Effects Of Delta Sleep-inducing Peptide Research Articles

Modulatory effects of delta sleep-inducing peptide in a lindane model of generalized seizures

Delta sleep-inducing peptide (DSIP) is an endogenous peptide that is constantly present in several different brain regions. Lindane is used as a pesticide and scabicide, but it also induces seizures refractory to conventional antiepileptics. The aim of this paper was to determine whether DSIP modulates lindane-induced seizures in rats in a behavioral and electroencephalographic (EEG) study. DSIP (1 mg/kg, i.p.) or dimethyl-sulfoxide (DMSO, 0.5 ml/kg, intraperitoneally (i.p.)) were injected 30 min before lindane (8 mg/kg, i.p.) to adult male rats with previously implanted electrodes for EEG registration. During the following 30 min, the EEG was registered, and the following behavioral characteristics of seizures were observed: incidence, latency and intensity. A descriptive scale with grades from 0 to 4 provided an estimate of seizure intensity. In the EEG, the number and duration of ictal periods were analyzed using NeuroSciLaBG (Belgrade, Serbia) software. The lethality rate was also analyzed. DSIP-treated animals showed significantly modified characteristics of lindane-induced seizures when compared to the group without DSIP pretreatment (i.e. a reduced seizure intensity and a prolonged seizure latency period). However, no significant effects of DSIP on seizure incidence and lindane-induced lethality were observed. EEG analyses showed a significantly decreased number of lindane-induced EEG ictal periods in DSIP-treated animals, but with unaltered duration. These results show that DSIP favorably modulates lindane-induced seizures in rats, showing a potential to be an adjuvant component of antiepileptic treatment strategy for refractory seizures.

Expression and Purification of Delta Sleep-Inducing Peptide Fused with Protein Transduction Domain and Human Serum Albumin in Pichia pastoris.

Sleep is a natural part of every individual's life. Delta sleep-inducing peptide (DSIP) is a nonapeptide that could promote sleep through the induction of slow wave sleep. However, little is known about the pharmacological effect of DSIP on insomnia. The main objective of this study was to analyze the pharmacological effect of DSIP on insomnia. We designed a fusion protein containing N-terminal TAT-based transduction domain followed by human serum albumin and DSIP and designated this protein as PHD fusion protein. The PHD fusion protein were expressed in Pichia pastoris and purified. Mice were administered single subcutaneous injections three concentrations of PHD fusion protein (0.5, 1, 2 mg/kg), and the pharmacological activity of PHD fusion protein was studied using classic pentobarbitalinduced sleep test. We expressed the PHD fusion protein in P. pastoris; furthermore, the PHD fused protein was purified to near homogeneity by DEAE Sepharose FF, Phenyl Sepharose HP and Blue Sepharose 6 FF. Our result showed that the increase of pentobarbital-induced hypnotic effect characterized by reducing sleep latency and prolonged sleep duration was observed for increasing concentrations of PHD fusion protein (P<0.05); moreover, different dose of PHD fusion protein could induce the mice to re-sleep in a dose-dependent manner, whereas higher doses of PHD fusion protein (1.0, 2.0 mg/kg) significantly increased the rate of sleep re-onset compared with the vehicle group of mice (P<0.05). PHD fusion protein increased the hypnotic effects of pentobarbital by reducing sleep latency and prolonged sleep duration. The present study suggested PHD fusion protein could be a new drug candidate for insomnia.

Effect of Delta Sleep-Inducing Peptide on Functional State of Hepatocytes in Rats During Restraint Stress.

We studied the effect of delta sleep-inducing peptide (40, 120, and 360 μg/kg intraperitoneally, 1 h before the experiment) on free radical oxidation in the liver, aminotransferase activity, and total serum protein content in male Wistar rats during restraint stress. Treatment with the peptide in a dose of 40 μg/kg increased catalase and superoxide dismutase (SOD) activities and malonic dialdehyde (MDA) concentration in the liver homogenate of animals subjected to acute stress. No significant changes were found after administration of this peptide in other doses. Under conditions of chronic stress, the peptide in a dose of 40 μg/kg caused the most pronounced effect. Catalase and SOD activities and MDA concentration decreased, while aminotransferase activity and protein content remained unchanged under these conditions. Administration of the peptide in a dose of 120 μg/kg was accompanied by a decrease in SOD activity and MDA concentration, increase in total protein content, and reduction of AST activity. Increasing the peptide dose to 360 μg/kg abolished its effects.

The infl uence of the treatment with deltalycyn on clinical, functional and morphological manifestations of diabetic retinopathy

Aim. Protective effects of delta sleep-inducing peptide (DSIP) on retinopathy has been shown earlier on the model of streptozotocin diabetes mellitus. 52 patients with non-prolypherative form of diabetic retinopathy (DR) were prescribed treatment with deltalcyn intranasal administration– drug, which was composed on the DSIP basis. This medication was taken during month twice per half of year.Methods and results. Severity of DR was 20 – 35 units in accordance to ETDRS scale. It was established that in half of year index of optical density of macular pigment, which was determined in heterochrome fl icker – photometry test, increased by 32,4% (P&lt;0.05) in compare to control group of patients (traditional treatment of 35 patients with DR). And exceeded the index which was registered before treatment by35,1% (P&lt;0.05). Vision acuteness increased by9,4 % (P&lt;0,05), along with the reduction of the number of created microaneurisms – by 16,4% (P&lt;0,05). It was observed during this period.Conclusion. Deltalycyn possessed protective activity against not-prolypherative form of DR.

Effect of Delta Sleep-Inducing Peptide on the Expression of Antioxidant Enzyme Genes in the Brain and Blood of Rats during Physiological Aging

Subcutaneous injections of exogenous delta sleep-inducing peptide in a dose of 100 μg/kg (monthly, 5-day courses) to rats of various age groups (2-24 months) were followed by an increase in the expression of genes for SOD 1 (Sod1) and glutathione peroxidase 1 (Gpx1) in the brain and nucleated blood cells. The expression of these genes was shown to decrease during physiological aging of the body.

Effect of Delta Sleep-Inducing Peptide on Oxidative Modification of Proteins in Rat Tissues and Blood during Physiological Aging

Accumulation of oxidized proteins (evaluated by the levels of carbonyl and SH groups) in tissues of 2-24-month-old rats (spleen>myocardium>testicles>liver>skeletal muscles) has been demonstrated. Exogenous delta sleep-inducing peptide injected subcutaneously to rats of different age in a dose of 100 μg/kg by monthly 5-day courses protected proteins of the studied tissues from oxidation; its effect was tissue-specific. Delta sleep-inducing peptide exhibited a hypoglycemic effect: it prevented nonenzymatic glycosylation of hemoglobin and reduced the level of defective protein molecules during aging.

Changes in Duodenal Lymphoid Structures in Rats with Different Levels of Behavioral Activity Treated with Delta Sleep-Inducing Peptide and during Acute Emotional Stress

The effects of delta sleep-inducing peptide (DSIP) on intestinal lymphoid formations were studied. Experiments were performed on 42 male Wistar rats which had previously been tested in an open field. The results of this test were used to divide the rats into behaviorally active (predicted to be stress-resistant) and passive (stress-susceptible) animals. Stress was applied by restraining the animals in boxes with electrical stimulation of the back for 1 h. Administration of i.p. DSIP to rats led to decreases in the number of eosinophils in animals of all experimental groups. In active rats of the control group, administration of DSIP produced increases in the numbers of small and intermediate lymphocytes which were greater than increases in passive rats. After acute stress, behaviorally active rats showed increases in the number of lymphoid cells, mainly due to small and intermediate lymphocytes. In passive rats, stress and injection of DSIP were followed by increases in the numbers of plasma cells in all the duodenal mucosal structures studied.

Delta sleep-inducing peptide and Deltaran: Potential approaches to antistress protection

The aims of the present work were to perform a comparative study of the effects of delta sleep-inducing peptide and Deltaran on neurons in emotiogenic brain structures and to address the question of whether it is possible to prevent or decrease the negative influences of stress loads on the severity of subsequent cerebral ischemia in rats, using glycine with delta sleep-inducing peptide combined in the neuroprotective formulation Deltaran. The results showed that Deltaran and delta sleep-inducing peptide had largely the same actions on the nature of spike activity of neurons in the dorsal hippocampus, paraventricular nucleus of the hypothalamus, and ventral anterior nuclei of the thalamus, evoking activation of some of the neurons in these brain structures. The dorsal hippocampus was dominated by activation of spike activity in response to administration of delta sleep-inducing peptide; Deltaran produced activation mainly in the paraventricular nuclei of the hypothalamus. In all animals given Deltaran, the index of brain blood supply was significantly greater than in animals not given Deltaran. The survival rate of cerebral ischemia was 100% in animals given Deltaran. Death occurred in 38% of animals not given Deltaran.

Effect of prenatal application of delta-sleep-inducing peptide and prenatal emotional stress on brain monoamine oxidase and on the behavior of adult male progeny of DD mice

Prenatal administration of delta-sleep-inducing peptide (DSIP) at a high dose (120 μg per 100 g of body weight) and low dose (12 μg per 100 g of body weight) and prenatal emotional stress resulted in aggressive behavior of two-month-old male progeny of DD mice in the resident-intruder test. However, no increase in the aggressiveness of male progeny of the highly aggressive C57BL mice, which we studied previously, was observed. These data suggest that the prenatal effect of DSIP on the behavior of DD and C57BL mice depended on the individual genotype. The aggressiveness of two-month-old male progeny of the DD mice that were subjected to prenatal treatment with DSIP was accompanied by enhanced activity of monoamine oxidase A (MAO A) in the cerebral hemispheres. These results suggest that DSIP should be considered as a regulatory peptide that controls the expression of the MAO A gene, and that MAO A was probably involved in the development of aggressiveness of the male progeny of the DD mice after the prenatal administration of DSIP. Prenatal emotional stress had no significant influence on the activity of MAO A in the brain of two-month-old male progeny of DD mice. Development of the aggressiveness of two-month-old male progeny of DD mice which were produced by stressed mothers was possibly not associated with fluctuations in the activity of MAO A in the brain.

Delta sleep-inducing peptide and its analogues alleviate the severity of metaphit-induced audiogenic seizures in rats

We investigated the potential of delta sleep-inducing peptide (DSIP) and its analogue DSIP-12 (a nonapeptide with alanine in position 2 of DISP molecule substituted by beta-alanine) and tetrapeptide analogue DSIP1-4, to antagonize metaphit(1-1 (3-isothiocyanatophenl)-cvyclohexyl piperidine) induced generalized reflex audiogenic seizures in adult male Wistar albino rats. Five groups of adult male Wistar rats were intraperitoneally treated with: (1) saline; (2) metaphit: (3) metaphit + DSIP, (4) metaphit + DSIPI-4 and (5) metaphit + DSIP-12. To examine the blocking effects of DSIP and its analogues on fully developed metaphit seizures, in the last three groups they were administered 8h after metaphit injection. The rats were stimulated using an electric bell (1003 dB, 5-8 kHz, 60 s) one hour after metaphit injection and afterwards at hourly intervals during the experiment. For EEG recordings and power spectra three gold-plated screws were implanted into the skull. In metaphit-treated animals EEGs appeared as polyspikes and spike-wave complexes, while power spectra were increasing. The incidence and severity of netaphit-induced audiogenic seizures reached a peak value at 7-12 h after injection. Both DSIP and DSIP analogues significantly increased power spectra of delta waves and decreased the incidence of seizures, as well as mean seizure grade and tonic component of metaphit-induced convulsions. Taken together, these results suggest that DSIP and its analogues should be considered as potential antiepileptic agents.

Effects of delta sleep-inducing peptide on pre-and postsynaptic glutamate and postsynaptic GABA receptors in neurons of the cortex, hippocampus, and cerebellum in rats

We studied the effect of delta sleep-inducing peptide on GABA receptors of hippocampal and cerebellar neurons in rats. It was shown that delta sleep-inducing peptide considerably and dose-dependently potentiates GABA-activated currents in these neurons and blocks NMDA-activated potentiation in cortical and hippocampal neurons. The peptide modulates activity of presynaptic NMDA receptors, which is seen from changes in (45)Ca(2+) uptake into synaptosomes of the brain cortex after uptake stimulation with glutamate and NMDA.

Effect of delta sleep-inducing peptide on macromolecule biosynthesis in brain tissue of stressed rodents

For evaluation of the nature of adaptogenic properties of delta sleep-inducing peptide we studied the effect of this substance on macromolecule biosynthesis in the brain of rats and mice exposed to burn injury and psychoemotional stress, respectively. Anabolic activity of delta sleep-inducing peptide depended on the purpose of adaptation corresponding to the type of stress.

Interaction of delta sleep-inducing peptide and its analogues with cellular membranes: A structure-function analysis

The possibility of a correlation between the membrane properties of the delta sleep-inducing peptide (DSIP) and its analogues and their biological activity in vivo was examined by a comparative study of the membrane effects of these peptides. The peptides exhibiting biological activity in vivo were shown to cause a statistically reliable disordering of lipids in thrombocyte plasma membranes similar to the effect of DSIP. The membrane effect of the D-Val2, D-Tyr2, and Tyr1, Pro2 analogues of DSIP had the same bimodal dose dependence characteristic of natural DSIP. Only a slight nonspecific lipid disordering was registered for Trp-Asp-Ala-Ser-Gly-Glu, a biologically inactive hexapeptide analogue. These results indicate a correlation between the biological activity of the peptides during in vivo tests and their membrane properties in vitro. The structure-function relationship was studied within the group of DSIP analogues examined in vitro. The DSIP modeling effect, especially pronounced under the action of stress factors, was suggested to be directly associated with the ability of DSIP to change the dynamic structure of biological membranes.

Behavioral and electroencephalographic effects of delta sleep inducing peptide and its analogue on metaphit-induced audiogenic seizures in rats

Delta sleep inducing peptide (DSIP) is well known natural somnogenic peptide that has many other physiological functions. DSIP analogues representing hepta- and octapeptides (also known as long) as well as tetrapeptide (termed short, used in our experiments) were synthesized with a view to evaluate the peptide specificity in sleep. The effects of DSIP and its analogue DSIP1-4 on metaphit 1-[1(3-isothiocyanatophenylciclohexyl)-piperidine] induced audiogenic seizures were evaluated in rats. Male Wistar albino rats were divided into 4 groups: 1. Saline; 2. Metaphit; 3. Metaphit + DSIP, and 4. Metaphit + DSIP1-4. To examine the blocking effects of DSIP and its analogue on fully developed metaphit seizures, the last two groups were injected after the 8th audiogenic testing. Animals were injected with metaphit (10 mg/kg) intraperitoneally (i.p.) and exposed to sound stimulation (100 +/- 3 dB, 60 s) at hourly intervals. The incidence and severity (running, clonus and tonus) of seizures were analyzed. For electroencephalographic (EEG) recordings, three gold-plated electrodes were used. Convulsive behavior was assessed by incidence of motor seizure and by seizure severity grade, determined by descriptive rating scale ranging from 0 to 3: 0--no response, 1--wild running only; 2--wild running followed by clonic seizures of all four limbs with body rollover; 3--wild running progressing to generalized clonic convulsions followed by tonic extension of fore- and hind legs and tail. Sound onset, seizure events, and sound offset, along with the animal's behavior (convulsive or other) were characterized with EEG changes. In most animals, the administration of metaphit resulted in electroencephalographic abnormalities, elicited epileptiform activity in the form of spikes, polyspikes and spike-wave complexes. Maximum incidence and severity of metaphit convulsions occurred 8 h after the injection (9/12, 75%), then abated gradually and disappeared 30 h later. Both DSIP and DSIP1-4 significantly increased the power spectra of d waves and decreased the incidence of seizures, mean seizure grade and tonic component of metaphit-induced convulsions. Metaphit has been shown to induce audiogenic seizures after systemic and intracerebroventricular administration and to be truly epileptic in small rodents, although about 8 h after metaphit administration, the power spectra increased and was more intense in the period of sound onset and seizure events. Taken together, DSIP makes an optimal ratio between inhibitory and excitatory amino acid neurotransmitters and may represent one of the endogenous control systems of the brain, thus exerting the protective effect against the seizures. The results obtained throughout the present study corroborate and broaden the data on prolonged antiepileptic DSIP effect. The results of the present study strongly suggest that treatment of adult rats with DSIP and its analogue DSIP1-4 should be considered as potential natural antiepileptics.

Delta sleep-inducing peptide and its tetrapeptide analogue alleviate severity of metaphit seizures

The effects of delta sleep-inducing peptide (DSIP) and its tetrapeptide analogue, DSIP(1-4), on metaphit-induced audiogenic seizures were studied. Five groups of adult male Wistar rats were intraperitoneally treated with (1) saline, (2) metaphit, (3) DSIP, (4) metaphit+DSIP and (5) metaphit+DSIP(1-4). To examine blocking effects of DSIP and its analogue on fully developed metaphit seizures, the last two groups were injected after the eight audiogenic testing. The rats were stimulated using electric bell (on the top of the cage, generating 100±3 dB and frequency 5–8 kHz, for 60 s) 1 h after metaphit and afterwards at hourly intervals during the experiment. For EEG recordings and power spectra, three gold-plated screws were implanted into the skull. In metaphit-treated animals, EEGs appeared as polyspikes and spike-wave complexes while the power spectra were increasing for 30-h period. The incidence and severity of metaphit-induced audiogenic seizures reached peak value 7–12 h after the injection. Both DSIP and DSIP(1-4) significantly increased power spectra of delta waves and decreased incidence of seizures, mean seizure grade and tonic component of metaphit-induced convulsions. Taken together, these results suggest that DSIP and its analogue DSIP(1-4) should be considered as potential antiepileptics.

The Delta-Sleep Inducing Peptide in Cerebral Mechanisms of Emotional Stress

The problem of the anti-stressor effect of the delta-sleep inducing peptide (DSIP) and of its neurophysiological mechanisms of action is considered. Physiological data are exposed that indicate an intraventricular administration of DSIP in rats to results in an increase of resistance to emotional stress, according to behavioral and autonomous reactions, and in a decrease of excitability of the brain structures responsible for protective reaction. Radioimmunological evidence is presented for the resistance of animals to emotional stress to depend on the content in hypothalamus of certain oligopeptides, such as β-endorphin, DSIP, and the substance P. It was shown that animals resistant to emotional stress had a higher content of these oligopeptides in hypothalamus than those predisposed to stress. The issue is discussed that the prolonged anti-stressor effects after the DSIP administration are determined by considerable changes of the content of other polypeptides and hormones in hypothalamus and blood, which are involved in the reaction under the effect of DSIP.

The effects of delta sleep-inducing peptide on incidence and severity in metaphit-induced epilepsy in rats

The effects of delta sleep-inducing peptide (DSIP) on metaphit- (1-(1(3-isothiocyanatophenyl)-cyclohexyl) (piperidine)-) induced audiogenic seizures in adult male Wistar rats were studied. The animals were divided into four experimental groups: 1. saline injected; 2. metaphit administered (10 mg kg −1); 3. metaphit administered plus DSIP injected (dose range 0.1–1 mg kg −1) and 4. DSIP injected (1 mg kg −1). Upon treatment, the rats were exposed to sound stimulation ( 100 ± 3 dB, 60 s) at hourly intervals and the incidence and severity (running, clonus and tonus) of seizures were analyzed. In most animals, metaphit led to EEG abnormalities and elicited epileptiform activity recorded as spikes, polyspikes and spike–wave complex and increased power spectra. Time-course studies revealed the peak of convulsive activity 7–12 h after the injection in metaphit-treated rats. DSIP acted as an anticonvulsant and the most potent anticonvulsive dose of 1 mg kg −1significantly increased power spectra of δwaves (2–11 h) in comparison with the saline-control group and decreased the incidence and duration of convulsive response, as well as mean seizure grade of metaphit-induced convulsions. These results suggest that DSIP should be considered as having potential anticonvulsant activity in this animal model.

The effects of delta sleep-inducing peptide on the intensity of lipid peroxidation and xanthine oxidase activity in rat tissues during cold stress.

Exogenous delta sleep-inducing peptide given i.p. to intact rats at a dose of 12 microg/100 g decreased the levels of diene conjugates and Schiff bases in liver and brain tissues and had no effect on xanthine oxidase activity in these tissues. Cold stress was accompanied by increases in xanthine oxidase activity in rat liver and brain, with a consequent accumulation of diene conjugates and Schiff bases, as compared with intact animals. Preliminary administration of delta sleep-inducing peptide before three days of cold stress led to decreases in xanthine oxidase activity and lipid peroxidation products in the liver and brain, as compared with values in stressed rats. The protective effect of delta sleep-inducing peptide in stress is discussed.

Expression of the c-fos gene during emotional stress in rats: the clocking effect of delta sleep-inducing peptide.

Emotional stress induced more marked increases in the expression of the c-fos gene in limbo-reticular structures of the brain in rats prognostically predisposed to emotional stress. I.p. doses of delta sleep-inducing peptide (DSIP) (60 nmol/kg) weakened the stress-induced expression of the c-fos gene. This effect was more apparent in animals predisposed to emotional stress, in which preliminary injections decreased stress-induced c-fos expression in the paraventricular hypothalamus and the medial and lateral parts of the septum. The decreased expression of the early gene c-fos in emotional stress after preliminary dosage with DSIP may reflect the leading mechanism of the anti-stress action of this peptide.

Neurochemical characteristics of the effects of delta sleep-inducing peptide in wistar rats with hyperactivity of the dopaminergic system

Neurochemical characteristics of the effects of delta sleep-inducing peptide in wistar rats with hyperactivity of the dopaminergic system