Delta sleep-inducing peptide
Encyclopedia
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.
Its aminoacid sequence is Тrр
-Аlа
-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. Given this, everything ever written about DSIP may be artifact or indirect and non-specific actions of the synthetic peptide, which may be purchased.
in rabbits, but studies on the subject have been contradictory.
Delta-sleep-inducing peptide (DSIP)-like material has been found in human breast milk.
N-Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu-C
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. 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 receptor
s. In another study Delta sleep-inducing peptide stimulated Acetyltransferase activity through α1 receptors in rats. 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. 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, but as yet no structure or gene has been found for this precursor.
Evidence supports the current belief that it is regulated by glucocorticoids.
Gimble et al. suggest that DSIP interacts with components of the MAPK cascade and is homologous to glucocorticoid-induced leucine zipper (GILZ). GILZ can be induced by Dexamethasone
. It prevents Raf-1 activation, which inhibits phosphorylation
and activation of ERK
.
and antibodies.
Safety and possible side-effects of long-term DSIP use hasn't been established in clinical research studies.
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
that when infused into the mesodiencephalic ventricle of
recipient rabbits induces spindle and delta EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
activity and reduced motor activities.
Its aminoacid sequence is Тrр
Tryptophan
Tryptophan is one of the 20 standard amino acids, as well as an essential amino acid in the human diet. It is encoded in the standard genetic code as the codon UGG...
-Аlа
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...
-Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-Gly-Asp
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
-Ala-Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-Gly-Glu
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
. However, it is the only neuropeptide in history whose gene is unknown, raising serious questions regarding the actual existence of this peptide in nature. Given this, everything ever written about DSIP may be artifact or indirect and non-specific actions of the synthetic peptide, which may be purchased.
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 sleepSlow-wave sleep
Slow-wave sleep , often referred to as deep sleep, consists of stages 3 and 4 of non-rapid eye movement sleep, according to the Rechtschaffen & Kales standard of 1968. As of 2008, the American Academy of Sleep Medicine has discontinued the use of stage 4, such that the previous stages 3 and 4 now...
in rabbits, but studies on the subject have been contradictory.
Delta-sleep-inducing peptide (DSIP)-like material has been found in human breast milk.
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
It has been found in both free and bound forms in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
, limbic system
Limbic system
The limbic system is a set of brain structures including the hippocampus, amygdala, anterior thalamic nuclei, septum, limbic cortex and fornix, which seemingly support a variety of functions including emotion, behavior, long term memory, and olfaction. The term "limbic" comes from the Latin...
and pituitary as well as various peripheral organs, tissues and body fluids. In the pituitary it co-localises with many peptide and non-peptide mediators such as corticotropin-like intermediate peptide
Corticotropin-like intermediate peptide
Corticotropin-like intermediate [lobe] peptide , also known as adrenocorticotropic hormone fragment 18-39 , is a naturally-occurring, endogenous neuropeptide with a docosapeptide structure and the amino acid sequence...
(CLIP), adrenocorticotrophic hormone (ACTH), melanocyte-stimulating hormone
Melanocyte-stimulating hormone
The melanocyte-stimulating hormones are a class of peptide hormones that are produced by cells in the intermediate lobe of the pituitary gland...
(MSH), thyroid-stimulating hormone
Thyroid-stimulating hormone
Thyrotrophin-stimulating hormone is a peptide hormone synthesized and secreted by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid gland.- Physiology :...
(TSH) and melanin concentrating hormone
Melanin concentrating hormone
Melanin-concentrating hormone is a cyclic 19-amino acid orexinogenic hypothalamic peptide originally isolated from the pituitary gland of teleost fish where it controls skin pigmentation....
(MCH). It is abundant in the gut secretory cells and in the pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
where it co-localises with glucagon
Glucagon
Glucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
.
In the brain its action may be mediated by NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s. In another study Delta sleep-inducing peptide stimulated Acetyltransferase activity through α1 receptors in rats. 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
Aminopeptidase
Aminopeptidase is a zinc-dependent enzyme produced and secreted by glands of the small intestine. It helps the enzymatic digestion of proteins. Additional digestive enzymes produced by these glands include dipeptidases, maltase, sucrase, lactase, and enterokinase.Aminopeptidases catalyze the...
-like enzyme. 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, but as yet no structure or gene has been found for this precursor.
Evidence supports the current belief that it is regulated by glucocorticoids.
Gimble et al. suggest that DSIP interacts with components of the MAPK cascade and is homologous to glucocorticoid-induced leucine zipper (GILZ). GILZ can be induced by Dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
. It prevents Raf-1 activation, which inhibits phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
and activation of ERK
Extracellular signal-regulated kinases
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
.
Function
Many roles for DSIP have been suggested following research carried out using peptide analogues with a greater molecular stability and through measuring DSIP-like immunological (DSIP-LI) response by injecting DSIP antiserumAntiserum
Antiserum is blood serum containing polyclonal antibodies. Antiserum is used to pass on passive immunity to many diseases. Passive antibody transfusion from a previous human survivor is the only known effective treatment for Ebola infection .The most common use of antiserum in humans is as...
and antibodies.
Roles in endocrine regulation
- Decreases basal corticotropin level and blocks its release.
- Stimulates release of luteinizing hormoneLuteinizing hormoneLuteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(LH). - Stimulates release of somatoliberin and somatotrophin secretion and inhibits somatostatinSomatostatinSomatostatin is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones.Somatostatin...
secretion.
Roles in physiological processes
- Can act as a stress limiting factor.
- May have a direct or indirect effect on body temperature and alleviating hypothermiaHypothermiaHypothermia is a condition in which core temperature drops below the required temperature for normal metabolism and body functions which is defined as . Body temperature is usually maintained near a constant level of through biologic homeostasis or thermoregulation...
. - Can normalize blood pressure and myocardial contraction.
- It has been shown to enhance the efficiency of oxidative phosphorylationOxidative phosphorylationOxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
in rat mitochondria in vitro, suggesting it may have antioxidantAntioxidantAn antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
effects. - There is also conflicting evidence as to its involvement in sleep patterns. Some studies suggest a link between DSIP and slow-wave sleepSlow-wave sleepSlow-wave sleep , often referred to as deep sleep, consists of stages 3 and 4 of non-rapid eye movement sleep, according to the Rechtschaffen & Kales standard of 1968. As of 2008, the American Academy of Sleep Medicine has discontinued the use of stage 4, such that the previous stages 3 and 4 now...
(SWS) promotion and suppression of paradoxical sleep, (PS) while some studies show no correlation. Stronger effects on sleep have been noted for the synthesized analogues of DSIP. - It may have an impact on human lensLens (anatomy)The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a...
epithelial cell function via the MAPK pathway, which is involved in cell proliferation, differentiation, motility, survival, and apoptosisApoptosisApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
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.
- 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 marrowBone marrowBone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
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 fluidCerebrospinal fluidCerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
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.
- Studies have demonstrated a direct link between GILZ expression (homologous to DSIP) and adipogenesisAdipogenesisAdipogenesis is the process of cell differentiation by which preadipocytes become adipocytes.. Adipogenesishas been one of the most intensively studied model of cellular differentiation.-References:...
which has links to obesity and metabolic syndromeMetabolic syndromeMetabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
.
- In studies on rats with metaphitMetaphitMetaphit is a research chemical that acts as an acylator of NMDARAn, sigma & DAT binding sites in the CNS. It is the m-isothiocyanate derivative of phencyclidine & binds irreversibly to the PCP binding site on the NMDA receptor complex...
-induced epilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
DSIP acted as an anticonvulsant, significantly decreasing the incidence and duration of fits suggesting DSIP as a potential treatment for epilepsy.
- DSIP has been found to have an analgesicAnalgesicAn analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
effect. In studies on mice it was found to have a potent antinociceptive effect when administered intracerebroventricularly or intracisternally (see: Route of administrationRoute of administrationA route of administration in pharmacology and toxicology is the path by which a drug, fluid, poison, or other substance is taken into the body.-Classification:Routes of administration are usually classified by application location...
).
- 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 isofluraneIsofluraneIsoflurane is a halogenated ether used for inhalational anesthesia. Together with enflurane and halothane, it replaced the flammable ethers used in the pioneer days of surgery. Its name comes from being a structural isomer of enflurane, hence they have the same empirical formula...
anaesthesia actually increased the heart rate and reduced the depth of anaesthesia instead of deepening it as expected.
- Low plasma concentrations of DSIP have been found in patients with Cushing's syndromeCushing's syndromeCushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...
.
- In Alzheimer's patients levels of DSIP have been found to be slightly elevated, though this is unlikely to be causal.
- A preparation of DSIP, Deltaran, has been used to correct central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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 chemotherapyChemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
-induced impairment in the bioelectrical activity of 9 out of the 10 children was reduced by administration of DSIP.
- DSIP can act antagonistically on opiate receptors to significantly inhibit the development of opioidOpioidAn opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
and alcohol dependence and is currently being used in clinical trials to treat withdrawal syndromeWithdrawal syndromeA withdrawal syndrome, also called a discontinuation syndrome, occurs when a person suddenly stops taking or reduces the dosage of some types of medications...
. 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.
- In some studies administration of DSIP has alleviated narcolepsyNarcolepsyNarcolepsy is a chronic sleep disorder, or dyssomnia, characterized by excessive sleepiness and sleep attacks at inappropriate times, such as while at work. People with narcolepsy often experience disturbed nocturnal sleep and an abnormal daytime sleep pattern, which often is confused with insomnia...
and normalized disturbed sleeping patterns.
Safety and possible side-effects of long-term DSIP use hasn't been established in clinical research studies.