Delta sleep-inducing peptide
Delta sleep-inducing peptide, abbreviated DSIP, is a neuropeptide that when infused into the mesodiencephalic ventricle of recipient rabbits induces spindle and delta EEG activity and reduced motor activities.[1]
Its aminoacid sequence is trp-ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu. However, it is the only neuropeptide in history whose gene is unknown, raising serious questions regarding the actual existence of this peptide in nature.
Discovery
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.[2]
Delta-sleep-inducing peptide (DSIP)-like material has been found in human breast milk.[3]
Structure and Interactions
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[4]
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.[5] 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.[4]
In the brain its action may be mediated by NMDA receptors.[6] In another study Delta sleep-inducing peptide stimulated Acetyltransferase activity through ***945;1 receptors in rats.[7] 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.[8] 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,[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.[10]
Gimble et al. suggest that DSIP interacts with components of the MAPK cascade and is homologous to glucocorticoid-induced leucine zipper (GILZ).[11] GILZ can be induced by Dexamethasone. It prevents Raf-1 activation, which inhibits phosphorylation and activation of ERK.[12]
Function
Many roles for DSIP have been suggested following research carried out using peptide analogues with a greater molecular stability [13] and through measuring DSIP-like immunological (DSIP-LI) response by injecting DSIP antiserum and antibodies.[14]
Roles in endocrine regulation
Decreases basal corticotropin level and blocks its release.[8]
Stimulates release of luteinizing hormone (LH).[15]
Stimulates release of somatoliberin and somatotrophin secretion and inhibits somatostatin secretion.[16]
Roles in physiological processes
Can act as a stress limiting factor.[17][18][19]
May have a direct or indirect effect on body temperature and alleviating hypothermia.[20][21][22]
Can normalize blood pressure and myocardial contraction.[8][23]
It has been shown to enhance the efficiency of oxidative phosphorylation in rat mitochondria in vitro, suggesting it may have antioxidant effects.[19]
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[24][25] and suppression of paradoxical sleep, (PS)[26][27] while some studies show no correlation.[28] Stronger effects on sleep have been noted for the synthesized analogues of DSIP.[29]
It may have an impact on human lens epithelial cell function via the MAPK pathway, which is involved in cell proliferation, differentiation, motility, survival, and apoptosis.[12]
Roles in Disease and Medicine
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.[30]
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.[10][31][32]
Studies have demonstrated a direct link between GILZ expression (homologous to DSIP) and adipogenesis which has links to obesity and ********* syndrome.[33]
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.[34][35]
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).[36]
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.[37]
Low plasma concentrations of DSIP have been found in patients with Cushing's syndrome.[38]
In Alzheimer's patients levels of DSIP have been found to be slightly elevated, though this is unlikely to be causal.[39]
A preparation of DSIP, Deltaran, has been used to correct central nervous system function in children after antiblastomic 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.[40]
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.[41][42] 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.[43]
In some studies administration of DSIP has alleviated narcolepsy and normalized disturbed sleeping patterns.[44][45]
Safety and possible side-effects of long-term DSIP use hasn't been established in clinical research studies.
References
1^ Monnier M, Dudler L, G?chter R, Maier PF, Tobler HJ, Schoenenberger GA (April 1977). "The delta sleep inducing peptide (DSIP). Comparative properties of the original and synthetic nonapeptide". Experientia 33 (4): 548?52. doi:10.1007/BF01922266. PMID 862769.
2^ Schoenenberger GA, Maier PF, Tobler HJ and Monnier M (1977). "A naturally occurring delta-EEG enhancing nonapeptide in rabbits". European Journal of Physiology 369 (2): 99?109. doi:10.1007/BF00591565. PMID 560681.
3^ Graf MV, Hunter CA, Kastin AJ (1984). "Presence of Delta-Sleep-Inducing Peptide-Like Material in Human Milk". Journal of Clinical Endocrinology & Metabolism 59 (1): 127?32. doi:10.1210/jcem-59-1-127. PMID 6547144.
4^ a b Kovalzon VM and Strekalova TV (2006). "Delta sleep-inducing peptide (DSIP): a still unresolved riddle". Journal of Neurochemistry 97 (2): 303?309. doi:10.1111/j.1471-4159.2006.03693.x. PMID 16539679.
5^ Charnay Y, Bouras C, Vallet PG, Golaz J, Guntern R, Constantinidis J (1989). "Immunohistochemical distribution of delta sleep inducing peptide in the rabbit brain and hypophysis". Neuroendocrinology 49 (2): 169?175. doi:10.1159/000125110. PMID 2657475.
6^ Sudakova KV, Umriukhina PE, Rayevskyb KS (2004). "Delta-sleep inducing peptide and neuronal activity after glutamate microiontophoresis: the role of NMDA-receptors". Pathophysiology 11 (2): 81?86. doi:10.1016/j.pathophys.2004.03.003. PMID 15364118.
7^ Graf MV, Schoenenberger, GA (1987). "Delta Sleep-Inducing Peptide Modulates the Stimulation of Rat Pineal N-Acetyltransferase Activity by Involving the ***945;1-Adrenergic Receptor". Journal of Neurochemistry 48 (4): 1252?1257. doi:10.1111/j.1471-4159.1987.tb05654.x. PMID 3029331.
8^ a b c Schoenenberger GA (1984). "Characterization, properties and multivariate functions of Delta-Sleep Inducing Peptide (DSIP)". European Neurology 23 (5): 321?345. doi:10.1159/000115711. PMID 6548966.
9^ Inou? S and Borbely AA, ed. (1985). Endogenous Sleep Substances And Sleep Regulation: Proceedings of the Taniguchi Symposia on Brain Sciences. Boston: Brill Academic Publishers. ISBN 90-6764-058-1.
10^ a b Westrin A, Ekman R, and Traskman-Bendz L (1998). "High Delta Sleep-Inducing Peptide-Like Immunoreactivity in Plasma in Suicidal Patients with Major Depressive Disorder". Biological Psychiatry 43 (10): 734?739. doi:10.1016/S0006-3223(97)00254-0. PMID 9606527.
11^ Gimble JM, Ptitsyn AA, Goh BC, Hebert T, Yu G, Wu X, Zvonic S, Shi X-M and Floyd ZE (2009). "Delta sleep-inducing peptide and glucocorticoidinduced leucine zipper: potential links between circadian mechanisms and obesity?". Obesity reviews 10: 46?51. doi:10.1111/j.1467-789X.2009.00661.x. PMID 19849801.
12^ a b Gupta V, Awasthi N and Wagner BJ (2007). "Specific Activation of the Glucocorticoid Receptor and Modulation of Signal Transduction Pathways in Human Lens Epithelial Cells". Investigative Ophthalmology and Visual Science 48 (4): 1724?1734. doi:10.1167/iovs.06-0889. PMC 2814520. PMID 17389505.
13^ synthesized 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
14^ Charnay Y, Golaz J, Vallet PG, Bouras C (1992). "Production and immunohistochemical application of monoclonal antibodies against delta sleep-inducing peptide". J Chem Neuroanat 5 (6): 503?9. doi:10.1016/0891-0618(92)90005-B. PMID 1476667.
15^ Iyer KS and McCann SM (1987). "Delta sleep inducing peptide (DSIP) stimulates the release of LH but not FSH via a hypothalamic site of action in the rat". Brain Research Bulletin 15 (5): 535?538. doi:10.1016/0361-9230(87)90069-4. PMID 3121137.
16^ Koval'zon VM (1994). "[DSIP: the sleep peptide or an unknown hypothalamic hormone?]" (in Russian). Zh. Evol. Biokhim. Fiziol. 30 (2): 310?9. PMID 7817664.: Kovalzon VM (1994). "DSIP: a sleep peptide or unknown hypothalamic hormone?". J. Evol. Biochem. Physiol. 30: 195?199.
17^ Kitayama I, Kawguchi S Murase S, Otani M, Takayama M, Nakamura T Komoiri T Nomura, Natotani N, Fuse K (1992). "Noradrenergic and neuroendocrine function in chronic walking stress-induced model of depression in rats". In Kvet***328;ansk? R, McCarty R, Axelrod J. Stress: Neuroendocrine and Molecular Approaches. Boca Raton: CRC Press. pp. 59?72. ISBN 2-88124-506-4.
18^ Sudakova KV, Coghlan JP, Kotov AV, Salieva RM, Polyntsev YV, Koplik EV (1995). "Delta-sleep inducing peptide sequels in mechanisms of resistance to emotional stress". Ann. N.Y. Acad. Sci. 771: 240?251. doi:10.1111/j.1749-6632.1995.tb44685.x. PMID 8597403.
19^ a b Khvatova EM, Samartzev VN, Zagoskin PP, Prudchenko IA, Mikhaleva II (2003). "Delta sleep inducing peptide (DSIP): effect on respiration activity in rat brain mitochondria and stress protective potency under experimental hypoxia". Peptides 24 (2): 307?311. doi:10.1016/S0196-9781(03)00040-8. PMID 12668217.
20^ Pollard BJ and Pomfrett CJD (2001). "Delta sleep-inducing peptide". Eur. J. Anaesthesiol. 18 (7): 419?422. PMID 11437870.
21^ Yehuda S, Kastin AJ and Coy DH (1980). "Thermoragulatory and locomotor effects of DSIP: paradoxical interaction with d-amphetamine". Pharmacol. Biochem. Behav. 13 (6): 895?900. doi:10.1016/0091-3057(80)90225-7. PMID 6894196.
22^ Yehuda S and Mostofsky DI (1984). "Modification of the hypothermic circadian cycles induced by DSIP and melatonin in pinealectomized and hypophysectomised rats". Peptides 5 (3): 495?497. doi:10.1016/0196-9781(84)90076-7. PMID 6548024.
23^ Yehuda S, Carasso RL (February 1988). "DSIP--a tool for investigating the sleep onset mechanism: a review". Int. J. Neurosci. 38 (3-4): 345?53. doi:10.3109/00207458808990695. PMID 3286557.
24^ Iyer KS, Marks GA, Kastin AJ, and McCann SM (1988). "Evidence for a role of delta sleep-inducing peptide in slow-wave sleep and sleep-related growth hormone release in the rat". Proc Natl Acad Sci U S A 85 (10): 3653?3656. doi:10.1073/pnas.85.10.3653. PMC 280272. PMID 3368469.
25^ Susi***263; V, Masirevi***263; G, Toti***263; S (1987). "The effects of delta-sleep-inducing peptide (DSIP) on wakefulness and sleep patterns in the cat". Brain Research 414 (2): 262?70. doi:10.1016/0006-8993(87)90006-0. PMID 3620931.
26^ Seifritz E, Muller M, Schonenberger G, Trachsel L, Hemmeter U, Hatzinger M, Ernst A, Moore P and Holsboer-Trachsler E (1995). "Human plasma DSIP decreases at the initiation of sleep at different circadian times". Peptides 16 (8): 1475?1481. doi:10.1016/0196-9781(95)02027-6. PMID 8745061.
27^ Steiger A and Holsboer F (1997). "Neuropeptides and human sleep". Sleep 20 (11): 1038?1052. PMID 9456470.
28^ Nakagaki K, Ebihara S, Usui S, Honda Y, Takahashi Y, Kato N (1986). "Effects of intraventricular injection of anti-DSIP serum on sleep in rats". Yakubutsu Seishin Kodo (Japanese journal of psychopharmacology) 6: 259?65.
29^ Kovalzon VM (2001). "Sleep-Inducing Properties of DSIP Analogs: Structural and Functional Relationships". Biology Bulletin 28: 394?400. doi:10.1023/A:1016679208936.
30^ Popovich IG, Voitenkov BO, Anisimov VN, Ivanov VT, Mikhaleva II, Zabezhinski MA, Alimova IN, Baturin DA, Zavarzina NY, Rosenfeld SV, Semenchenko AV, Yashin Aromatase inhibitor (AI) (2003). "Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice". Mechanisms of Ageing and Development 124 (6): 721?731. doi:10.1016/S0047-6374(03)00082-4. PMID 12782416.
31^ Walleus H, Widerl?v E and Ekman R (1985). "Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients". Nordic Journal of Psychiatry 39: 63?67. doi:10.3109/08039488509101959.
32^ Bjartell A, Ekman R, Sundler F and Widerl?v E (1988). "Delta sleep-inducing peptide (DSIP): An overview of central actions and possible relationship to psychiatric illnesses". Nordic Journal of Psychiatry 42: 111?117. doi:10.3109/08039488809103215.
33^ Shi X, Shi W, Li Q, Song B, Wan M, Bai S (2003). "A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells". EMBO Rep 4 (4): 374?380. doi:10.1038/sj.embor.embor805. PMC 1319161. PMID 12671681.
34^ Stanojilovic OP, Zivanovic DP and Su Sic VT (2002). "The effects of Delta Sleep-Inducing Peptide on incidence and severity in metaphit-induced epilepsy in rats". Pharmacological Research 45 (3): 241?247. doi:10.1006/phrs.2001.0938. PMID 11884222.
35^ Stanojlovi***263; O, Zivanovi***263; D, Mirkovi***263; S, Mikhaleva I (February 2004). "Delta sleep-inducing peptide and its tetrapeptide analogue alleviate severity of metaphit seizures". Pharmacol. Biochem. Behav. 77 (2): 227?34. doi:10.1016/j.pbb.2003.10.014. PMID 14751449.
36^ Nakamura A, Nakashima M, Sugao T, Kanemoto H, Fukumura Y, Shiomi H (1988). "Potent antinociceptive effect of centrally administered delta-sleep-inducing peptide (DSIP)". Eur J Pharmacol 155 (3): 247?53. doi:10.1016/0014-2999(88)90510-9. PMID 2853064.
37^ Pomfrett CJD, Dolling S, Anders NRK, Glover DG, Bryan A, Pollard BJ (2009). "Delta sleep-inducing peptide alters bispectral index, the electroencephalogram and heart rate variability when used as an adjunct to isoflurane anaesthesia". Eur J Anaesthesiol 26 (2): 128?34. doi:10.1097/EJA.0b013e32831c8644. PMID 19142086.
38^ Friedman TC, Garc?a-Borreguero D, Hardwick D, Akuete CN, Doppman JL, Dorn LD, Barker CN, Yanovski JA, Chrousos GP (December 1994). "Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome". Neuroendocrinology 60 (6): 626?34. doi:10.1159/000126806. PMID 7700506.
39^ Torreilles F and Touchon J (2002). "Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease". Progress in Neurobiology 66 (3): 191?203. doi:10.1016/S0301-0082(01)00030-2. PMID 11943451.
40^ Sinyukhin AB, Timoshinov GP, Komilov VA, Shabanov PD (2009). "Delta sleep-inducing peptide analogue corrects the eNS functional state of children treated with antiblastomic therapy". European Neuropsychopharmacology 19: S681. doi:10.1016/S0924-977X(09)71101-0.
41^ Soyka M and Rothenhaeusler H (1997). "Delta Sleep-Inducing Peptide Opioid Detoxi***64257;cation". Am. J. Psychiat. 154 (5): 714?715. PMID 9137140.
42^ Yukhananov RY, Tennila TML, Miroshnichenko II, Kudrina VS, Ushakov AN and Melnik EI (1992). "Ethanol and Delta Sleep Inducing Peptide effects on brain monoamines". Pharmacol. Bio-chem. Behav. 43: 683?687. doi:10.1016/0091-3057(92)90396-W.
43^ Backmund M, Meyer K, Rothenhaeusler HB and Soyka M (1998). "Opioid detoxi***64257;cation with delta sleep-inducing peptide: results of an open clinical trial.". J. Clin. Psychopharmacol. 18 (3): 257?258. doi:10.1097/00004714-199806000-00016. PMID 9617990.
44^ Schneider-Helmert D (1986). "DSIP in Sleep Disturbances". Eur Neurol 25: 154?157. doi:10.1159/000116097. PMID 3758119.
45^ Schneider-Helmert D and Schoenenberger GA (1981). "The influence of synthetic DSIP (delta-sleep-inducing-peptide) on disturbed human sleep". Cellular and Molecular Life Sciences 37: 913?917. doi:10.1007/BF01971753
Delta sleep-inducing peptide, abbreviated DSIP, is a neuropeptide that when infused into the mesodiencephalic ventricle of recipient rabbits induces spindle and delta EEG activity and reduced motor activities.[1]
Its aminoacid sequence is trp-ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu. However, it is the only neuropeptide in history whose gene is unknown, raising serious questions regarding the actual existence of this peptide in nature.
Discovery
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.[2]
Delta-sleep-inducing peptide (DSIP)-like material has been found in human breast milk.[3]
Structure and Interactions
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[4]
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.[5] 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.[4]
In the brain its action may be mediated by NMDA receptors.[6] In another study Delta sleep-inducing peptide stimulated Acetyltransferase activity through ***945;1 receptors in rats.[7] 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.[8] 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,[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.[10]
Gimble et al. suggest that DSIP interacts with components of the MAPK cascade and is homologous to glucocorticoid-induced leucine zipper (GILZ).[11] GILZ can be induced by Dexamethasone. It prevents Raf-1 activation, which inhibits phosphorylation and activation of ERK.[12]
Function
Many roles for DSIP have been suggested following research carried out using peptide analogues with a greater molecular stability [13] and through measuring DSIP-like immunological (DSIP-LI) response by injecting DSIP antiserum and antibodies.[14]
Roles in endocrine regulation
Decreases basal corticotropin level and blocks its release.[8]
Stimulates release of luteinizing hormone (LH).[15]
Stimulates release of somatoliberin and somatotrophin secretion and inhibits somatostatin secretion.[16]
Roles in physiological processes
Can act as a stress limiting factor.[17][18][19]
May have a direct or indirect effect on body temperature and alleviating hypothermia.[20][21][22]
Can normalize blood pressure and myocardial contraction.[8][23]
It has been shown to enhance the efficiency of oxidative phosphorylation in rat mitochondria in vitro, suggesting it may have antioxidant effects.[19]
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[24][25] and suppression of paradoxical sleep, (PS)[26][27] while some studies show no correlation.[28] Stronger effects on sleep have been noted for the synthesized analogues of DSIP.[29]
It may have an impact on human lens epithelial cell function via the MAPK pathway, which is involved in cell proliferation, differentiation, motility, survival, and apoptosis.[12]
Roles in Disease and Medicine
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.[30]
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.[10][31][32]
Studies have demonstrated a direct link between GILZ expression (homologous to DSIP) and adipogenesis which has links to obesity and ********* syndrome.[33]
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.[34][35]
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).[36]
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.[37]
Low plasma concentrations of DSIP have been found in patients with Cushing's syndrome.[38]
In Alzheimer's patients levels of DSIP have been found to be slightly elevated, though this is unlikely to be causal.[39]
A preparation of DSIP, Deltaran, has been used to correct central nervous system function in children after antiblastomic 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.[40]
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.[41][42] 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.[43]
In some studies administration of DSIP has alleviated narcolepsy and normalized disturbed sleeping patterns.[44][45]
Safety and possible side-effects of long-term DSIP use hasn't been established in clinical research studies.
References
1^ Monnier M, Dudler L, G?chter R, Maier PF, Tobler HJ, Schoenenberger GA (April 1977). "The delta sleep inducing peptide (DSIP). Comparative properties of the original and synthetic nonapeptide". Experientia 33 (4): 548?52. doi:10.1007/BF01922266. PMID 862769.
2^ Schoenenberger GA, Maier PF, Tobler HJ and Monnier M (1977). "A naturally occurring delta-EEG enhancing nonapeptide in rabbits". European Journal of Physiology 369 (2): 99?109. doi:10.1007/BF00591565. PMID 560681.
3^ Graf MV, Hunter CA, Kastin AJ (1984). "Presence of Delta-Sleep-Inducing Peptide-Like Material in Human Milk". Journal of Clinical Endocrinology & Metabolism 59 (1): 127?32. doi:10.1210/jcem-59-1-127. PMID 6547144.
4^ a b Kovalzon VM and Strekalova TV (2006). "Delta sleep-inducing peptide (DSIP): a still unresolved riddle". Journal of Neurochemistry 97 (2): 303?309. doi:10.1111/j.1471-4159.2006.03693.x. PMID 16539679.
5^ Charnay Y, Bouras C, Vallet PG, Golaz J, Guntern R, Constantinidis J (1989). "Immunohistochemical distribution of delta sleep inducing peptide in the rabbit brain and hypophysis". Neuroendocrinology 49 (2): 169?175. doi:10.1159/000125110. PMID 2657475.
6^ Sudakova KV, Umriukhina PE, Rayevskyb KS (2004). "Delta-sleep inducing peptide and neuronal activity after glutamate microiontophoresis: the role of NMDA-receptors". Pathophysiology 11 (2): 81?86. doi:10.1016/j.pathophys.2004.03.003. PMID 15364118.
7^ Graf MV, Schoenenberger, GA (1987). "Delta Sleep-Inducing Peptide Modulates the Stimulation of Rat Pineal N-Acetyltransferase Activity by Involving the ***945;1-Adrenergic Receptor". Journal of Neurochemistry 48 (4): 1252?1257. doi:10.1111/j.1471-4159.1987.tb05654.x. PMID 3029331.
8^ a b c Schoenenberger GA (1984). "Characterization, properties and multivariate functions of Delta-Sleep Inducing Peptide (DSIP)". European Neurology 23 (5): 321?345. doi:10.1159/000115711. PMID 6548966.
9^ Inou? S and Borbely AA, ed. (1985). Endogenous Sleep Substances And Sleep Regulation: Proceedings of the Taniguchi Symposia on Brain Sciences. Boston: Brill Academic Publishers. ISBN 90-6764-058-1.
10^ a b Westrin A, Ekman R, and Traskman-Bendz L (1998). "High Delta Sleep-Inducing Peptide-Like Immunoreactivity in Plasma in Suicidal Patients with Major Depressive Disorder". Biological Psychiatry 43 (10): 734?739. doi:10.1016/S0006-3223(97)00254-0. PMID 9606527.
11^ Gimble JM, Ptitsyn AA, Goh BC, Hebert T, Yu G, Wu X, Zvonic S, Shi X-M and Floyd ZE (2009). "Delta sleep-inducing peptide and glucocorticoidinduced leucine zipper: potential links between circadian mechanisms and obesity?". Obesity reviews 10: 46?51. doi:10.1111/j.1467-789X.2009.00661.x. PMID 19849801.
12^ a b Gupta V, Awasthi N and Wagner BJ (2007). "Specific Activation of the Glucocorticoid Receptor and Modulation of Signal Transduction Pathways in Human Lens Epithelial Cells". Investigative Ophthalmology and Visual Science 48 (4): 1724?1734. doi:10.1167/iovs.06-0889. PMC 2814520. PMID 17389505.
13^ synthesized 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
14^ Charnay Y, Golaz J, Vallet PG, Bouras C (1992). "Production and immunohistochemical application of monoclonal antibodies against delta sleep-inducing peptide". J Chem Neuroanat 5 (6): 503?9. doi:10.1016/0891-0618(92)90005-B. PMID 1476667.
15^ Iyer KS and McCann SM (1987). "Delta sleep inducing peptide (DSIP) stimulates the release of LH but not FSH via a hypothalamic site of action in the rat". Brain Research Bulletin 15 (5): 535?538. doi:10.1016/0361-9230(87)90069-4. PMID 3121137.
16^ Koval'zon VM (1994). "[DSIP: the sleep peptide or an unknown hypothalamic hormone?]" (in Russian). Zh. Evol. Biokhim. Fiziol. 30 (2): 310?9. PMID 7817664.: Kovalzon VM (1994). "DSIP: a sleep peptide or unknown hypothalamic hormone?". J. Evol. Biochem. Physiol. 30: 195?199.
17^ Kitayama I, Kawguchi S Murase S, Otani M, Takayama M, Nakamura T Komoiri T Nomura, Natotani N, Fuse K (1992). "Noradrenergic and neuroendocrine function in chronic walking stress-induced model of depression in rats". In Kvet***328;ansk? R, McCarty R, Axelrod J. Stress: Neuroendocrine and Molecular Approaches. Boca Raton: CRC Press. pp. 59?72. ISBN 2-88124-506-4.
18^ Sudakova KV, Coghlan JP, Kotov AV, Salieva RM, Polyntsev YV, Koplik EV (1995). "Delta-sleep inducing peptide sequels in mechanisms of resistance to emotional stress". Ann. N.Y. Acad. Sci. 771: 240?251. doi:10.1111/j.1749-6632.1995.tb44685.x. PMID 8597403.
19^ a b Khvatova EM, Samartzev VN, Zagoskin PP, Prudchenko IA, Mikhaleva II (2003). "Delta sleep inducing peptide (DSIP): effect on respiration activity in rat brain mitochondria and stress protective potency under experimental hypoxia". Peptides 24 (2): 307?311. doi:10.1016/S0196-9781(03)00040-8. PMID 12668217.
20^ Pollard BJ and Pomfrett CJD (2001). "Delta sleep-inducing peptide". Eur. J. Anaesthesiol. 18 (7): 419?422. PMID 11437870.
21^ Yehuda S, Kastin AJ and Coy DH (1980). "Thermoragulatory and locomotor effects of DSIP: paradoxical interaction with d-amphetamine". Pharmacol. Biochem. Behav. 13 (6): 895?900. doi:10.1016/0091-3057(80)90225-7. PMID 6894196.
22^ Yehuda S and Mostofsky DI (1984). "Modification of the hypothermic circadian cycles induced by DSIP and melatonin in pinealectomized and hypophysectomised rats". Peptides 5 (3): 495?497. doi:10.1016/0196-9781(84)90076-7. PMID 6548024.
23^ Yehuda S, Carasso RL (February 1988). "DSIP--a tool for investigating the sleep onset mechanism: a review". Int. J. Neurosci. 38 (3-4): 345?53. doi:10.3109/00207458808990695. PMID 3286557.
24^ Iyer KS, Marks GA, Kastin AJ, and McCann SM (1988). "Evidence for a role of delta sleep-inducing peptide in slow-wave sleep and sleep-related growth hormone release in the rat". Proc Natl Acad Sci U S A 85 (10): 3653?3656. doi:10.1073/pnas.85.10.3653. PMC 280272. PMID 3368469.
25^ Susi***263; V, Masirevi***263; G, Toti***263; S (1987). "The effects of delta-sleep-inducing peptide (DSIP) on wakefulness and sleep patterns in the cat". Brain Research 414 (2): 262?70. doi:10.1016/0006-8993(87)90006-0. PMID 3620931.
26^ Seifritz E, Muller M, Schonenberger G, Trachsel L, Hemmeter U, Hatzinger M, Ernst A, Moore P and Holsboer-Trachsler E (1995). "Human plasma DSIP decreases at the initiation of sleep at different circadian times". Peptides 16 (8): 1475?1481. doi:10.1016/0196-9781(95)02027-6. PMID 8745061.
27^ Steiger A and Holsboer F (1997). "Neuropeptides and human sleep". Sleep 20 (11): 1038?1052. PMID 9456470.
28^ Nakagaki K, Ebihara S, Usui S, Honda Y, Takahashi Y, Kato N (1986). "Effects of intraventricular injection of anti-DSIP serum on sleep in rats". Yakubutsu Seishin Kodo (Japanese journal of psychopharmacology) 6: 259?65.
29^ Kovalzon VM (2001). "Sleep-Inducing Properties of DSIP Analogs: Structural and Functional Relationships". Biology Bulletin 28: 394?400. doi:10.1023/A:1016679208936.
30^ Popovich IG, Voitenkov BO, Anisimov VN, Ivanov VT, Mikhaleva II, Zabezhinski MA, Alimova IN, Baturin DA, Zavarzina NY, Rosenfeld SV, Semenchenko AV, Yashin Aromatase inhibitor (AI) (2003). "Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice". Mechanisms of Ageing and Development 124 (6): 721?731. doi:10.1016/S0047-6374(03)00082-4. PMID 12782416.
31^ Walleus H, Widerl?v E and Ekman R (1985). "Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients". Nordic Journal of Psychiatry 39: 63?67. doi:10.3109/08039488509101959.
32^ Bjartell A, Ekman R, Sundler F and Widerl?v E (1988). "Delta sleep-inducing peptide (DSIP): An overview of central actions and possible relationship to psychiatric illnesses". Nordic Journal of Psychiatry 42: 111?117. doi:10.3109/08039488809103215.
33^ Shi X, Shi W, Li Q, Song B, Wan M, Bai S (2003). "A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells". EMBO Rep 4 (4): 374?380. doi:10.1038/sj.embor.embor805. PMC 1319161. PMID 12671681.
34^ Stanojilovic OP, Zivanovic DP and Su Sic VT (2002). "The effects of Delta Sleep-Inducing Peptide on incidence and severity in metaphit-induced epilepsy in rats". Pharmacological Research 45 (3): 241?247. doi:10.1006/phrs.2001.0938. PMID 11884222.
35^ Stanojlovi***263; O, Zivanovi***263; D, Mirkovi***263; S, Mikhaleva I (February 2004). "Delta sleep-inducing peptide and its tetrapeptide analogue alleviate severity of metaphit seizures". Pharmacol. Biochem. Behav. 77 (2): 227?34. doi:10.1016/j.pbb.2003.10.014. PMID 14751449.
36^ Nakamura A, Nakashima M, Sugao T, Kanemoto H, Fukumura Y, Shiomi H (1988). "Potent antinociceptive effect of centrally administered delta-sleep-inducing peptide (DSIP)". Eur J Pharmacol 155 (3): 247?53. doi:10.1016/0014-2999(88)90510-9. PMID 2853064.
37^ Pomfrett CJD, Dolling S, Anders NRK, Glover DG, Bryan A, Pollard BJ (2009). "Delta sleep-inducing peptide alters bispectral index, the electroencephalogram and heart rate variability when used as an adjunct to isoflurane anaesthesia". Eur J Anaesthesiol 26 (2): 128?34. doi:10.1097/EJA.0b013e32831c8644. PMID 19142086.
38^ Friedman TC, Garc?a-Borreguero D, Hardwick D, Akuete CN, Doppman JL, Dorn LD, Barker CN, Yanovski JA, Chrousos GP (December 1994). "Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome". Neuroendocrinology 60 (6): 626?34. doi:10.1159/000126806. PMID 7700506.
39^ Torreilles F and Touchon J (2002). "Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease". Progress in Neurobiology 66 (3): 191?203. doi:10.1016/S0301-0082(01)00030-2. PMID 11943451.
40^ Sinyukhin AB, Timoshinov GP, Komilov VA, Shabanov PD (2009). "Delta sleep-inducing peptide analogue corrects the eNS functional state of children treated with antiblastomic therapy". European Neuropsychopharmacology 19: S681. doi:10.1016/S0924-977X(09)71101-0.
41^ Soyka M and Rothenhaeusler H (1997). "Delta Sleep-Inducing Peptide Opioid Detoxi***64257;cation". Am. J. Psychiat. 154 (5): 714?715. PMID 9137140.
42^ Yukhananov RY, Tennila TML, Miroshnichenko II, Kudrina VS, Ushakov AN and Melnik EI (1992). "Ethanol and Delta Sleep Inducing Peptide effects on brain monoamines". Pharmacol. Bio-chem. Behav. 43: 683?687. doi:10.1016/0091-3057(92)90396-W.
43^ Backmund M, Meyer K, Rothenhaeusler HB and Soyka M (1998). "Opioid detoxi***64257;cation with delta sleep-inducing peptide: results of an open clinical trial.". J. Clin. Psychopharmacol. 18 (3): 257?258. doi:10.1097/00004714-199806000-00016. PMID 9617990.
44^ Schneider-Helmert D (1986). "DSIP in Sleep Disturbances". Eur Neurol 25: 154?157. doi:10.1159/000116097. PMID 3758119.
45^ Schneider-Helmert D and Schoenenberger GA (1981). "The influence of synthetic DSIP (delta-sleep-inducing-peptide) on disturbed human sleep". Cellular and Molecular Life Sciences 37: 913?917. doi:10.1007/BF01971753
Delta sleep-inducing peptide, abbreviated DSIP, is a neuropeptide that when infused into the mesodiencephalic ventricle of recipient rabbits induces spindle and delta EEG activity and reduced motor activities.[1]
Its aminoacid sequence is trp-ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu. However, it is the only neuropeptide in history whose gene is unknown, raising serious questions regarding the actual existence of this peptide in nature.
Discovery
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.[2]
Delta-sleep-inducing peptide (DSIP)-like material has been found in human breast milk.[3]
Structure and Interactions
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[4]
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.[5] 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.[4]
In the brain its action may be mediated by NMDA receptors.[6] In another study Delta sleep-inducing peptide stimulated Acetyltransferase activity through ***945;1 receptors in rats.[7] 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.[8] 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,[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.[10]
Gimble et al. suggest that DSIP interacts with components of the MAPK cascade and is homologous to glucocorticoid-induced leucine zipper (GILZ).[11] GILZ can be induced by Dexamethasone. It prevents Raf-1 activation, which inhibits phosphorylation and activation of ERK.[12]
Function
Many roles for DSIP have been suggested following research carried out using peptide analogues with a greater molecular stability [13] and through measuring DSIP-like immunological (DSIP-LI) response by injecting DSIP antiserum and antibodies.[14]
Roles in endocrine regulation
Decreases basal corticotropin level and blocks its release.[8]
Stimulates release of luteinizing hormone (LH).[15]
Stimulates release of somatoliberin and somatotrophin secretion and inhibits somatostatin secretion.[16]
Roles in physiological processes
Can act as a stress limiting factor.[17][18][19]
May have a direct or indirect effect on body temperature and alleviating hypothermia.[20][21][22]
Can normalize blood pressure and myocardial contraction.[8][23]
It has been shown to enhance the efficiency of oxidative phosphorylation in rat mitochondria in vitro, suggesting it may have antioxidant effects.[19]
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[24][25] and suppression of paradoxical sleep, (PS)[26][27] while some studies show no correlation.[28] Stronger effects on sleep have been noted for the synthesized analogues of DSIP.[29]
It may have an impact on human lens epithelial cell function via the MAPK pathway, which is involved in cell proliferation, differentiation, motility, survival, and apoptosis.[12]
Roles in Disease and Medicine
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.[30]
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.[10][31][32]
Studies have demonstrated a direct link between GILZ expression (homologous to DSIP) and adipogenesis which has links to obesity and ********* syndrome.[33]
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.[34][35]
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).[36]
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.[37]
Low plasma concentrations of DSIP have been found in patients with Cushing's syndrome.[38]
In Alzheimer's patients levels of DSIP have been found to be slightly elevated, though this is unlikely to be causal.[39]
A preparation of DSIP, Deltaran, has been used to correct central nervous system function in children after antiblastomic 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.[40]
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.[41][42] 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.[43]
In some studies administration of DSIP has alleviated narcolepsy and normalized disturbed sleeping patterns.[44][45]
Safety and possible side-effects of long-term DSIP use hasn't been established in clinical research studies.
References
1^ Monnier M, Dudler L, G?chter R, Maier PF, Tobler HJ, Schoenenberger GA (April 1977). "The delta sleep inducing peptide (DSIP). Comparative properties of the original and synthetic nonapeptide". Experientia 33 (4): 548?52. doi:10.1007/BF01922266. PMID 862769.
2^ Schoenenberger GA, Maier PF, Tobler HJ and Monnier M (1977). "A naturally occurring delta-EEG enhancing nonapeptide in rabbits". European Journal of Physiology 369 (2): 99?109. doi:10.1007/BF00591565. PMID 560681.
3^ Graf MV, Hunter CA, Kastin AJ (1984). "Presence of Delta-Sleep-Inducing Peptide-Like Material in Human Milk". Journal of Clinical Endocrinology & Metabolism 59 (1): 127?32. doi:10.1210/jcem-59-1-127. PMID 6547144.
4^ a b Kovalzon VM and Strekalova TV (2006). "Delta sleep-inducing peptide (DSIP): a still unresolved riddle". Journal of Neurochemistry 97 (2): 303?309. doi:10.1111/j.1471-4159.2006.03693.x. PMID 16539679.
5^ Charnay Y, Bouras C, Vallet PG, Golaz J, Guntern R, Constantinidis J (1989). "Immunohistochemical distribution of delta sleep inducing peptide in the rabbit brain and hypophysis". Neuroendocrinology 49 (2): 169?175. doi:10.1159/000125110. PMID 2657475.
6^ Sudakova KV, Umriukhina PE, Rayevskyb KS (2004). "Delta-sleep inducing peptide and neuronal activity after glutamate microiontophoresis: the role of NMDA-receptors". Pathophysiology 11 (2): 81?86. doi:10.1016/j.pathophys.2004.03.003. PMID 15364118.
7^ Graf MV, Schoenenberger, GA (1987). "Delta Sleep-Inducing Peptide Modulates the Stimulation of Rat Pineal N-Acetyltransferase Activity by Involving the ***945;1-Adrenergic Receptor". Journal of Neurochemistry 48 (4): 1252?1257. doi:10.1111/j.1471-4159.1987.tb05654.x. PMID 3029331.
8^ a b c Schoenenberger GA (1984). "Characterization, properties and multivariate functions of Delta-Sleep Inducing Peptide (DSIP)". European Neurology 23 (5): 321?345. doi:10.1159/000115711. PMID 6548966.
9^ Inou? S and Borbely AA, ed. (1985). Endogenous Sleep Substances And Sleep Regulation: Proceedings of the Taniguchi Symposia on Brain Sciences. Boston: Brill Academic Publishers. ISBN 90-6764-058-1.
10^ a b Westrin A, Ekman R, and Traskman-Bendz L (1998). "High Delta Sleep-Inducing Peptide-Like Immunoreactivity in Plasma in Suicidal Patients with Major Depressive Disorder". Biological Psychiatry 43 (10): 734?739. doi:10.1016/S0006-3223(97)00254-0. PMID 9606527.
11^ Gimble JM, Ptitsyn AA, Goh BC, Hebert T, Yu G, Wu X, Zvonic S, Shi X-M and Floyd ZE (2009). "Delta sleep-inducing peptide and glucocorticoidinduced leucine zipper: potential links between circadian mechanisms and obesity?". Obesity reviews 10: 46?51. doi:10.1111/j.1467-789X.2009.00661.x. PMID 19849801.
12^ a b Gupta V, Awasthi N and Wagner BJ (2007). "Specific Activation of the Glucocorticoid Receptor and Modulation of Signal Transduction Pathways in Human Lens Epithelial Cells". Investigative Ophthalmology and Visual Science 48 (4): 1724?1734. doi:10.1167/iovs.06-0889. PMC 2814520. PMID 17389505.
13^ synthesized 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
14^ Charnay Y, Golaz J, Vallet PG, Bouras C (1992). "Production and immunohistochemical application of monoclonal antibodies against delta sleep-inducing peptide". J Chem Neuroanat 5 (6): 503?9. doi:10.1016/0891-0618(92)90005-B. PMID 1476667.
15^ Iyer KS and McCann SM (1987). "Delta sleep inducing peptide (DSIP) stimulates the release of LH but not FSH via a hypothalamic site of action in the rat". Brain Research Bulletin 15 (5): 535?538. doi:10.1016/0361-9230(87)90069-4. PMID 3121137.
16^ Koval'zon VM (1994). "[DSIP: the sleep peptide or an unknown hypothalamic hormone?]" (in Russian). Zh. Evol. Biokhim. Fiziol. 30 (2): 310?9. PMID 7817664.: Kovalzon VM (1994). "DSIP: a sleep peptide or unknown hypothalamic hormone?". J. Evol. Biochem. Physiol. 30: 195?199.
17^ Kitayama I, Kawguchi S Murase S, Otani M, Takayama M, Nakamura T Komoiri T Nomura, Natotani N, Fuse K (1992). "Noradrenergic and neuroendocrine function in chronic walking stress-induced model of depression in rats". In Kvet***328;ansk? R, McCarty R, Axelrod J. Stress: Neuroendocrine and Molecular Approaches. Boca Raton: CRC Press. pp. 59?72. ISBN 2-88124-506-4.
18^ Sudakova KV, Coghlan JP, Kotov AV, Salieva RM, Polyntsev YV, Koplik EV (1995). "Delta-sleep inducing peptide sequels in mechanisms of resistance to emotional stress". Ann. N.Y. Acad. Sci. 771: 240?251. doi:10.1111/j.1749-6632.1995.tb44685.x. PMID 8597403.
19^ a b Khvatova EM, Samartzev VN, Zagoskin PP, Prudchenko IA, Mikhaleva II (2003). "Delta sleep inducing peptide (DSIP): effect on respiration activity in rat brain mitochondria and stress protective potency under experimental hypoxia". Peptides 24 (2): 307?311. doi:10.1016/S0196-9781(03)00040-8. PMID 12668217.
20^ Pollard BJ and Pomfrett CJD (2001). "Delta sleep-inducing peptide". Eur. J. Anaesthesiol. 18 (7): 419?422. PMID 11437870.
21^ Yehuda S, Kastin AJ and Coy DH (1980). "Thermoragulatory and locomotor effects of DSIP: paradoxical interaction with d-amphetamine". Pharmacol. Biochem. Behav. 13 (6): 895?900. doi:10.1016/0091-3057(80)90225-7. PMID 6894196.
22^ Yehuda S and Mostofsky DI (1984). "Modification of the hypothermic circadian cycles induced by DSIP and melatonin in pinealectomized and hypophysectomised rats". Peptides 5 (3): 495?497. doi:10.1016/0196-9781(84)90076-7. PMID 6548024.
23^ Yehuda S, Carasso RL (February 1988). "DSIP--a tool for investigating the sleep onset mechanism: a review". Int. J. Neurosci. 38 (3-4): 345?53. doi:10.3109/00207458808990695. PMID 3286557.
24^ Iyer KS, Marks GA, Kastin AJ, and McCann SM (1988). "Evidence for a role of delta sleep-inducing peptide in slow-wave sleep and sleep-related growth hormone release in the rat". Proc Natl Acad Sci U S A 85 (10): 3653?3656. doi:10.1073/pnas.85.10.3653. PMC 280272. PMID 3368469.
25^ Susi***263; V, Masirevi***263; G, Toti***263; S (1987). "The effects of delta-sleep-inducing peptide (DSIP) on wakefulness and sleep patterns in the cat". Brain Research 414 (2): 262?70. doi:10.1016/0006-8993(87)90006-0. PMID 3620931.
26^ Seifritz E, Muller M, Schonenberger G, Trachsel L, Hemmeter U, Hatzinger M, Ernst A, Moore P and Holsboer-Trachsler E (1995). "Human plasma DSIP decreases at the initiation of sleep at different circadian times". Peptides 16 (8): 1475?1481. doi:10.1016/0196-9781(95)02027-6. PMID 8745061.
27^ Steiger A and Holsboer F (1997). "Neuropeptides and human sleep". Sleep 20 (11): 1038?1052. PMID 9456470.
28^ Nakagaki K, Ebihara S, Usui S, Honda Y, Takahashi Y, Kato N (1986). "Effects of intraventricular injection of anti-DSIP serum on sleep in rats". Yakubutsu Seishin Kodo (Japanese journal of psychopharmacology) 6: 259?65.
29^ Kovalzon VM (2001). "Sleep-Inducing Properties of DSIP Analogs: Structural and Functional Relationships". Biology Bulletin 28: 394?400. doi:10.1023/A:1016679208936.
30^ Popovich IG, Voitenkov BO, Anisimov VN, Ivanov VT, Mikhaleva II, Zabezhinski MA, Alimova IN, Baturin DA, Zavarzina NY, Rosenfeld SV, Semenchenko AV, Yashin Aromatase inhibitor (AI) (2003). "Effect of delta-sleep inducing peptide-containing preparation Deltaran on biomarkers of aging, life span and spontaneous tumor incidence in female SHR mice". Mechanisms of Ageing and Development 124 (6): 721?731. doi:10.1016/S0047-6374(03)00082-4. PMID 12782416.
31^ Walleus H, Widerl?v E and Ekman R (1985). "Decreased concentrations of delta-sleep inducing peptide in plasma and cerebrospinal fluid from depressed patients". Nordic Journal of Psychiatry 39: 63?67. doi:10.3109/08039488509101959.
32^ Bjartell A, Ekman R, Sundler F and Widerl?v E (1988). "Delta sleep-inducing peptide (DSIP): An overview of central actions and possible relationship to psychiatric illnesses". Nordic Journal of Psychiatry 42: 111?117. doi:10.3109/08039488809103215.
33^ Shi X, Shi W, Li Q, Song B, Wan M, Bai S (2003). "A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells". EMBO Rep 4 (4): 374?380. doi:10.1038/sj.embor.embor805. PMC 1319161. PMID 12671681.
34^ Stanojilovic OP, Zivanovic DP and Su Sic VT (2002). "The effects of Delta Sleep-Inducing Peptide on incidence and severity in metaphit-induced epilepsy in rats". Pharmacological Research 45 (3): 241?247. doi:10.1006/phrs.2001.0938. PMID 11884222.
35^ Stanojlovi***263; O, Zivanovi***263; D, Mirkovi***263; S, Mikhaleva I (February 2004). "Delta sleep-inducing peptide and its tetrapeptide analogue alleviate severity of metaphit seizures". Pharmacol. Biochem. Behav. 77 (2): 227?34. doi:10.1016/j.pbb.2003.10.014. PMID 14751449.
36^ Nakamura A, Nakashima M, Sugao T, Kanemoto H, Fukumura Y, Shiomi H (1988). "Potent antinociceptive effect of centrally administered delta-sleep-inducing peptide (DSIP)". Eur J Pharmacol 155 (3): 247?53. doi:10.1016/0014-2999(88)90510-9. PMID 2853064.
37^ Pomfrett CJD, Dolling S, Anders NRK, Glover DG, Bryan A, Pollard BJ (2009). "Delta sleep-inducing peptide alters bispectral index, the electroencephalogram and heart rate variability when used as an adjunct to isoflurane anaesthesia". Eur J Anaesthesiol 26 (2): 128?34. doi:10.1097/EJA.0b013e32831c8644. PMID 19142086.
38^ Friedman TC, Garc?a-Borreguero D, Hardwick D, Akuete CN, Doppman JL, Dorn LD, Barker CN, Yanovski JA, Chrousos GP (December 1994). "Decreased delta-sleep and plasma delta-sleep-inducing peptide in patients with Cushing syndrome". Neuroendocrinology 60 (6): 626?34. doi:10.1159/000126806. PMID 7700506.
39^ Torreilles F and Touchon J (2002). "Pathogenic theories and intrathecal analysis of the sporadic form of Alzheimer's disease". Progress in Neurobiology 66 (3): 191?203. doi:10.1016/S0301-0082(01)00030-2. PMID 11943451.
40^ Sinyukhin AB, Timoshinov GP, Komilov VA, Shabanov PD (2009). "Delta sleep-inducing peptide analogue corrects the eNS functional state of children treated with antiblastomic therapy". European Neuropsychopharmacology 19: S681. doi:10.1016/S0924-977X(09)71101-0.
41^ Soyka M and Rothenhaeusler H (1997). "Delta Sleep-Inducing Peptide Opioid Detoxi***64257;cation". Am. J. Psychiat. 154 (5): 714?715. PMID 9137140.
42^ Yukhananov RY, Tennila TML, Miroshnichenko II, Kudrina VS, Ushakov AN and Melnik EI (1992). "Ethanol and Delta Sleep Inducing Peptide effects on brain monoamines". Pharmacol. Bio-chem. Behav. 43: 683?687. doi:10.1016/0091-3057(92)90396-W.
43^ Backmund M, Meyer K, Rothenhaeusler HB and Soyka M (1998). "Opioid detoxi***64257;cation with delta sleep-inducing peptide: results of an open clinical trial.". J. Clin. Psychopharmacol. 18 (3): 257?258. doi:10.1097/00004714-199806000-00016. PMID 9617990.
44^ Schneider-Helmert D (1986). "DSIP in Sleep Disturbances". Eur Neurol 25: 154?157. doi:10.1159/000116097. PMID 3758119.
45^ Schneider-Helmert D and Schoenenberger GA (1981). "The influence of synthetic DSIP (delta-sleep-inducing-peptide) on disturbed human sleep". Cellular and Molecular Life Sciences 37: 913?917. doi:10.1007/BF01971753
Delta sleep-inducing peptide, abbreviated DSIP, is a neuropeptide that when infused into the mesodiencephalic ventricle of recipient rabbits induces spindle and delta EEG activity and reduced motor activities.[1]
Its aminoacid sequence is trp-ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu. However, it is the only neuropeptide in history whose gene is unknown, raising serious questions regarding the actual existence of this peptide in nature.
Discovery
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.[2]
Delta-sleep-inducing peptide (DSIP)-like material has been found in human breast milk.[3]
Structure and Interactions
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[4]
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.[5] 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.[4]
In the brain its action may be mediated by NMDA receptors.[6] In another study Delta sleep-inducing peptide stimulated Acetyltransferase activity through ***945;1 receptors in rats.[7] 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.[8] 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,[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.[10]
Gimble et al. suggest that DSIP interacts with components of the MAPK cascade and is homologous to glucocorticoid-induced leucine zipper (GILZ).[11] GILZ can be induced by Dexamethasone. It prevents Raf-1 activation, which inhibits phosphorylation and activation of ERK.[12]
Function
Many roles for DSIP have been suggested following research carried out using peptide analogues with a greater molecular stability [13] and through measuring DSIP-like immunological (DSIP-LI) response by injecting DSIP antiserum and antibodies.[14]
Roles in endocrine regulation
Decreases basal corticotropin level and blocks its release.[8]
Stimulates release of luteinizing hormone (LH).[15]
Stimulates release of somatoliberin and somatotrophin secretion and inhibits somatostatin secretion.[16]
Roles in physiological processes
Can act as a stress limiting factor.[17][18][19]
May have a direct or indirect effect on body temperature and alleviating hypothermia.[20][21][22]
Can normalize blood pressure and myocardial contraction.[8][23]
It has been shown to enhance the efficiency of oxidative phosphorylation in rat mitochondria in vitro, suggesting it may have antioxidant effects.[19]
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[24][25] and suppression of paradoxical sleep, (PS)[26][27] while some studies show no correlation.[28] Stronger effects on sleep have been noted for the synthesized analogues of DSIP.[29]
It may have an impact on human lens epithelial cell function via the MAPK pathway, which is involved in cell proliferation, differentiation, motility, survival, and apoptosis.[12]
Roles in Disease and Medicine
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.[30]
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.[10][31][32]
Studies have demonstrated a direct link between GILZ expression (homologous to DSIP) and adipogenesis which has links to obesity and ********* syndrome.[33]
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.[34][35]
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).[36]
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.[37]
Low plasma concentrations of DSIP have been found in patients with Cushing's syndrome.[38]
In Alzheimer's patients levels of DSIP have been found to be slightly elevated, though this is unlikely to be causal.[39]
A preparation of DSIP, Deltaran, has been used to correct central nervous system function in children after antiblastomic 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.[40]
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.[41][42] 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.[43]
In some studies administration of DSIP has alleviated narcolepsy and normalized disturbed sleeping patterns.[44][45]
Safety and possible side-effects of long-term DSIP use hasn't been established in clinical research studies.
References
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