DSIP (Delta Sleep-Inducing Peptide): What the Published Literature Reports

Delta sleep-inducing peptide (DSIP) is a nonapeptide that was isolated and characterised between 1963 and 1977 from dialysate collected from the cerebral venous blood of rabbits kept asleep by electrical stimulation of the ventromedian intralaminar thalamus, and subsequent intravenous administration in several animal species was reported to produce sleep lasting hours [1]. The same body of work described a parabolic rather than monotonic dose–response relationship across intracerebroventricular, intravenous and subcutaneous routes, species-specific effects (with REM sleep predominating in cats), and a phosphorylated Ser7 derivative (DSIP-P) that both it and DSIP were detected in human cerebrospinal fluid [1]. A later critical review argued that the link between DSIP and sleep has never been adequately characterised, noting the absence of an isolated DSIP gene, protein or receptor, and described the sleep-factor hypothesis as poorly documented [2]. An earlier update review catalogued reported sleep and extra-sleep effects in animals alongside immunohistochemical and radioimmunochemical mapping of DSIP-like material in the body, and concluded that the peptide's physiological functions and a proposed mechanism involving modulation of adrenergic transmission remained to be established [3]. Structure–activity work in rats bears on this uncertainty. When DSIP and three analogues were injected intracerebroventricularly at dark onset and sleep–wake activity was recorded across 12-hour dark and light periods, DSIP itself did not increase sleep, whereas [D-Trp1]-DSIP and [D-Tyr1]-DSIP promoted sleep in the first part of the night and the truncated [D-Trp1]-DSIP1-6 produced a prompt arousing effect; the authors attributed DSIP's inactivity to rapid degradation [4]. The critical review cited above likewise emphasised that significant slow-wave-sleep-promoting activity in rabbits and rats was observed with certain artificial DSIP analogues rather than with DSIP itself, and proposed the existence of a distinct DSIP-like peptide accounting for the observed immunoreactivity and biological activity [2]. Human work has been conducted mainly in small sleep-laboratory studies. In six normal volunteers given synthetic DSIP by slow intravenous infusion in the morning under a double-blind cross-over design, median total sleep time increased by 59% over a 130-minute post-treatment interval relative to placebo, with delayed effects on subsequent night sleep including shorter sleep onset and reduced stage 1, while behavioural and EEG analyses showed no classical pharmacological sedation [6]. In six middle-aged chronic insomniacs given a single acute intravenous dose, the investigators reported longer sleep duration, fewer interruptions, slightly more REM sleep, and no daytime sedation, with the sleep-promoting effect confined to the second hour after injection and a slight arousing effect in the first hour [5]. A placebo-controlled double-blind study in 14 middle-aged chronic insomniacs administering DSIP over seven successive nights reported improved night sleep and increased daytime alertness and performance, with effects persisting into the first placebo post-treatment night [7]. Two other controlled trials were more equivocal: a double-blind crossover polysomnographic study in chronic insomniacs found that reductions in awakenings and waking time did not differ significantly from baseline or placebo nights and concluded that the sleep improvement was of little clinical significance [8], and a double-blind matched-pairs parallel-group study in 16 chronic insomniacs found higher sleep efficiency and shorter sleep latency but judged the effects weak and partly attributable to a change in the placebo group [9]. A separate human literature measured endogenous DSIP-like immunoreactivity (DSIP-LI) rather than administering the peptide. In 15 drug-free men with schizophrenia undergoing lumbar puncture and three nights of polysomnography, cerebrospinal fluid DSIP-LI correlated with stage 3 and delta sleep measures on the preceding night and negatively with stage 2 percentage [10]. Radioimmunoassay of cerebrospinal fluid across neurological groups found DSIP-LI and phosphorylated P-DSIP-LI positively correlated with age and significantly decreased DSIP-LI relative to age-matched controls in middle and late Alzheimer-type dementia, multi-infarct dementia, Parkinson's disease, vascular disease and communicating hydrocephalus, with no pathology-related differences in P-DSIP-LI [11]. Plasma DSIP-LI was reported to be significantly elevated in suicide attempters with major depressive disorder, with a correlation between pre-dexamethasone cortisol and DSIP-LI in healthy controls [12]. Conversely, in patients with Cushing syndrome the percentage of time in delta sleep and 08.00 h plasma DSIP-LI were both reduced relative to normal volunteers, and the correlation between delta sleep and DSIP-LI was negative, which the authors described as arguing against a causal relationship [13]. Animal studies have examined endpoints beyond sleep. In Wistar and August rats subjected to repeated restraint stress, DSIP administration altered hypothalamic and plasma substance P, beta-endorphin and corticosterone levels, with different response patterns in the two strains [14]. In Sprague-Dawley rats with focal stroke induced by intraluminal middle cerebral artery occlusion, intranasal DSIP given before occlusion and for seven days after reperfusion was associated with significantly recovered rotarod motor performance, although the reduction in infarct volume did not reach significance [15]. In a metaphit-provoked audiogenic seizure model in adult male Wistar rats, DSIP and the analogue DSIP-12 increased delta and theta band power and decreased seizure incidence, mean grade and duration, with DSIP-12 more effective than DSIP [16]. In rats exposed to simulated high altitude hypobaric hypoxia, intraperitoneal phosphorylated DSIP was associated with increased non-REM and REM sleep, improved Morris water maze performance, altered monoamine levels and regulatory enzyme expression, and changes in hippocampal CREB and p-CREB that were reversed by naloxone [17]. Biophysical and biochemical work has been done outside living systems. Solution-state NMR, circular dichroism, FT-IR and fluorescence spectroscopy with molecular modelling indicated that DSIP exists in a dynamic equilibrium between unordered and folded structures, with residues 2–5 and 6–9 tending to form type I beta-turns in aqueous solution and a more ordered helix-like structure inducible in 40% trifluoroethanol [18]. In vitro enzymology showed that DSIP can serve as a substrate for casein kinase II using either ATP or GTP as phosphoryl donor, with phosphorylation inhibited by heparin and enhanced by spermine [19]. A recent narrative review grouped DSIP with epithalon and pinealon as agents described as targeting circadian and mitochondrial regulators, and stated that while preclinical work is suggestive there is a current lack of clinical trials for the therapeutic peptides it surveyed [20].