Delta-sleep-inducing peptide

Delta-sleep-inducing peptide was first discovered in 1974 by the Swiss Schoenenberger-Monnier group who isolated it from the cerebral venous blood of rabbits in an induced state of sleep. It was primarily believed to be involved in sleep regulation due to its apparent ability to induce slow-wave sleep in rabbits, but studies on the subject have been contradictory.{{cite journal | doi = 10.1007/BF00591565 |vauthors=Schoenenberger GA, Maier PF, Tobler HJ, Monnier M | title = A naturally occurring delta-EEG enhancing nonapeptide in rabbits | journal = European Journal of Physiology | volume = 369 | issue = 2 | pages = 99–109 | year = 1977 | pmid = 560681|s2cid=8845219 }}

DSIP-like material has been found in human breast milk.{{cite journal |vauthors=Graf MV, Hunter CA, Kastin AJ | title = Presence of Delta-Sleep-Inducing Peptide-Like Material in Human Milk | journal = Journal of Clinical Endocrinology & Metabolism | volume = 59 | issue = 1 | pages = 127–32 | year = 1984 | doi = 10.1210/jcem-59-1-127|url=http://jcem.endojournals.org/cgi/content/abstract/59/1/127 | pmid=6547144| url-access = subscription }}

DSIP is an amphiphilic peptide of molecular weight 850 daltons with the amino acid motif:
N-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-C{{cite journal | doi = 10.1111/j.1471-4159.2006.03693.x |vauthors=Kovalzon VM, Strekalova TV| title = Delta sleep-inducing peptide (DSIP): a still unresolved riddle | journal = Journal of Neurochemistry | volume = 97 | issue = 2 | pages = 303–309 | year = 2006 | pmid = 16539679| doi-access = free }}

It has been found in both free and bound forms in the hypothalamus, limbic system and pituitary as well as various peripheral organs, tissues and body fluids.{{cite journal | doi = 10.1159/000125110 |vauthors=Charnay Y, Bouras C, Vallet PG, Golaz J, Guntern R, Constantinidis J | title = Immunohistochemical distribution of delta sleep inducing peptide in the rabbit brain and hypophysis | journal = Neuroendocrinology | volume = 49 | issue = 2 | pages = 169–175 | year = 1989 | pmid = 2657475}} In the pituitary it co-localises with many peptide and non-peptide mediators such as corticotropin-like intermediate peptide (CLIP), adrenocorticotrophic hormone (ACTH), melanocyte-stimulating hormone (MSH), thyroid-stimulating hormone (TSH) and melanin concentrating hormone (MCH). It is abundant in the gut secretory cells and in the pancreas where it co-localises with glucagon.

In the brain its action may be mediated by NMDA receptors.{{cite journal | doi = 10.1016/j.pathophys.2004.03.003 |vauthors=Sudakova KV, Umriukhina PE, Rayevskyb KS | title = Delta-sleep inducing peptide and neuronal activity after glutamate microiontophoresis: the role of NMDA-receptors | journal = Pathophysiology | volume = 11 | issue = 2 | pages = 81–86 | year = 2004 | pmid = 15364118}} In another study delta-sleep-inducing peptide stimulated acetyltransferase activity through α₁ receptors in rats.{{cite journal | doi = 10.1111/j.1471-4159.1987.tb05654.x | vauthors = Graf MV, Schoenenberger GA | title = Delta Sleep-Inducing Peptide Modulates the Stimulation of Rat Pineal N-Acetyltransferase Activity by Involving the α₁-Adrenergic Receptor | journal = Journal of Neurochemistry | pmid = 3029331 | volume = 48 | issue = 4 | pages = 1252–1257 | year = 1987 | s2cid = 21467144 }} It is unknown where DSIP is synthesized.

In vitro it has been found to have a low molecular stability with a half life of only 15 minutes due to the action of a specific aminopeptidase-like enzyme.{{cite journal | doi = 10.1159/000115711 | vauthors = Schoenenberger GA | title = Characterization, properties and multivariate functions of Delta-Sleep Inducing Peptide (DSIP) | journal = European Neurology | volume = 23 | issue = 5 | pages = 321–345 | year = 1984 | pmid = 6548966}} It has been suggested that in the body it complexes with carrier proteins to prevent degradation, or exists as a component of a large precursor molecule,{{cite book |vauthors=Inoué S, Borbely AA| title = Endogenous Sleep Substances And Sleep Regulation: Proceedings of the Taniguchi Symposia on Brain Sciences | publisher = Brill Academic Publishers | location = Boston | year = 1985 | isbn = 978-90-6764-058-9 }} but as yet no structure or gene has been found for this precursor.

Evidence supports the current belief that it is regulated by glucocorticoids.{{cite journal | doi = 10.1016/S0006-3223(97)00254-0 |vauthors=Westrin A, Ekman R, Traskman-Bendz L | title = High Delta Sleep-Inducing Peptide-Like Immunoreactivity in Plasma in Suicidal Patients with Major Depressive Disorder | journal = Biological Psychiatry | volume = 43 | issue = 10 | pages = 734–739 | year = 1998 | pmid = 9606527|s2cid=37126381 }}

Gimble et al. suggest that DSIP interacts with components of the MAPK cascade and is homologous to glucocorticoid-induced leucine zipper (GILZ).{{cite journal | doi = 10.1111/j.1467-789X.2009.00661.x |vauthors=Gimble JM, Ptitsyn AA, Goh BC, Hebert T, Yu G, Wu X, Zvonic S, Shi XM, Floyd ZE | title = Delta sleep-inducing peptide and glucocorticoidinduced leucine zipper: potential links between circadian mechanisms and obesity? | journal = Obesity Reviews | volume = 10 | pages = 46–51 | year = 2009 | pmid = 19849801|s2cid=5943377 }} GILZ can be induced by Dexamethasone. It prevents Raf-1 activation, which inhibits phosphorylation and activation of ERK.

Many roles for DSIP have been suggested following research carried out using peptide analogues with a greater molecular stabilitysynthesized by V. N. Kalikhevich and S. I. Churkina, University Chemical Institute, St. Petersburg, Russia, and I. I. Mikhaleva and I. A. Prudchenko, Institute of Bio-organic Chemistry, Russian Academy of Sciences, Moscow and through measuring DSIP-like immunological (DSIP-LI) response by injecting DSIP antiserum and antibodies.{{cite journal | doi = 10.1016/0891-0618(92)90005-B |vauthors=Charnay Y, Golaz J, Vallet PG, Bouras C | title = Production and immunohistochemical application of monoclonal antibodies against delta sleep-inducing peptide | journal = J Chem Neuroanat | volume = 5 | issue = 6 | pages = 503–9 | year = 1992 | pmid = 1476667|s2cid=10260659 }}

• Decreases basal corticotropin level and blocks its release.
• Stimulates release of luteinizing hormone (LH).{{cite journal | vauthors = Iyer KS, McCann SM | title = Delta sleep inducing peptide (DSIP) stimulates the release of LH but not FSH via a hypothalamic site of action in the rat | journal = Brain Research Bulletin | volume = 19 | issue = 5 | pages = 535–538 | date = November 1987 | pmid = 3121137 | doi = 10.1016/0361-9230(87)90069-4 | s2cid = 7710977 }}
• Stimulates release of somatoliberin and somatotrophin secretion and inhibits somatostatin secretion.{{cite journal | vauthors = Koval'zon VM | title = [DSIP: the sleep peptide or an unknown hypothalamic hormone?] | language = ru | journal = Zhurnal Evoliutsionnoi Biokhimii I Fiziologii | volume = 30 | issue = 2 | pages = 310–319 | year = 1994 | pmid = 7817664 }}: {{cite journal | vauthors = Koval'zon VM | title = [DSIP: the sleep peptide or an unknown hypothalamic hormone?] | language= Russian | journal = Zhurnal Evoliutsionnoi Biokhimii I Fiziologii | volume = 30 | issue = 2 | pages = 310–319 | year = 1994 | pmid = 7817664 }}

• Can act as a stress limiting factor.{{cite book | vauthors = Kitayama I, Kawguchi S, Murase S, Otani M, Takayama M, Nakamura T, Komoiri T, Nomura N, Natotani N, Fuse K|veditors=Kvetňanský R, McCarty R, Axelrod J | title = Stress: Neuroendocrine and Molecular Approaches | publisher = CRC Press | location = Boca Raton | year = 1992 | pages = 59–72 | isbn = 978-2-88124-506-0 | chapter = Noradrenergic and neuroendocrine function in chronic walking stress-induced model of depression in rats}}{{cite journal | doi = 10.1111/j.1749-6632.1995.tb44685.x |vauthors=Sudakova KV, Coghlan JP, Kotov AV, Salieva RM, Polyntsev YV, Koplik EV | title = Delta-sleep inducing peptide sequels in mechanisms of resistance to emotional stress | journal = Annals of the New York Academy of Sciences | volume = 771 | pages = 240–251 | year = 1995 |issue=1 | pmid = 8597403|bibcode=1995NYASA.771..240S |s2cid=40317428 }}{{cite journal | doi = 10.1016/S0196-9781(03)00040-8 |vauthors=Khvatova EM, Samartzev VN, Zagoskin PP, Prudchenko IA, Mikhaleva II | title = Delta sleep inducing peptide (DSIP): effect on respiration activity in rat brain mitochondria and stress protective potency under experimental hypoxia | journal = Peptides | volume = 24 | issue = 2 | pages = 307–311 | year = 2003 | pmid = 12668217|s2cid=23492463 }}
• May have a direct or indirect effect on body temperature and alleviating hypothermia.{{cite journal |vauthors=Pollard BJ, Pomfrett CJ| title = Delta sleep-inducing peptide | journal = Eur. J. Anaesthesiol. | volume = 18 | issue = 7 | pages = 419–422 | year = 2001 | pmid = 11437870 | doi=10.1046/j.1365-2346.2001.00917.x| doi-access = free }}{{cite journal | doi = 10.1016/0091-3057(80)90225-7 |vauthors=Yehuda S, Kastin AJ, Coy DH | title = Thermoragulatory and locomotor effects of DSIP: paradoxical interaction with d-amphetamine | journal = Pharmacol. Biochem. Behav. | volume = 13 | issue = 6 | pages = 895–900 | year = 1980 | pmid = 6894196|s2cid=25905115 }}{{cite journal | doi = 10.1016/0196-9781(84)90076-7 |vauthors=Yehuda S, Mostofsky DI| title = Modification of the hypothermic circadian cycles induced by DSIP and melatonin in pinealectomized and hypophysectomised rats | journal = Peptides | volume = 5 | issue = 3 | pages = 495–497 | year = 1984 | pmid = 6548024|s2cid=3854206}}
• Can normalize blood pressure and myocardial contraction.{{cite journal |vauthors=Yehuda S, Carasso RL | title = DSIP--a tool for investigating the sleep onset mechanism: a review | journal = Int. J. Neurosci. | volume = 38 | issue = 3–4 | pages = 345–53 |date=February 1988 | pmid = 3286557 | doi = 10.3109/00207458808990695 }}
• It has been shown to enhance the efficiency of oxidative phosphorylation in rat mitochondria in vitro, suggesting it may have antioxidant effects.
• There is also conflicting evidence as to its involvement in sleep patterns. Some studies suggest a link between DSIP and slow-wave sleep (SWS) promotion{{cite journal | doi = 10.1073/pnas.85.10.3653 |vauthors=Iyer KS, Marks GA, Kastin AJ, McCann SM | title = Evidence for a role of delta sleep-inducing peptide in slow-wave sleep and sleep-related growth hormone release in the rat | journal = Proc Natl Acad Sci U S A | volume = 85 | issue = 10 | pages = 3653–3656 | year = 1988 | pmid = 3368469 | pmc = 280272|bibcode=1988PNAS...85.3653I |doi-access=free }}{{cite journal | doi = 10.1016/0006-8993(87)90006-0 |vauthors=Susić V, Masirević G, Totić S | title = The effects of delta-sleep-inducing peptide (DSIP) on wakefulness and sleep patterns in the cat | journal = Brain Research | volume = 414 | issue = 2 | pages = 262–70 | year = 1987 | pmid = 3620931|s2cid=27734954 }} and suppression of rapid eye movement sleep (REM),{{cite journal | doi = 10.1016/0196-9781(95)02027-6 |vauthors=Seifritz E, Muller M, Schonenberger G, Trachsel L, Hemmeter U, Hatzinger M, Ernst A, Moore P, Holsboer-Trachsler E | title = Human plasma DSIP decreases at the initiation of sleep at different circadian times | journal = Peptides | volume = 16 | issue = 8 | pages = 1475–1481 | year = 1995 | pmid = 8745061|s2cid=40634977 }}{{cite journal |vauthors=Steiger A, Holsboer F| title = Neuropeptides and human sleep | journal = Sleep | volume = 20 | issue = 11 | pages = 1038–1052 | year = 1997 | pmid = 9456470}} while some studies show no correlation.{{cite journal |vauthors=Nakagaki K, Ebihara S, Usui S, Honda Y, Takahashi Y, Kato N | title = Effects of intraventricular injection of anti-DSIP serum on sleep in rats | journal = Yakubutsu Seishin Kodo (Japanese Journal of Psychopharmacology) | volume = 6 | pages = 259–65 | year = 1986| issue = 2 | pmid = 3776352 }} Stronger effects on sleep have been noted for the synthesized analogues of DSIP.{{cite journal | doi = 10.1023/A:1016679208936 | vauthors = Kovalzon VM | title = Sleep-Inducing Properties of DSIP Analogs: Structural and Functional Relationships | journal = Biology Bulletin | volume = 28 | issue = 4 | pages = 394–400 | year = 2001| s2cid = 26029559 }}
• It may affect human lens epithelial cell function via the MAPK pathway, which is involved in cell proliferation, differentiation, motility, survival, and apoptosis.{{cite journal | doi = 10.1167/iovs.06-0889 |vauthors=Gupta V, Awasthi N, Wagner BJ | title = Specific Activation of the Glucocorticoid Receptor and Modulation of Signal Transduction Pathways in Human Lens Epithelial Cells | journal = Investigative Ophthalmology and Visual Science | volume = 48 | issue = 4 | pages = 1724–1734 | year = 2007 | pmid = 17389505 | pmc = 2814520}}

• It has been found to have anticarcinogenic properties. In a study on mice, injecting a preparation of DSIP over the mice's lifetime decreased total spontaneous tumor incidence 2.6-fold.{{cite journal | doi = 10.1016/S0047-6374(03)00082-4 |vauthors=Popovich IG, Voitenkov BO, Anisimov VN, Ivanov VT, Mikhaleva II, Zabezhinski MA, Alimova IN, Baturin DA, Zavarzina NY, Rosenfeld SV, Semenchenko AV, Yashin AI | title = Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice | journal = Mechanisms of Ageing and Development | volume = 124 | issue = 6 | pages = 721–731 | year = 2003 | pmid = 12782416|s2cid=12666819 | doi-access = free }}
• The same study found it to also have geroprotective effects: it slowed down the age-related switching-off of oestrous function; it decreased by 22.6% the frequency of chromosome aberrations in bone marrow cells and it increased by 24.1% maximum life span in comparison with the control group.
• Levels of DSIP may be significant in patients diagnosed with major depressive disorder (MDD). In several studies, levels of DSIP in the plasma and cerebrospinal fluid are significantly deviated from the norm in patients with MDD, though there are contradictions as to whether levels are higher or lower than healthy control patients.{{cite journal | doi = 10.3109/08039488509101959 |vauthors=Walleus H, Widerlöv E, Ekman R | title = Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients | journal = Nordic Journal of Psychiatry | volume = 39 | pages = 63–67 | year = 1985}}{{cite journal | doi = 10.3109/08039488809103215 |vauthors=Bjartell A, Ekman R, Sundler F, Widerlöv E | title = Delta sleep-inducing peptide (DSIP): An overview of central actions and possible relationship to psychiatric illnesses | journal = Nordic Journal of Psychiatry | volume = 42 |issue=2 | pages = 111–117 | year = 1988}}
• Studies have demonstrated a direct link between GILZ expression (homologous to DSIP) and adipogenesis which has links to obesity and metabolic syndrome.{{cite journal | doi = 10.1038/sj.embor.embor805 |vauthors=Shi X, Shi W, Li Q, Song B, Wan M, Bai S | title = A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells | journal = EMBO Reports| volume = 4 | issue = 4 | pages = 374–380 | year = 2003 | pmid = 12671681 | pmc = 1319161}}
• In studies on rats with metaphit-induced epilepsy DSIP acted as an anticonvulsant, significantly decreasing the incidence and duration of fits suggesting DSIP as a potential treatment for epilepsy.{{cite journal | doi = 10.1006/phrs.2001.0938 |vauthors=Stanojilovic OP, Zivanovic DP, Su Sic VT | title = The effects of Delta Sleep-Inducing Peptide on incidence and severity in metaphit-induced epilepsy in rats | journal = Pharmacological Research | volume = 45 | issue = 3 | pages = 241–247 | year = 2002 | pmid = 11884222}}{{cite journal |vauthors=Stanojlović O, Zivanović D, Mirković S, Mikhaleva I | title = Delta sleep-inducing peptide and its tetrapeptide analogue alleviate severity of metaphit seizures | journal = Pharmacol. Biochem. Behav. | volume = 77 | issue = 2 | pages = 227–34 |date=February 2004 | pmid = 14751449 | doi = 10.1016/j.pbb.2003.10.014 | s2cid = 25447645 }}
• DSIP has been found to have an analgesic effect. In studies on mice it was found to have a potent antinociceptive effect when administered intracerebroventricularly or intracisternally (see: Route of administration).{{cite journal | doi = 10.1016/0014-2999(88)90510-9 |vauthors=Nakamura A, Nakashima M, Sugao T, Kanemoto H, Fukumura Y, Shiomi H | title = Potent antinociceptive effect of centrally administered delta-sleep-inducing peptide (DSIP) | journal = Eur J Pharmacol | volume = 155 | issue = 3 | pages = 247–53 | year = 1988 | pmid = 2853064}}
• Due to its possible effects on sleep and nociception, trials have been carried out to determine whether DSIP can be used as an anaesthetic. One such study found that administration of DSIP to humans as an adjunct to isoflurane anaesthesia actually increased the heart rate and reduced the depth of anaesthesia instead of deepening it as expected.{{cite journal | doi = 10.1097/EJA.0b013e32831c8644 |vauthors=Pomfrett CJ, Dolling S, Anders NR, Glover DG, Bryan A, Pollard BJ | title = Delta sleep-inducing peptide alters bispectral index, the electroencephalogram and heart rate variability when used as an adjunct to isoflurane anaesthesia | journal = Eur J Anaesthesiol | volume = 26 | issue = 2 | pages = 128–34 | year = 2009 | pmid = 19142086|s2cid=33791960 | doi-access = free }}
• Low plasma concentrations of DSIP have been found in patients with Cushing's syndrome.{{cite journal |vauthors=Friedman TC, García-Borreguero D, Hardwick D, Akuete CN, Doppman JL, Dorn LD, Barker CN, Yanovski JA, Chrousos GP | title = Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome | journal = Neuroendocrinology | volume = 60 | issue = 6 | pages = 626–34 |date=December 1994 | pmid = 7700506 | doi = 10.1159/000126806 |url=https://zenodo.org/record/1235434}}
• In Alzheimer's patients levels of DSIP have been found to be slightly elevated, though this is unlikely to be causal.{{cite journal | doi = 10.1016/S0301-0082(01)00030-2 |vauthors=Torreilles F, Touchon J| title = Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease | journal = Progress in Neurobiology | volume = 66 | issue = 3 | pages = 191–203 | year = 2002 | pmid = 11943451|s2cid=37402263}}
• A preparation of DSIP, Deltaran, has been used to correct central nervous system function in children after antiblastic therapy. Ten children aged 3–16 years were given a ten-day course of Deltaran and their bioelectric activity recorded. It was found that the chemotherapy-induced impairment in the bioelectrical activity of 9 out of the 10 children was reduced by administration of DSIP.{{cite journal | doi = 10.1016/S0924-977X(09)71101-0 |vauthors=Sinyukhin AB, Timoshinov GP, Komilov VA, Shabanov PD | title = Delta sleep-inducing peptide analogue corrects the eNS functional state of children treated with {{sic|nolink=y|reason=error in source|antiblastomic}} therapy | journal = European Neuropsychopharmacology | volume = 19 | pages = S681–S682 | year = 2009|s2cid=54240550 }}
• DSIP can act antagonistically on opiate receptors to significantly inhibit the development of opioid and alcohol dependence and is currently being used in clinical trials to treat withdrawal syndrome.{{cite journal |vauthors=Soyka M, Rothenhaeusler H| title = Delta Sleep-Inducing Peptide Opioid Detoxification | journal = Am. J. Psychiatry | volume = 154 | issue = 5 | pages = 714–715 | year = 1997 | doi = 10.1176/ajp.154.5.714b | pmid = 9137140}}{{cite journal | doi = 10.1016/0091-3057(92)90396-W |vauthors=Yukhananov RY, Tennila TM, Miroshnichenko II, Kudrina VS, Ushakov AN, Melnik EI | title = Ethanol and Delta Sleep Inducing Peptide effects on brain monoamines | journal = Pharmacol. Biochem. Behav. | volume = 43 |issue=3 | pages = 683–687 | year = 1992|pmid=1448465 |s2cid=54364363 }} In one such trial it was reported that in 97% of opiate-dependent and 87% of alcohol-dependent patients the symptoms were alleviated by DSIP administration.{{cite journal | doi = 10.1097/00004714-199806000-00016 |vauthors=Backmund M, Meyer K, Rothenhaeusler HB, Soyka M | title = Opioid detoxification with delta sleep-inducing peptide: results of an open clinical trial. | journal = J. Clin. Psychopharmacol. | volume = 18 | issue = 3 | pages = 257–258 | year = 1998 | pmid = 9617990}}
• In some studies administration of DSIP has alleviated narcolepsy and normalized disturbed sleeping patterns.{{cite journal | doi = 10.1159/000116097 | author = Schneider-Helmert D | title = DSIP in Sleep Disturbances | journal = Eur Neurol | volume = 25 | issue = 2 | pages = 154–157 | year = 1986 | pmid = 3758119}}{{cite journal | doi = 10.1007/BF01971753 |vauthors=Schneider-Helmert D, Schoenenberger GA| title = The influence of synthetic DSIP (delta-sleep-inducing-peptide) on disturbed human sleep | journal = Cellular and Molecular Life Sciences | volume = 37 |issue=9| pages = 913–917 | year = 1981|pmid=7028502|s2cid=33195794}}

Safety and possible side-effects of long-term DSIP use haven't been established in clinical research studies.

{{Reflist|33em}}

• {{MeshName|Delta+sleep-inducing+peptide}}
• [https://web.archive.org/web/20090901201206/http://www.deltaran.com/sec/index.html "Deltaran"]

{{neuroscience}}

{{Neuropeptides}}

{{DEFAULTSORT:Delta Sleep-Inducing Peptide}}

Category:Nonapeptides

Category:Sleep physiology