DSIP (Delta Sleep-Inducing Peptide) in Animal Models: A Research Literature Overview

Delta sleep-inducing peptide (DSIP) was isolated from the extracorporeal dialysate of cerebral venous blood in rabbits subjected to hypnogenic electrical stimulation of the intralaminar thalamic area, and characterised as the nonapeptide Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu [1]. In that work, the synthetic nonapeptide, five possible metabolic fragments, two analogues with amino acid exchanges and a related tripeptide were each infused intraventricularly in rabbits under double-blind conditions, and only the full synthetic DSIP sequence produced significant enhancement of delta and spindle EEG patterns [1]. A companion report using computer-analysed fast-Fourier transformation of neocortical and limbic EEG in rabbits described a mean increase in delta activity relative to vehicle-infused controls, and noted that only the pure alpha-aspartyl form was highly active in contrast to its beta-Asp isomer [2]. A subsequent review by the originating group summarised that sleep induction appeared species-specific in animal work, with REM sleep predominantly affected in cats, and that administration by intracerebroventricular, intravenous and subcutaneous routes yielded parabolic rather than monotonic dose-response curves in animals [3]. The cat literature is internally divergent. Intraventricular injection of synthetic DSIP in cats was followed by decreased sleep latency and increased total sleep and total slow-wave sleep over an 8-hour recording period, with the increase attributed exclusively to deep slow-wave sleep while light slow-wave sleep decreased and REM sleep measures were unchanged [4]. Subcutaneous administration in cats was reported to significantly increase deep slow-wave sleep, with non-significant trends in waking time, sleep onset latency and REM latency [5]. By contrast, intraperitoneal injection in cats was followed by reduced total sleep, specifically light slow-wave sleep and REM sleep, along with increased REM sleep latency [6]. In rats injected intracerebroventricularly at dark onset, DSIP itself did not increase sleep, whereas the analogues [D-Trp1]-DSIP and [D-Tyr1]-DSIP promoted sleep in the first part of the dark period and the fragment [D-Trp1]-DSIP1-6 had a prompt arousing effect; the authors interpreted this as rapid degradation of native DSIP together with an arousing fragment within the sequence [7]. Two narrative reviews from the 1980s catalogued animal findings beyond EEG, including effects reported on electrophysiological activity, brain neurotransmitter levels, circadian and locomotor patterns, hormonal levels and the activity of neuropharmacological drugs [8], and a later update noted accumulating animal sleep data alongside immunohistochemical and radioimmunochemical mapping of DSIP-like material, while stating that the physiological functions and a possible mechanism involving modulation of adrenergic transmission remained to be established [9]. A 2006 mini-review argued that the link between DSIP and sleep had never been further characterised, in part because the DSIP gene, protein and a candidate receptor had not been isolated, and hypothesised the existence of a DSIP-like peptide accounting for DSIP-like immunoreactivity; the authors noted that certain artificial DSIP analogues, but not DSIP itself, had shown slow-wave sleep-promoting activity in their earlier rabbit and rat studies [10]. Neuroendocrine studies used ovariectomised rats. Intraventricular DSIP did not alter LH release in untreated ovariectomised rats but stimulated LH release in oestrogen- and progesterone-primed ovariectomised rats, while having no effect on basal or LHRH-induced LH release from hemipituitaries in vitro [11]. A second rat study reported elevated LH within 30 minutes of third-ventricle injection with FSH unchanged, no response from dispersed cultured pituitary cells in vitro, and increased LHRH release from median eminence fragments incubated in vitro, which the authors took as evidence for a hypothalamic site of action [12]. In thermoregulatory work, DSIP and phosphorylated DSIP enhanced apomorphine-induced hypothermia in rats, with an inverted bell-shaped dose-response relationship, abolition of the DSIP effect by anti-DSIP pretreatment and antagonism of both peptides by haloperidol [13]. Metabolic and injury-model work has also been reported in rats. In isolated rat brain mitochondria and brain homogenates, DSIP increased the rate of phosphorylated respiration and the respiratory control ratio in vitro, and in rats subjected to experimental hypoxia, pretreatment inhibited the hypoxia-associated reduction of mitochondrial respiratory activity [14]. In Sprague-Dawley rats with focal stroke induced by intraluminal middle cerebral artery occlusion, intranasal DSIP given before and after occlusion was associated with recovery of rotarod motor performance over 21 days, while the difference in brain infarction volume versus vehicle did not reach significance [15]. Transport and distribution studies span several species. In anaesthetised dogs, intravenous DSIP and analogues produced significant increases in cerebrospinal fluid immunoreactivity, with chromatographic evidence of intact peptide and reversible binding to a large plasma molecule [16]. In perfused in situ choroid plexuses of sheep, unidirectional flux data indicated low-to-moderate permeability with a saturable, high-affinity, low-capacity mechanism, while ventriculo-cisternal perfusion in rabbits indicated no significant efflux of intact peptide from CSF [17]. In unweaned rat pups, an orally fed DSIP analogue produced increases in plasma DSIP-like immunoreactivity and radioactivity in blood and brain, which the authors interpreted as gastrointestinal absorption into the systemic circulation [18]. Immunohistochemistry and radioimmunoassay localised DSIP-like immunoreactivity to gut endocrine cells in human, pig and rat tissue, with the human specimens showing the highest concentrations [19], and immunofluorescence in the cartilaginous fish Scyliorhinus canicula localised DSIP-like immunoreactive perikarya mainly to the hypothalamic nucleus lateralis tuberis and to pituitary cells co-storing melanin-concentrating hormone [20].