Hepatoprotective Effect of Neonatal Administration of Non-Opioid Leu-Enkephalin Analogue in Adult Albino Rats Subjected to Antenatal Hypoxia.

We studied the effects of neonatal administration of non-opioid leu-enkephalin analogue peptide NALE) on the morphological parameters of the liver and redox status of 60-dayold albino rats subjected to antenatal hypoxia. In animals subjected to antenatal hypoxia, a decrease body weight and reduction of the area of hepatocytes and total area of their nucleoli were observed; these changes were accompanied by activation of free-radical processes and impairment of antioxidant defense in the liver and blood serum. Intraperitoneal administration of NALE (100 µg/kg, daily) during postnatal days 2-6 normalized body weight, hepatocyte area, and total area of their nucleoli, significantly reduced the intensity of ROS generation, and improved antioxidant protection in the liver and blood serum in 60-day-old animals subjected to antenatal hypoxia.

Delayed Effects of Neonatal Administration of Non-Opioid Analog of Leu-Enkephalin on Cerebral Consequences of Antenal Hypoxia.

In 60-day-old male rats after antenatal hypoxia, the body weight and the absolute weight of the cerebral hemispheres were significantly lower than in the progeny of intact animals. Analysis of brain sections stained with silver nitrate revealed reduced number of nucleoli in neocortical layer II and hippocampal CA1 neurons and smaller area of neuronal nuclei in neocortical layer V and total area of nucleoli in neurons of all studied zones. The animals demonstrated increased locomotor activity in the elevated plus-maze test. Chemiluminescent analysis of brain homogenates revealed the presence of oxidative stress at the organ level. Neonatal administration of non-opioid analog of leu-enkephalin (peptide NALE) after antenatal hypoxia normalized body weight, neutralized morphometric changes in the nucleoli and nuclei of neurons in the neocortex and hippocampus, and improved oxidative status of the brain. In 30- and 60-day-old male rats subjected to antenatal hypoxia and receiving peptide NALE during the neonatal period, behavioral responses were partially normalized. Non-opioid analog of leu-enkephalin can be a promising drug for correction of cerebral consequences of antenatal hypoxia.

δ opioid receptor antagonist, ICI 174,864, is suitable for the early treatment of uncontrolled hemorrhagic shock in rats.

BACKGROUND: Fluid resuscitation is the essential step for early treatment of traumatic hemorrhagic shock. However, its implementation is greatly limited before hospital or during evacuation. The authors investigated whether δ opioid receptor antagonist ICI 174,864 was suitable for the early treatment of traumatic hemorrhagic shock. METHODS: With uncontrolled hemorrhagic-shock rats, the antishock effects of six dosages of ICI 174,864 (0.1, 0.3, 0.5, 1, 3, and 5 mg/kg) infused with or without a small volume of lactated Ringer's solution (LR) before bleeding controlled or bleeding cessation at different times were observed. RESULTS: ICI 174,864 (0.1-3 mg/kg) with or without 1/4 volume of LR infusion showed dose-dependent increase in the mean arterial blood pressure, and significantly prolonged the survival time and 8-h survival rate, as compared with ICI 174,864 plus 1/2 volume of LR infusion. The best effect was shown with 3 mg/kg of ICI 174,864. Bleeding cessation at 1, 2, or 3 h during infusion of ICI 174,864 (3 mg/kg) plus 1/4 volume of LR improved subsequent treatment (70% 24-h survival rate vs. 50 and 10% 24-h survival rate in hypotensive resuscitation and LR group, respectively). There was significant improvement in hemodynamic parameters, oxygen delivery, and tissue perfusion of hemorrhagic-shock rats with 3 mg/kg of ICI 174,864 plus 1/4 volume of LR infusion. CONCLUSION: δ Opioid receptor antagonist ICI 174,864 alone or with small volume of fluid infusion has good beneficial effect on uncontrolled hemorrhagic shock. Its early application can "buy" time for subsequent treatment of traumatic shock.

[Effect of opiod peptides on free radical oxidation in a bone regenerate after fracture].

Opioid peptides (DSLET and DAGO) stimulating bone tissue regeneration were studied for effects on content of free radical products in regenerate tissue from the region of leg fracture in mice at various terms of reparative osteogenesis. These opioids reduce concentration of malonic dialdehyde and dienic conjugastes in bone for 10 days after fracture.

[Correction of temperature homeostasis and microcirculation under the stress-protection anesthesia in hip replacement]. / Korrektsiia temperaturnogo gomeostaza i mikrotsirkuliatsii v usloviiakh stress-protektornoi anestezii pri éndoprotezirovanii tazobedrennogo sustava.

Prolonged epidural anesthesia belongs to the most effective anesthetic management schemes in total hip replacement. However, its use is related with compensatory stress-induced vasoconstriction resulting in an impaired vasoconstriction registered above the block level. It entails, in its turn, an impaired thermoregulation (hypothermia, postoperative muscle trembling), a reduced renal blood flow with diminished diuresis and metabolic lactate-acidosis. The preoperative preparation with daralgin (15 microg/kg, 3 intramuscular injections per day for 2-3 days) with its subsequent intraoperative infusion (30 microg/h) made concurrently with premedication by clofelin (1.5 microg/kg) arrest the above hemostasis impairments. Finally, the ability of stress-protection drugs to diminish the rate of postoperative fever and muscle trembling was registered.

Improved blood-brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation.

Neuropeptide pharmaceuticals have potential for the treatment of neurological disorders, but the blood-brain barrier (BBB) limits entry of peptides to the brain. Several strategies to improve brain delivery are currently under investigation, including glycosylation. In this study we investigated the effect of O-linked glycosylation on Ser(6) of a linear opioid peptide amide Tyr-D-Thr-Gly-Phe-Leu-Ser-NH(2) on metabolic stability, BBB transport, and analgesia. Peptide stability was studied in brain and serum from both rat and mouse by high-performance liquid chromatography. BBB transport properties were investigated by rat in situ perfusion. Tail-flick analgesia studies were performed on male ICR mice, injected i.v. with 100 microg of peptide ligand. Glycosylation of Ser(6) of the peptide led to a significant increase in enzymatic stability in both serum and brain. Glycosylation significantly increased the BBB permeability of the peptide from a value of 1.0 +/- 0.2 microl x min(-1) x g(-1) to 2.2 +/- 0.2 microl x min(-1) x g(-1) (p < 0.05), without significantly altering the initial volume of distribution. Analgesia studies showed that the glycosylated peptide gave a significantly improved analgesia after i.v. administration compared with nonglycosylated peptide. The improved analgesia profile shown by the glycosylated peptide is due in part to an improvement in bioavailability to the central nervous system. The bioavailability is increased by improving stability and transport into the brain.

Peculiarities of ischemic cardiac arrhythmias in cats against the background of stimulation of sensorimotor cortex and administration of selective opiate receptor agonists.

In acute experiments on Nembutal-anesthetized cats, the effect of opiate receptor agonists DAGO, DSLET, and dinorphin A(1-13) on the incidence of idioventricular rhythm disturbances, including ventricular tachycardia and fibrillation, was studied under conditions of occlusion of circumflex branch of the left coronary artery and stimulation of the sensorimotor cortex. The most pronounced effects were observed with DSLET and dinorphin A(1-13). These preparations completely prevented ventricular fibrillation. DAGO produced a less pronounced protective effect probably because of parallel increase in plasma catecholamine concentration.

[Peptide correction of arrhythmias induced by stimulation of the vagal sympathetic trunk in cats]. / Peptidnaia korrektsiia aritmii, vyzvannykh razdrazheniem vagosimpaticheskogo stvola u koshek.

The effects of met-enkephalin, leu-enkephalin, D-Ala2-metenkephalin, and somatostatin on Wenckebach arrhythmia and atrioventricular dissociation was investigated in experiments on anesthesized cats. Arrhythmias were induced by stimulation of the vagus with short repetitive bursts of pulses. Enkephalins evoked a protective effect in both arrhythmias whereas somatostatin had no antiarrhythmic properties. The protective effect of enkephalins persisted after blockage of mu-opiate receptors with naloxone (0.2 mg/kg), but in high doses (2 mg/kg), which blocked both mu- and delta-opiate receptors, antiarrhythmic effects was abolished. It is concluded that the protective effect of enkephalins against vagally induced arrhythmias may be due to the stimulation of delta-opiate receptors located on the presynaptic vagal endings. As a results, stimulation-evoked acetylcholine release is diminished, which prevent the arrhythmogenic effect of the vagus nerve.

[A pharmacological analysis of the antiedematous action of GABA-ergic and opioidergic agents in craniocerebral trauma]. / Farmakologicheskii analiz protivootechnogo deistviia GAMK- i opioidergicheskikh sredtsv pri cherepno-mozgovoi travme.

Experiments on rats with skull inquiry show that biculline (dose 2 mg/kg) removes antiedematous effect of fenibut (50 mg/kg), sodium hydroxybutirate (200 mg/kg), promedol (1 mg/kg), and synthetic analogs of encephalines DAGO and DSLET (100 mg/kg). Naloxon at a dose 1 mg/kg blocks antiedematous effect of ligands of opiate receptors, but does not change the effect of fenibut and sodium hydroxybutirate. The presence of close inter-regulatory interactions between GAMK-ergic and opioidergic systems in forming the traumatic correction is suggested.

[Microcirculatory disorders in cerebral ischemia in rats and their correction by using leu-enkephalin]. / Narusheniia mikrotsirkuliatsii pri ishemii mozga u krys i korrketsiia ikh s pomoshch'iu lei-énkefalina.

Leu-enkephalin (LE) induced mainly a constriction of pial arterioles, diameter of the venules did not change. The effect of the LE involved preservation of the cerebral blood flow and that in microvessels, constriction of some arterioles and reduced dilatation against the background of decreased arterial pressure, bradycardia, increased lymphatic flow and survival of the animals during first hours of occlusion of common carotid arteries.

[The effect of various types of stress-limiting therapy on the outcome of myocardial infarction]. / Vliianie razlichnykh variantov stress-limitiruiushchei terapii na iskhod infarkta miokarda.

A method for computed determination of death probability was used to examine the effects of various modalities of stress-limiting therapy on mortality rates within a month after myocardial infarction. The examination was made in 591 patients with large myocardial infarction. A significant decrease in mortality rates was seen in patients on finoptin and phosphocreatine (by 9.6 and 11.2, respectively) as compared to the expected drop. Other agents given within the first hours of myocardial infarction such as beta-blockers, opioid peptides, sodium oxybutyrate, piracetam, antioxidants were demonstrated to cause no reduction in mortality rates.

[Treatment of peptic ulcer hemorrhage with leucine enkephalin analog dalargin]. / Lechenie iazvennykh gastroduodenal'nykh krovotechenii s primeneniem analoga leitsin--enkefalina-dalargina.

The article discusses treatment of 72 patients suffering from duodenal ulcer complicated by bleeding with the Soviet-made preparation Dalargin which is a synthetic analogue of leucine-enkephalin. The preparation was infused intravenously in a dose of 3 mg in physiological solution once daily. No other additional antiulcerative agents were give. The diagnosis was established on the basis of endoscopy. Dalargin led to cicatrization of the ulcers in 20.3 days in 60% of patient, obvious positive dynamics was noted in 32% of patients; in 8% of patients Dalargin proved ineffective. Basal hydrochloric acid secretion reduced by 56% during treatment.

[Effect of the leucine enkephalin analog dalargin on the components of the sympathetico-adrenal system in experimental myocardial infarction]. / Vliianie analoga leitsin-énkefalina-dalargina-na sostoianie komponentov simpatiko-adrenalovoi sistemy pri eksperimental'- nom infarkte miokarda.

A histofluorescence study was made of catecholamine saturation of the adrenergic nervous plexuses of the intact zone of rabbit left ventricles and adrenal medullas on days 3 and 7 of experimental myocardial infarction induced by ligation of the anterior branch of the left coronary artery when dalargrin, a leucine-enkephalin analogue, was administered. Dalargin was shown to decrease catecholamine saturation of myocardial nervous plexuses and to reduce detection rates of mediator accumulation in the sympathetic axons of nervous fascicles. In addition, the agent caused a decrease in the hormone content in chromaffinocytes on day 3 of the experiment and contributed to recovery of their functional homogeneity.

[Effects of dalargin on proliferative processes and vertical migration of cells of the corneal epithelium during stress]. / Vliianie dalargina na proliferativnye protsessy i vertikal'nuiu migratsiiu kletok épiteliia rogovitsy pri stresse.

We studied the effect of synthetic analogue of opioid peptides dalargin on kinetics of cell population of corneal epithelium during stress. It was found out that dalargin introduction before stress decreased the level of pathological mitoses induced by the acute stress action in white rats early in the morning. Dalargin prevented the activation of the proliferative process after the repeated stress activation, made stress milder. The stress induced vertical migration of the cells of the corneal epithelium normalized by dalargin. We believe these results show that dalargin has a good protective effect.

[The inhibitory effect of the synthetic leu-enkephalin analog dalargin on carcinogenesis]. / Tormoziashchee vliianie sinteticheskogo analoga leiénkefalina dalargina na kantserogenez.

Dalargin, an opioid peptide (Tyr-D-Ala-Gly-Phe-Leu-Arg), was shown to significantly inhibit the carcinogenic effect of 50 mg/kg body weight nitrosomethylurea given as single i. v. infection. The treatment was followed by an increase in the tumor latency period. Moreover, the overall incidence of tumors decreased by 20% whereas that of malignant neoplasms and breast adenocarcinoma--by 33 and 27%, respectively. Pronounced inhibitory effect of dalargin on hematopoietic tumor induction was identified, too.

[A comparative study of the effectiveness of regulatory peptides in acute experimental pancreatitis]. / Sravnitel'naia otsenka éffektivnosti reguliatornykh peptidov pri ostrom éksperimental'nom pankreatite.

The effect of regulatory peptides on the functional activity of pancreatic cells and phagocytic cells of reticuloendothelial system were determined in intact dogs against the background of acute experimental pancreatitis. Assessment of the efficacy of regulatory peptides was made with the aid of scintigraphic studies in gamma chamber using for this purpose colloid 198Au and 75Se-methionine. It was established that introduction of regulatory peptides to dogs leads to inhibition of capture of labeled methionine by pancreatocytes, practically not influencing the elimination of colloid gold from circulation.