Neuronal activity in the dorsal hippocampus after lateral hypothalamus stimulation: effects of delta-sleep-inducing peptide.

We studied central effects of delta-sleep-inducing peptide in the mechanisms of positive emotional state formation in rats. In Wistar rats preliminary tested in an open field, the reactions of 57 neurons of the dorsal hippocampus were analyzed during lateral hypothalamus stimulation and microionophoretic application of delta-sleep-inducing peptide. It was found that the number of neurons not responding to stimulation in the lateral hypothalamus surpassed the number of sensitive neurons (63 and 37%, respectively). Hippocampal neurons in active animals were less sensitive to stimulation of the lateral hypothalamus than in passive rats (33 vs. 42%) After application of delta-sleep-inducing peptide, only 28% neurons responded to stimulation. Thus, delta-sleep-inducing peptide reduced the sensitivity of hippocampal neurons to stimulation of the lateral hypothalamus.

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.

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.

Delta sleep-inducing peptide blocks excitatory effects of glutamate on rat brain neurons.

Microiontophoresis of delta sleep-inducing peptide primarily activated neurons in the dorsal hippocampus, anteroventral thalamic nucleus, lateral hypothalamus, and sensorimotor cortex. Microiontophoretic administration of glutamate markedly enhanced neuronal activity, while preliminary microionophoresis of delta sleep-inducing peptide blocked the excitatory effect of glutamate on neurons in these brain structures.

Cycloheximide prevents inhibition of expression of immediate early gene c-fos in paraventricular nuclei of rat hypothalamus produced by delta sleep-inducing peptide.

We studied expression of the immediate early gene c-fos in hypothalamic paraventricular nuclei in rats with different prognostic resistance to emotional stress receiving delta-sleep-inducing peptide after intracerebroventricular administration of cycloheximide. Delta-sleep-inducing peptide inhibited expression of the c-fos gene in rats receiving intracerebroventricular injection of physiological saline. Pretreatment with the protein synthesis blocker cycloheximide abolished changes produced by delta-sleep-inducing peptide.

[c-fos Gene expression during emotional stress in rats: blocking by delta sleep-inducing peptide]. / Ekspressiia gena c-fos pri émotsional'nom stresse u krys: blokiruiushchaia rol' peptida, vyzyvaiushchego del'ta-son.

An emotional stress induces an obvious immediate early gene c-fos expression in the brain limbic structures in the rats predisposed to emotional stress. Administration of the delta-sleep-inducing peptide (DSIP) was shown to inhibit the c-fos expression. It led to an obvious inhibition of the c-fos expression in paraventricular nuclei of the hypothalamus, medial and lateral parts of the septum of rats predisposed to emotional stress. This mechanism seems to play an important role in the DSIP anti-stress effects.

[Amphetamine-induced hyperfunction of the dopaminergic system and delta sleep-inducing peptide]. / Amfetaminovaia giperfunktsiia dofaminergicheskoi sistemy i peptid del'ta-sna.

Following amphetamine administration, the DSIP aggravated behavioural patterns but the EEG remained unaltered in the visual and motor cortex, and in the caudate nucleus. The findings suggest that the peptides modulating action depends on the way of dopamine hyperfunction initiation.

Studies of the mechanism of the anticonvulsant effect of delta-sleep-inducing peptide in conditions of increased oxygen tension.

Studies of the protective actions of three doses of delta-sleep-inducing peptide (DSIP) given at different times before barochamber compression of animals to an oxygen tension of 0.7 MPa showed that the optimum DSIP dose is 12 micrograms/100 g. Intraperitoneal administration of this dose of DSIP delayed the onset of generalized convulsive activity by a factor of 2-2.5 in animals exposed to an oxygen tension of 0.7 MPa and promoted normalization of the sleep-walking cycle within 24 h after exposure to hyperbaric oxygen (HBO), by creating an optimal balance between excitatory and inhibitory amino acid neuromediators.

[The delta sleep-inducing peptide, its analogs and the serotoninergic system in the development of anticonvulsant action]. / Del'ta-son indutsiruiushchii peptid, ego analogi i serotoninergicheskaia sistema v razvitii protivosudorozhnogo deistviia.

A seizure-protecting effect of the delta-sleep-inducing peptide (DSIP) and its analogues was revealed. An intensive sorption of H3 tryptophan occurred under the effect of the DSIP and its analogues. The data obtained suggests that the serotoninergic system plays no important part in the seizure-protecting effect.

[Comparative investigation of anticonvulsive effects of putrescine and structural analogues of delta-sleep-inducing peptide]. / Sravnitel'noe izuchenie protivosudorozhnykh effektov putrestsina i strukturnykh analogov indutsiruiushchego delta-son peptida.

Intracysternal putrescine before a session of hyperbaric oxygenation (0.7 MPa) was shown to be more effective in prolonging the latent period of onset of generalized convulsive activity than intraperitoneal delta-sleep-inducing peptide or its structural analogues ID-1 or ID-3. Biochemical studies indicated that putrescine was also more effective in preventing hyperbaric oxygenation-induced decreases in the levels of GABA and homocarnosine in the brain and the accumulation of lipid peroxidation products in the brain and serum.

[The mechanism of the anticonvulsive effect of the delta sleep-inducing peptide under conditions of elevated oxygen pressure]. / Issledovanie mekhanizma protivosudorozhnogo éffekta del'ta-son indutsiruiushchego peptida v usloviiakh povyshennogo davleniia kisloroda.

Delta-sleep-inducing peptide (DSIP) exerted a protective effect against seizures, the effect depending on the DSIP ability to create an optimal ratio between inhibitory and excitatory amino acid neurotransmitters. Administration of the DSIP dramatically increased the contents of gamma-aminobutyric acid and homocarnosine while decreasing the glutamate and aspartate contents in the rat brain cortex.

[The neuromediator mechanism of the additive action of the delta sleep-inducing peptide in experimental audiogenic epilepsy caused by hypokinesia]. / Neiromediatornyi mekhanizm adaptivnogo deistviia del'ta-son indutsiruiushchego peptida pri éksperimental'noi audiogennoi épilepsii, vyzvannoi gipokineziei.

The DSIP influence on the rat cortex, thalamic and hypothalamic adrenaline, noradrenaline, DOPA, dopamine and serotonin level under normal, hypokinetic stress condition (1 h in duration) and experimental audiogenic epilepsy was studied. It was found, that a single intraperitoneal DSIP injection (12 microns/100 g body weigh, 1 h before placing the animals into the stress condition) prevented spontaneous epileptic activity development due to creation of optimal ratio between monoamines in brain structures.

Delta-sleep-inducing peptide sequels in the mechanisms of resistance to emotional stress.

The aim of this study is to investigate time-related changes in substance P (SP), beta-endorphin (BE), and corticosterone (CORT) levels due to DSIP aftereffects in the control and stress rats. Experiments were carried out on male Wistar and August rats. The SP and BE immunoreactivity in the hypothalamus and plasma samples was determined radioimmunologically. Blood CORT level was determined radioimmunologically. The rats were stressed at nighttime in special cages and tied by tails to the back side of the cage. The stress experiments were repeated for 12 hours for 5 days. There were 6 groups: 1. control animals, 2. stress animals, 3. rats that received DSIP in a dose of 60 nmol/kg one hour before decapitation, 4. rats in which DSIP was injected 24 hour before decapitation, 5. stressed rats in which DSIP was injected one hour before decapitation during the 5th exposure to stress, 6. stressed rats to which DSIP was injected 12 hours before the 5th exposure to stress, i.e., 24 hours before decapitation. Our experiments showed that DSIP administration induced marked changes in SP, BE, and CORT levels in hypothalamus and blood plasma. This suggests that the long-term stress-coping effect of DSIP depends on considerable changes in the level of other oligopeptides and hormones induced by DSIP. Evidently, DSIP triggers these processes inducing a cascade of interrelated molecular reactions radically different in animals with different resistance to emotional stress. This cascade of sequential reactions is different in Wistar and August rats differing by their resistance to emotional stress. DSIP administration stimulates the mechanism of resistance in August rats to a lesser extent than in Wistar animals.

[Changes in the content of substance P, beta-endorphin and corticosterone in the hypothalamus and blood of rats with emotional stress after the administration of the delta sleep-inducing peptide]. / Izmenenie soderzhaniia veshchestva P, beta-éndorfina i kortikosterona v gipotalamuse i krovi krys pri émotsional'nom stresse posle vvedeniia peptida, vyzvaiushchego del'ta-son.

The aim of this study was to investigate time-related changes in substance P (SP) beta-endorphin (BE), and corticosteron (CORT) levels induced by DSIP administration in rats subjected to emotional stress. Experiments were carried out in male Wistar and August rats with different resistance to emotional stress. At night rats were tied by their tails to the backside of the special cages. These stress-inducing procedure was repeated for 12 hours daily in the course of 5 days. SP and BE immunoreactivity in the hypothalamus and plasma and blood CORT level were determined radioimmunologically. Six groups of animals were formed: 1. control animals; 2. stressed animals; 3. rats which received DSIP in a dose of 60 nmol/kg one hour before decapitation; 3. rats to which DSIP was injected 24 hours before decapitation; 5. stressed rats to which DSIP was injected one hour before decapitation during the 5th exposure to stress; 6. stressed rats to which DSIP was injected 12 hours before the 5th exposure to stress, i.e. 24 hours before decapitation. Our experiments showed that DSIP administration induced marked changes in SP, BE, and CORT levels in the hypothalamus and blood plasma. This suggests that long-term stress-coping effects of DSIP in underlied by considerable changes in the content of other oligopeptides and hormones. Evidently, DSIP triggers these processes inducing a cascade of interrelated molecular reactions which are different in Wistar and August rats. It seems likely that DSIP administration stimulates the mechanisms of resistance in August rats to a lesser extent than in Wistar rats.

[The effect of the intranigral use of the delta sleep-inducing peptide and its analogs on the motor and seizure activities of rats]. / Vliianie vnutrinigral'nogo primeneniia del'ta-son indutsiruiushchego peptida i ego analogov na dvigatel'nuiu i sudorozhnuiu aktivnost' krys.

The effects of delta-sleep inducing peptide (DSIP) and its analogues (1-4) administered into substantia nigra pars reticulata on locomotor and seizure activity were estimated in experiments in rats. It was shown that intranigral microinjection of DSIP as well as DSIP-1-DSIP-4 caused decreasing of horizontal, vertical locomotor activity and attendance of central sectors of the "open field". Antiseizure effects, i.e. the first and clonic-tonic picrotoxin-induced convulsive latent period lengthening and their intensity decreasing, revealed DSIP, DSIP-2 and DSIP-3. Authors suppose that changes of DSIP structure lead to changes of effects expression on locomotor and seizure activity in conditions of their administration into substantia nigra reticulata. Obtained data concerning protective effects of studied peptides on experimental seizure syndrome allow to conclude that there is interaction between DSIP-induced hypokinesia and DSIP analogues anticonvulsive effectiveness in case of their intranigral administration which is likelihood is one of the component of nigral-dependent seizure-suppressive mechanism.

[The frequency composition of the brain electrical activity in rats after the use of the delta-sleep peptide and its analogs]. / Chastotnyi sostav élektricheskoi aktivnosti mozga krys posle primeneniia peptida del'ya-sna i ego analogov.

Frequency spectra of brain electrograms in the course of 1 h after peripheral and central administration of the delta-sleep peptide (DSIP) or two its analogues were studied in freely moving rats. In autumn series of experiments carried out on 18 animals was revealed the phase action of DSIP being manifested in initial (up to 20 min after the injection) suppression of fast (20-26 Hz) oscillations in electrocorticograms and their augmentation in subsequent intervals. Under the identical conditions analogues of DSIP induced the effects characteristic for different phases of DSIP action. In spring-summer series of experiments carried out in 6 animals was revealed a significant increase of the delta-waves in electrical activity of the Putamen after intraperitoneal injection of DSIP and its first analogue. Under the conditions of intraventricular injection DSIP induced stable augmentation of oscillations in a diapason of 14-16 Hz in the neocortex, and its analogues induced similar changes in a nearby frequency diapason of 9.6-11 Hz.

Delta sleep-inducing peptide as a factor increasing the content of substance P in the hypothalamus and the resistance of rats to emotional stress.

The influence of delta sleep-inducing peptide (DSIP, 60 and 120 nmole/kg, intraperitoneally) on the content of substance P (SP) in the hypothalamus of rats was studied in male rats of the August line. It was demonstrated that the administration of DSIP significantly increases the average content of SP in the hypothalamus, as well as its content in animals resistant to and predisposed to emotional stress. A daily one-time administration of DSIP before placing the rats in conditions of stress increases the content of SP in the hypothalamus which was decreased during emotional stress. The preliminary one-time administration of DSIP to animals subjected to a stressor influence also increases the SP content in the hypothalamus. It was established that a one-time administration of DSIP in a dose of 60 nmole/kg sharply decreases the classical manifestations of stress such as the hypertrophy of the adrenals and involution of the thymus.