and 12 matched normal volunteers. In addition, DSIP-LI was measured every 30 min for 24 h in 9 patients with Cushing syndrome and 12 normal volunteers. The percentage of time spent in delta sleep (stages 3 and 4) was significantly reduced in patients with Cushing syndrome (5.8 +/- 1.4%; mean +/- SEM) compared to normal volunteers (14.0 +/- 2.5%) (p < 0.01). REM sleep indices, however, were not significantly different between the two groups. There was a significant negative correlation between amount of delta sleep and 08.00 h DSIP-LI (r = -0.43, p < 0.05), which is against the notion of a causal relationship between DSIP-LI and delta sleep. The circadian rhythm of plasma DSIP-LI was found to be similar in Cushing patients and normal volunteers. In study 2, we measured plasma levels of delta-sleep-inducing peptide-like immunoreactivity (DSIP-LI) at 08.00 h in 65 patients with Cushing syndrome and 49 normal volunteers. The 08.00 h DSIP-LI concentrations of 797 +/- 57 pmol/l (mean +/- SEM) in the patients with Cushing syndrome were significantly reduced compared to the level of 1,062 +/- 99 pmol/l found in the normal volunteers (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma concentration of nine hormones and neurotransmitters during usual activities or constant bed rest for 34 H.

Thyroid-stimulating hormone (TSH), cortisol, melatonin, prolactin, luteinizing hormone (LH), delta-sleep-inducing peptide (DSIP), its phosphorylated form (P-DSIP), heart rate, and body temperature were measured every half hour during two 24-h periods in five normal men. tau-Amino-butyric acid (GABA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured less frequently. The first period, the "activity" condition, included usual daily activities. The second period, or "rest" condition, consisted of fasting, constant bed rest during 34 h, and partial light deprivation. Compared with the "rest" condition, the "activity" condition increased heart rate, temperature, LH, and TSH in most subjects, and cortisol in two of five subjects. It retarded the onset of nocturnal cortisol and melatonin secretion. The temporal pattern and the absolute values of the concentrations of DSIP, P-DSIP, MHPG, GABA, and prolactin showed no or minimal changes during the two conditions. In spite of the influence of the "activity" versus "rest" condition on several hormones, the mean concentrations as well as the temporal organization of their secretion into plasma were quite stable within each subject, whereas they varied much more between individuals. TSH, cortisol, and melatonin values were also stable within an 8-month period in one subject who was studied on four occasions. The results illustrate that the patterns of hormones rhythms and their reactivity to changes in the environment are, to a large extent, specific to each subject.

Diurnal rhythm of plasma delta-sleep-inducing peptide in humans: evidence for positive correlation with body temperature and negative correlation with rapid eye movement and slow wave sleep.

Since delta-sleep-inducing peptide (DSIP) was isolated in 1977, numerous reports have suggested that this nonapeptide stimulates delta-sleep [slow wave sleep (SWS)]. Although DSIP-like immunoreactivity (DSIP-LI) has been found in the serum of many animals and man, its diurnal rhythm and relation to sleep stages have not been well defined. We hypothesized that circulating levels of this putative sleep hormone would be highest at night and would probably be elevated before or during episodes of SWS. We, therefore, measured plasma DSIP-LI levels every 30 min for 24 h in 12 normal volunteers in whom we obtained simultaneous polygraphic recordings. We found a distinct diurnal rhythm for plasma DSIP-LI levels, with the maximum at 1500 h and the minimum at 0100 h. DSIP-LI levels were substantially lower in rapid eye movement sleep (P < 0.005) and somewhat lower in SWS (P < 0.05) compared to awake values. DSIP-LI levels did not rise before, during, or after a significant percentage of episodes of SWS. We found, however, that the diurnal rhythm of DSIP-LI closely followed that of body temperature with a high degree of correlation (r2 = 0.66; P < 0.0001). We conclude that endogenous elevations of circulating DSIP may be associated with suppression of slow wave and rapid eye movement sleep, and that the circadian rhythm of this peptide is coupled directly or indirectly to that of body temperature.

Plasma levels of DSIP in infants in the first year of life and SIDS risk.

In searching for abnormalities related to the sudden infant death syndrome (SIDS), delta sleep-inducing peptide (DSIP), a regulatory peptide with sleep promoting actions, was investigated in the first year of life in four groups of children: (1) preterm infants (n = 28), (2) infants with a high mean apnea duration evaluated polysomnographically (n = 26), (3) healthy full-term infants (n = 37) and (4) siblings of SIDS-victims (n = 26). DSIP was radioimmunoassayed in plasma. Half of the infants were also investigated polygraphically during sleep. The ratio between quiet sleep and active sleep was determined. There was no age dependence of the plasma level of DSIP in the first year of life but there was an increase in the ratio of quiet/active sleep depending of maturity. The level of DSIP in healthy full-term infants was significantly higher (P less than 0.05) (median: 1885 pmol/l, interquartile range: 757 pmol/l) than in preterms (1595; 385) and in infants with a high mean apnea duration (1542; 373). There was no significant difference in DSIP concentrations between healthy full-term infants and SIDS-siblings (1605; 271).

Erythropoietin treatment and plasma levels of corticotropin-releasing hormone, delta sleep-inducing peptide and opioid peptides in hemodialysis patients.

An improvement of quality of life and objective brain function has been reported in patients receiving regular hemodialysis treatment (RDT) during treatment with recombinant human erythropoietin (r-huEPO). The mechanisms explaining this improvement are unknown. In this study the plasma levels of peptides known to be involved in CNS functions, namely corticotropin-releasing hormone, delta sleep-inducing peptide, beta-endorphin, methionine-enkephalin, beta-lipotropin and alpha-melanocyte-stimulating hormone, were measured by radioimmunoassay in seven stable RDT patients before the start of r-huEPO therapy and during 28 weeks' treatment. All patients responded with significantly increased hemoglobin concentrations. An improvement of well-being, state of mood and physical fitness was reported by the patients. There were no significant changes during the study in the plasma concentrations of any of the peptides measured. However, as the plasma levels of neuropeptides will not necessarily reflect the local concentrations in the vicinity of the nerve terminals, changes in the intracerebral concentrations of these peptides might occur in response to r-huEPO.

Elevated plasma levels of opioid peptides and delta sleep-inducing peptide but not of corticotropin-releasing hormone in patients receiving chronic hemodialysis.

The fasting plasma levels of corticotropin-releasing hormone (CRH), delta sleep-inducing peptide (DSIP), beta-endorphin (beta-END), methionine-enkephalin (m-ENK), beta-lipotropin (beta-LPH), and alpha-melanocyte-stimulating hormone (alpha-MSH) were measured by radioimmunoassay in 22 stable patients with chronic renal failure on regular hemodialysis treatment and compared with those of 10 healthy controls. The plasma concentrations of DSIP, beta-END, m-ENK, beta-LPH, and alpha-MSH were increased. The plasma level of CRH was not different from that of the controls. The elevated plasma levels of endogenous opioid peptides and DSIP may contribute to the uremic syndrome, although this must be further elucidated.

[Effects of beta endorphin and delta-sleep inducing peptide on resistance to emotional stress]. / Vliianie beta-éndorfina i peptida, vyzyvaiushchego del'ta-son, na ustoichivost' k émotional'nomu stressu.

Enzyme immunoassay was used to study the contents of beta-endorphin and delta-sleep inducing peptide (DSIP) in blood and hypothalamus in rats of Wistar and August lines under acute emotional stress. The stress-resistance of the animals was determined by using preliminary behavior tests. The rats were divided into two groups and predisposed to acute emotional stress. It was found that the contents of these peptides in Wistar-rats, which are more resistant to emotional stress, were higher compared with the August-rats, which are more predisposed to emotional stress. It was shown that the contents of beta-endorphin and DSIP in Wistar-rats is higher than in predisposed Wistar-rats.

[Delta sleep-inducing peptide in the blood and hypothalamus of rats with various resistance to emotional stress]. / Peptid, vyzyvaiushchii del'ta-son, v krovi i gipotalamuse u krys s razlichnoi ustoichivost'iu k émotsional'nomu stressu.

Enzyme immunoassay was used to study delta-sleep peptide content in blood and hypothalamus in rats of Wistar lines under acute emotional stress. It was found that the content of delta-sleep peptide in blood and hypothalamus of stable rats was higher as compared with rats predisposed to emotional stress. After 1.5-hour emotional stress the content of delta-sleep peptide increased in blood and hypothalamus both in stable rats and predisposed ones. After 3-hour stress there was an increase in delta-sleep peptide content in hypothalamus, and contrary to its decrease in blood in both stable and predisposed animals. It is supposed that delta-sleep peptide along with other oligopeptides is one of the factors determining individual animal resistance to emotional stress, which is supported by significant delta-sleep peptide increase in hypothalamus in stable rats.

Delta sleep-inducing peptide response to human corticotropin-releasing hormone (CRH) in major depressive disorder. Comparison with CRH-induced corticotropin and cortisol secretion.

Twenty-four subjects (12 patients with major depressive disorder and 12 controls matched for sex and age) received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an iv bolus dose. Healthy subjects exhibited a slight, but sustained, increase of plasma delta sleep-inducing peptide (DSIP) concentrations, whereas a marked reduction of DSIP levels was found in depressives. Compared to controls, depressed patients showed a significant attenuation of corticotropin (ACTH) responses, whereas cortisol secretion in response to hCRH was normal. Basal DSIP and cortisol concentrations were highly correlated and were higher in depressives than in controls. Both were negatively correlated with the DSIP responses to hCRH. These findings are compatible with the hypothesis that hypothalamic-pituitary-adrenal (HPA) overactivity in the depressive state is primarily due to central hypersecretion of CRH and support the view of a modulatory function of DSIP in the complex regulatory mechanism of the HPA system and of its pathophysiological significance for aberrant HPA axis function in major depressive disorder.

Passage of delta sleep-inducing peptide (DSIP) across the blood-cerebrospinal fluid barrier.

Unidirectional flux of 125I-labeled DSIP at the blood-tissue interface of the blood-cerebrospinal fluid (CSF) barrier was studied in the perfused in situ choroid plexuses of the lateral ventricles of the sheep. Arterio-venous loss of 125I-radioactivity suggested a low-to-moderate permeability of the choroid epithelium to the intact peptide from the blood side. A saturable mechanism with Michaelis-Menten type kinetics with high affinity and very low capacity (approximate values: Kt = 5.0 +/- 0.4 nM; Vmax = 272 +/- 10 fmol.min-1) was demonstrated at the blood-tissue interface of the choroid plexus. The clearance of DSIP from the ventricles during ventriculo-cisternal perfusion in the rabbit indicated no significant flux of the intact peptide out of the CSF. The results suggest that DSIP crosses the blood-CSF barrier, while the system lacks the specific mechanisms for removal from the CSF found with most, if not all, amino acids and several peptides.

Degradation and aggregation of delta sleep-inducing peptide (DSIP) and two analogs in plasma and serum.

The biostability of DSIP (delta sleep-inducing peptide) and two analogs in blood was investigated in order to determine if rates of inactivation contribute to variable effects in vivo. Incubation of DSIP in human or rat blood led to release of products having retention times on a gel filtration column equivalent to Trp. Formation of products was dependent on temperature, time, and species. Incubation of 125I-N-Tyr-DSIP and 125I-N-Tyr-P-DSIP, a phosphorylated analog, revealed slower degradation and, in contrast to DSIP, produced complex formation. An excess of unlabeled material did not displace the radioactivity supporting the assumption of non-specific binding/aggregation. It was concluded that the rapid disappearance of injected DSIP in blood was due to degradation, whereas complex formation together with slower degradation resulted in longer persistence of apparently intact analogs. Whether this could explain the sometimes stronger and more consistent effects of DSIP-analogs remains to be examined.

Separation of tryptophan from DSIP, a Trp-nonapeptide, by adsorption to aluminum oxide.

Delta sleep-inducing peptide (DSIP) has been found to induce sleep as well as extra-sleep effects. Although the presence of endogenous DSIP-like material has been demonstrated, the metabolic fate of injected DSIP has not been clarified so far. A major obstacle in monitoring degradation of DSIP has been the lack of an easy method to separate DSIP from tryptophan (Trp). Cleavage of the N-terminal Trp apparently represents the first and most important step in the metabolism of the peptide. Adsorption to aluminum oxide has been found to separate the two compounds and optimal conditions for the separation are described. Quantitative determination of the degradation of DSIP in plasma or serum is now rapidly achieved. The method should help to advance metabolic studies of DSIP. Other applications such as extraction of DSIP from solutions are also possible.

[Electroencephalographic analysis of inter-central relations in hypothalamo-reticulo-limbic brain structures during treatment with corticosteroids and neuropeptides]. / Elektroéntsefalograficheskii analiz mezhtsentral'nykh vzaimootnoshenii gipotalamoretikulolimbicheskikh struktur mozga pri deistvii kortikosteroidov i neiropeptidov.

Intercentral relations between hypothalamus, limbic system and reticular formation were studied in rabbits and rats under systemic and central action of DSIP, ACTH, corticosteroids and stress (aggressive-defensive behaviour). The results obtained demonstrate changes in the adrenal cortex resulting from stress-inducing adrenocortical hormone content. The increase was achieved by the rise in ACTH level resulting in corticosteroid level elevation (endogenous elevation-aggressive behaviour) and by corticosteroid injections (exogenous elevation). Correlation analysis of structural interrelations after ACTH and corticosteroid injections demonstrated an increased correlation between hypothalamo-reticular-limbic structures. DSIP was shown to have an opposite effect. Correlation analysis revealed the potentials for the formation of new functional interrelations between hypothalamo-reticular-limbic structure in the motivation of aggression (stress) and the levels of corticosterone and DSIP. DSIP action depends on the initial corticosteroid blood level and is more marked in stress-inducing concentrations.

Entry of DSIP peptides into dog CSF: role of physicochemical and pharmacokinetic parameters.

Delta sleep-inducing peptide (DSIP) or one of four DSIP analogs (desTrp-DSIP, D-Ala3-DSIP, D-Ala4-DSIP, D-Ala4-DSIP-NH2), was injected IV into dogs. Samples of cerebrospinal fluid (CSF) from the posterior fossa and blood were collected simultaneously at 2, 5, 10, 20, 30, 45, and 60 min after injection and concentrations of DSIP-like material measured by radioimmunoassay (RIA). The increase in peptide concentration in the CSF correlated significantly with the increase in plasma concentration, with plasma half-life, and with peptide lipophilicity, but not with the degree of plasma protein binding or with molecular weight. An even better correlation occurred when the three factors that correlated independently were combined into a single parameter (r = 0.813, p less than 0.00005). These results demonstrate that peptides can significantly penetrate the blood-CSF barrier of the dog. For DSIP and its analogs, the degree of penetration into the CSF is highly dependent on parameters such as the level of peptide in the plasma, plasma half-life, and the lipophilicity of the peptide.