Delta-Sleep Inducing Peptide (DSIP) and Analogs
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What is delta sleep inducing peptide?
In 1977, a naturally occurring chemical was originally considered a potential sleep-promoting agent when it was identified from rabbit cerebral venous blood by the Schoenenberger-Monnier group from Basel. This peptide has been called "delta sleep-inducing peptide (DSIP)" because injecting it into the ventricles of other rabbits' brains caused the electroencephalogram (EEG) to show delta waves. DSIP, a nonapeptide with a molecular weight of 849, was shown to primarily promote delta-sleep in rabbits, rats, mice, and humans, but a more noticeable impact on rapid eye movement (REM) sleep on cats.
Structure of DSIP and dermorphins. (Kovalzon V M., et al., 2006)
Delta sleep inducing peptide discovery
DSIP, a nonapeptide with a unique amino-acid sequence, was isolated from the cerebral venous blood of rabbits subjected to low-frequency ('hypnogenic') electrical stimulation of the intralaminar thalamic nuclei (the so-called 'trophotropic zone'; Hess W. R. by Schoenenberger-Monnier group from Basel in 1977). In the following three decades, extensive studies carried out in a number of laboratories (the total DSIP bibliography could be estimated at not less than 1500 references) have demonstrated that DSIP, or some structurally closely related peptide(s), is present in both free and bound forms in some cerebral structures, primarily the hypothalamus and limbic system, as well as pituitary and different peripheral organs, tissues and body fluids, where it co-localizes with several peptide and non-peptide mediators.
A series of histochemical investigations conducted by the Geneva group in the late 1980s and early 1990s utilized a combination of polyclonal and monoclonal antibodies that are extremely sensitive and selective, primarily to the DSIP5-9 epitope, in contrast to the earlier efforts that utilized low-sensitivity antibodies. In a number of mammals and cold-blooded animals, these investigations pinpointed the exact location of DSIP-like immunoreactivity (DSIP-LI) in the hypothalamus and neighboring neurosecretory nuclei, which are unimportant for sleep regulation. The researchers have discovered significant variations between different species. In conclusion, DSIP-LI may be found in the hypothalamus of several animals, including humans, guinea pigs, rabbits, rat, and cartilaginous fish (Scyliorhinus canicula). While DSIP-LI is found in the hypothalamus of mammals along with peptide hormones like luliberin (gonadoliberin) and oxitocin/neurophysin-1, it is not present in the hypothalamic median eminence of rodents like mice, hamsters, and gerbils. Along with adrenaline and noradrenaline in the adrenal medulla, DSIP-LI is found in the pituitary of vertebrates alongside peptides such as CLIP, ACTH, MSH, TSH, and MCH. Serum DSIP-LI does not seem to be synthesized in the human pituitary. In rats, pigs, and humans, DSIP-LI is found in abundance in the gut's secretory cells. It is found in close proximity to several peptides, including gastrin and cholecystokinin in the upper gut (antro-duodenic mucosa), secretin in the middle gut (small intestine), and peptide tyrosine in the lower gut (large intestine) along with glycocentin. Humans, pigs, and rabbits all have DSIP-LI co-localized with the peptide glucagon in the pancreatic islet. DSIP-LI is found in high concentrations in adrenal and intestinal malignant tumor cells; its co-localization with serotonin is notable in the intestine. Apart from a few inconsistencies, these statistics are scarcely insufficiently persuasive. But it's worth noting that immunohistochemistry can't confirm the peptide produced spontaneously in nature. Signs of the peptide in nerve terminal vesicles seen by electronic microscopy would be very suggestive. Additionally, microdialysis and HPLC might be used to monitor the peptide release, however using these techniques would be extremely difficult.
Biochemical investigations in living organisms and laboratory settings demonstrated that DSIP molecules are not very stable. The DSIP molecule has a half-life of no more than a few minutes in vivo after external administration because it breaks down quickly in the presence of a particular aminopeptidase-like enzyme, mainly by cleaving off the N-terminal amino-acid residue of Trp and the subsequent Ala. Theoretical calculations and physicochemical investigations have verified several folded conformations of the DSIP molecule in aqueous solutions and its lipophilic environment. These conformations degrade once the N-terminal Trp is cut off, which seems to cause peptide inactivation. Endogenous DSIP may primarily reside in the organism through a combination with a carrier protein that prevents its destruction or as one of three unidentified high-molecular-weight precursors. There may be a DSIP-like peptide family present in the body, and endogenous DSIP may exist in both its natural and phosphorylated or glycosylated forms.
DSIP-LI representation and co-localization in pituitary and adrenals of various vertebrates. (Kovalzon V M., et al., 2006)
Delta sleep inducing peptide function
Thermoregulation
Even while huge dosages of DSIP have surprisingly little impact on temperature, modest amounts injected intraperitoneally cause significant hypothermia. Hyperthermia may be induced in animals by administering tiny amounts of DSIP at room temperature.
Alleviate severity of seizures
After eight rounds of audiogenic testing, the remaining two groups were injected with DSIP and its counterpart to study the blocking effects on fully formed metaphit seizures. One hour after metaphit and at hourly intervals thereafter, the rats were stimulated with an electric bell (placed on top of the cage, producing 100±3 dB and frequency 5-8 kHz, for 60 s) throughout the experiment. In order to get power spectra and EEG recordings, three screws plated with gold were inserted into the skull. While the power spectra increased during a 30-hour period, electroencephalograms (EEGs) recorded from animals treated with metaphit showed signs of polyspikes and spike-wave complexes. Seven to twelve hours following injection, the frequency and intensity of audiogenic seizures caused by metaphit peaked. Seizures, mean seizure grade, and the tonic component of convulsions caused by metaphit were all reduced by both DSIP and its counterpart DSIP(1-4), but the power spectra of delta waves were much enhanced. All things considered, these findings point to the possibility that DSIP and its counterpart DSIP(1-4) might be used as antiepileptics.
DSIP reduces the incidence of metaphit-induced seizures. (Stanojlović O., et al., 2004)
Regulation of free radical processes
Antioxidant enzyme activities (such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase) and antioxidant concentrations (especially reduced glutathione) were enhanced in rat tissues and erythrocytes after an intraperitoneal injection of an exogenous DSIP at a dose of 12 μg/100 g body weight changed the prooxidant-antioxidant balance of free radical process (FRP). In blood neutrophils, the DSIP increased myeloperoxidase activity, but in the brain and liver, it had no influence on xanthine oxidase activity, an antioxidant enzyme. By increasing tissue xanthine oxidase and decreasing blood neutrophil myeloperoxidase activity, cold stress upset the prooxidant-antioxidant balance. It also suppressed enzyme antioxidant activities in tissues and erythrocytes, which were counteracted by increased ceruloplasmin activity in blood plasma and elevated levels of antioxidants in rat blood and tissues. An imbalance between prooxidant and antioxidant enzymes was corrected in cold-stressed animals after preliminary DSIP administration: myeloperoxidase activity in blood neutrophils was normalized, xanthine oxidase activity was decreased, and antioxidant enzyme activity in tissues and erythrocytes was increased, bringing the antioxidant level back to normal.
Endocrine regulation
DSIP enhances the production of luteinizing hormone, it stimulates the release of somatoliberin and somatotropin, and it inhibits the secretion of somatostatin. It results in a drop in the baseline corticotropin level and prevents its release that is induced by corticoliberin injection.
Relieve pain and depression
According to the results of the experiments, DSIP interacts with both endogenous opioid-peptidergic systems and exogenous morphine and amphetamine that are given intracerebrally or systemically in a modulating or "programming" manner. There have been reports of the stimulation of cerebral MAO-A activity, which has a significant impact on the circadian rhythms of locomotion, intracerebral neurotransmitter levels, plasma protein concentrations, and cortisol levels. Additionally, DSIP mitigated the effects of stress that animals were subjected to in an experimental setting. Not only did it have a noticeable impact on the pain states and psychomotor function of alcoholics and opiate addicts, but it also normalized their sleep patterns. This prompted a preliminary investigation into the peptide's potential effects on those with persistent, severe pain. Seven patients suffering from psychogenic pain episodes, persistent tinnitus, migraines, and vasomotor headaches were studied to determine the therapeutic impact. A statistical comparison was made between the anamnestic (baseline) results and the katamnestic control period. Six of the seven patients who received DSIP intravenously for five days in a row and then five injections every 48 to 72 hours reported a marked improvement in their pain levels. A remarkable decrease in the concurrent depressed states was noted at the same time.
Delta sleep inducing peptide benefits
Anticonvulsant benefit
An anticonvulsant effect of DSIP has been demonstrated in rats. As a result, DSIP raises the threshold for convulsions generated by NMDA and picrotoxin. This anticonvulsant impact could change during the day, with nighttime showing more antiepileptic action. Some substances, like DSIP, have different effects at different times of the day. For example, melatonin, b-endorphin, and dexamphetamine all have different effects on the seizure threshold at different times of the day. Another possibility is that DSIP is just one of the natural regulators of brain excitability. In mice, DSIP exhibits an antinociceptive effect that can be counteracted by naloxone.
Neuroprotective benefit
In rats, the results of bilateral carotid ligation showed a protective impact on the nervous system. Along with a decrease in postischaemia function, there was a decrease in mortality. Additionally, in a rat model of toxic cerebral oedema, DSIP decreased brain swelling.
Mood and hormone regulation benefits
In rats, DSIP decreases the stress-related emotional and psychological reactions as well as the stress-related central amine responses. Rat pituitary adrenocorticotrophic hormone (ACTH) production is inhibited as a result of attenuation of corticotrophin releasing factor activity on the pituitary gland. While one research found the same thing, another found no inhibitory impact on the adreno cortical axis to either physiological or stressor inputs, thus the issue isn't quite obvious in humans. Human volunteers did not show any changes in growth hormone or prolactin levels after receiving DSIP. Although DSIP 25 nmol/kg considerably reduced ACTH concentrations in one trial, infusions of 3 or 4 mg (an enormous dosage) had no influence on ACTH levels or cortisol production in another. DSIP concentrations change during certain psychiatric disorders. Patients suffering from schizophrenia and depression have lower plasma and cerebrospinal fluid concentrations of DSIP than comparable normal volunteers. Concentrations were also inversely correlated with sleep disturbance in those patients
Delta sleep inducing peptide production
Three tripeptide fragments were enzymatically combined to form the delta sleep-inducing peptide, including C-terminal tripeptide: Boc-Ser(Bzl)-Gly-Glu(OBzl)-N2H2Ph; the central fragment: Boc-Gly-Asp(OBz1)- Ala-OMe; N-terminal tripeptide: Z-Trp-Ala-Gly- OMe. Papain- or α-chymotrypsin-mediated synthesis was used to prepare all of the peptide linkages. By utilizing an alkaline pH and adding Nα-protected amino acid or peptide esters as carboxyl components, secondary hydrolysis was reduced. The C-terminal phenylhydrazide was deprotected by oxidizing the protected nonapeptide with ferric chloride, followed by hydrogenation. Using reversed-phase high-performance liquid chromatography, the homogenous peptide was successfully isolated. There were no discernible changes between the chemical and enzymatic preparations.
References
- Kovalzon V M., et al., Delta sleep‐inducing peptide (DSIP): a still unresolved riddle, Journal of neurochemistry, 2006, 97(2): 303-309.
- Pollard B J., et al., Delta sleep-inducing peptide, European Journal of Anaesthesiology, 2001, 18(7): 419-422.
- Tsunashima K., et al., The effect of delta sleep-inducing peptide (DSIP) on the changes of body (core) temperature induced by serotonergic agonists in rats, Peptides, 1994, 15(1): 61-65.
- Stanojlović O., et al., Delta sleep-inducing peptide and its tetrapeptide analogue alleviate severity of metaphit seizures, Pharmacology Biochemistry and Behavior, 2004, 77(2): 227-234.
- Shustanova T A., et al., Regulation of free radical processes by delta-sleep inducing peptide in rat tissues under cold stress, Biochemistry (Moscow), 2001, 66: 632-639.
- Larbig W., et al., Therapeutic effects of delta-sleep-inducing peptide (DSIP) in patients with chronic, pronounced pain episodes: a clinical pilot study, European neurology, 1984, 23(5): 372-385.
- Sakina K., et al., Enzymatic synthesis of delta sleep‐inducing peptide, International Journal of Peptide and Protein Research, 1988, 31(2): 245-252.
