Use of peptide acth (4-7) -pgp of hepatoprotective action

FIELD: biotechnology.

SUBSTANCE: hepatoprotector is used as peptide ACTH (4-7) -PGP (Semax) having the formula Met-Glu-His-Phe-Pro-Gly-Pro.

EFFECT: use of the said peptide with the aim of hepatoprotection under condition of the development of free-radical oxidation of hepatocytes enables to improve the efficiency of treatment of liver diseases accompanied by intensification of free radical oxidation processes.

1 tbl, 1 ex

 

The invention relates to medicine, namely to Hepatology, physiology, pathophysiology, and can be used for hepatoprotective effects.

It is known that in the body as a result of redox reactions constantly leads to the formation of reactive oxygen species (ROS), with high reactivity and catalytic processes of free radical oxidation of biomolecules.

In terms of the norms of free radicals play an important role in the vital processes of cells in various biological systems, participating in oxidative phosphorylation, the biosynthesis of prostaglandins and nucleic acids in the regulation of lipid metabolism, etc. But their role in biological systems are very dynamic, because free radicals are classified vysokoriskovannyh molecules, excessive formation which can quickly lead to disruption of cellular structures, disturbance of the functional activity of cells (Chesnokova N.P., Poucelina E.V., Lisenkova mathematical SCIENCES. Sources of free radicals and their importance in biological systems in terms of the norm // Modern high technologies. - 2006, №6. - P.28-34; VG Zaytsev, Zakrevsky VI Methodological aspects of the study of free radical oxidation and antioxidant system of the body // In the party Volgograd medical Academy. - 1998, T 4. 49-53. Mayansky, D.N. The problem of chronic inflammation in the modern pathophysiology // Pathol. Fiziol. and experimental. therapy. - 1994. No. 2. - P.51-55).

The toxic effect of ROS is prevented due to the functioning of antioxidant protection, presents the enzymatic and non-enzymatic components (Dubinin E.E. Role of reactive oxygen species as signaling molecules in tissue metabolism under oxidative stress // Questions of medical chemistry. - 2001, T, No. 6. - S-581). One of the first lines of defense cells from aggressive free radicals provide superoxide dismutase (SOD) and catalase, showing its activity in almost all cells of the human body, especially the liver, kidney, erythrocytes (Chesnokova N.P., Poucelina E.V., Lisenkova mathematical SCIENCES. Molecular and cellular mechanisms of inactivation of free radicals in biological systems // Successes of modern natural science. - 2006, No. 7. - P.29-36).

The liver as the most multifunctional organ belongs to a unique role in the regulation of the constancy of the internal environment of the body, has a high sensitivity to irritants (Zelikman O. Hepatotropic effects and monooxygenase system of the liver in chronic stress // Bulletin of the South Ural state University. - 2006, No. 3. S-122; skorupi VA Ultrastructure of liver cells p and stress. - Novosibirsk: Nauka, 1989. - 143 C.). Given the crucial role of the liver in homeostasis, this circumstance can adversely affect the health of other organs and systems.

In turn, the activation of free-radical oxidation processes underlies the pathogenesis of many diseases of the liver: nonalcoholic of steatohepatitis, viral diseases, and others, and the severity and prognosis of the disease is closely associated with the functional status of the antioxidant system of hepatocytes (Mesnjankina O.A., Naumov old Testament, Degtyarev O.V., Dujko CENTURIES of Free radical processes in the pathology of the liver in the elderly. Health organization Astrakhan medical journal. - 2011, No. 3. - P.39-43; breverb S.A. Oxidative stress and its role in liver damage // ROS. Journe. gastroenter., heat. and coloproctol. - 2002, No. 4. P.21-25).

This suggests that pharmacological agents that can activate the antioxidant enzymes must possess hepatoprotective properties (Ivanov Y., Matyushin I.A., Mishnev OD and other Effect of Mexidol in toxic liver damage // Bulletin of new medical technologies: the periodic theoretical and scientific-practical journal. - 2003. No. 3. - S-70).

Hepatoprotectors - drugs, improves metabolic processes in the liver, increasing its ostoich the stability to pathogenic influences, as well as contributing to the restoration of its functions under different damage (Karkishchenko NN. Clinical and environmental pharmacology terms and concepts. ): IMP-Medicine, 1995. - 304 S.).

Semax is heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro)obtained by synthetic analogue of a fragment 4-7 adrenocorticotropic hormone (ACTH), devoid of hormonal activity. He belongs to the group of cells with adaptive, analgesic and neuroprotective effects (Manchenko D.M., Glazov POSTGRADUATE, Levitskaya N.G. and other Neuroprotective and analgesic effects of Semax in various ways. - 2010. T, No. 10. - S-1023; Ivanov, D.M., Levitskaya N., Andreeva L.A. and other Comparative study of analgesic activity of a fragment of ACTH 4-10 and its analogue Semax // bul. the experimental. Biol. and medicine. - 2007, CH, No. 1. P.8-12).

Semax has antihypoxic effect (Ashmarin I.P., Nezavisimaya V.N., Meat eaters NF and other Nootropic similar adrenocorticotropin 4-10 - Semax (15-years experience of development and learning) // Ukr. the Supreme. a nerve. activity them. I.P. Pavlova. - 1997 T, No. 2. S-430; Levitskaya N.G., Sebentsov E.A., Andreeva L.A. and other Neuroprotective effects of Semax on the background of MPTP-induced disorders of the dopaminergic system of the brain // ROS. Fiziol. Journe. them. I.M. Sechenov. - 2002, T, No. 11. S-1377; Sebentsov E.A., Levitskaya N., Andreeva L.A. and other Effects this is KSA amid blockade of dopaminergic receptors by haloperidol // bul. the experimental. Biol. and medicine. - 2006, T, No. 2. S-132).

Semax administration has a stress-limiting effect on macrophage-proliferative and destructive processes in functionally-active zones of the spleen and limpidly plaques of the small intestine, inguinal lymph nodes, reduces stress-induced condition of the cells of the lymphoid series in peripheral blood (bachmat A.A. the Influence of some oligopeptides on the immune structure of lymphoid plaques small intestine // ROS. Journe. gastroenter., heat. and coloproctol. - 2008, No. 5. Ñ.38-44; bachmat A.A., Koplik E.V. anti-stress effect of Semax in the dynamics of recovery of lymphoid formations spleen after stress in rats with different behavioral activity // bul. exeem. Biol. and the honey. - 2012, T, No. 5. S-617; bachmat A.A. Morphological features of lymphoid structures of the inguinal lymph nodes of rats under emotional stress with the preliminary introduction of some oligopeptides // Saratov scientific medical journal. - 2009, Volume 5, No. 4. S-497).

Pepcid has anti-inflammatory effect (Gusev E.I., V.I. Skvortsova cerebral Ischemia. - M.: Medicine, 2001. 328 S.); able to prevent the increased generation of nitric oxide through the ischemic brain (Fadukova PU Semax prevents the increase of the generation of nitric oxide in the rat brain, due to incomplete Globa who enoy ischemia // Experiment. and the wedge. Pharmacol. - 2001, №64 (2). Pp.31-34).

In addition, the peptide ACTH (4-7)-GWP increases anticoagulant, total and non-enzymatic fibrinolytic activity, the activity of plasminogen activator in blood plasma of rats in conditions of immobilization stress (Ashmarin I.P., Lyapina L.A., Pastorova VE Modulation hemostatic reactions in vitro and in vivo representatives of the families of regulatory peptides, " Vestn. The RAMS. - 1996, No. 6. P.50-58; Grigorieva M.E. Ter-Minassian, Lyapina L.A. Anticoagulation and antiplatelet effects of the drug "Semax" in conditions of acute and chronic immobilization stress, Byull. experiment. Biol. and the honey. - 2010, CH, No. 1. 49-52), shows the antiaggregatory effects on platelets and reduces the level of heparin (Lyapina L.A., Pastorova V.E., Bergan T.U. Functional state of the anticoagulation system when exposed to a body of regulatory peptide Pro-Gly, Pro-Gly-Pro, the peptide and taphrina in connection with the natural heparin // Narkie. - 2008, V.25, No. 1-2. P.23-29); in norm increases the resistance of erythrocytes to hemolysis and reduces the interaction of red blood cells platelets, and in the conditions of immobilization stress without changing the rate of hemolysis, enhances the stability of erythrocytes (Golubeva MG Neuropeptide Semax alters the functional activity of erythrocytes and platelets in immobilization stress // Thrombosis,hemostasis and rheology. - 2010, No. 2. P.45-49).

The peptide increases the homeostasis of the gastric mucosa to the ulcerogenic action of such factors as ethanol and stress (Bakaeva ZINAIDA, Balikova CE, Klimov P.A. Mapping gastroprotective properties of Semax and its metabolites // Bulletin of Moscow University. Series 16: Biology. - 2009, issue 4. P.3-7).

However, the use of peptide ACTH (4-7)-GWP as hepatoprotector unknown.

The technical result is the new usage of the peptide ACTH (4-7)-GWP having the formula Met-Glu-His-Phe-Pro-Gly-Pro for the hepatoprotective effects.

The technical result is achieved by applying peptide ACTH (4-7)-GWP having the formula Met-Glu-His-Phe-Pro-Gly-Pro for the hepatoprotective effects. At the present time, because the known exact chemical formula of the peptide, it can be synthesized in any laboratory synthesis of peptides. The authors have used the drug, synthesized Russian cardiology research and production complex.

Dissolved in isotonic sodium chloride peptide ACTH (4-7)-GWP introduce experimental animals (rats) parenteral (intraperitoneal) in the dose of 5 and 50 mg/kg of body weight once a day for 5 days.

Specific example

Experimental animals (rats male Wistar) weighing 250-300 g were divided into group what s in 11 animals each (table). The animals were kept at the temperature of the air in the room at 22-24°C, light mode: 12 hours light, 12 hours dark, and received a standard pelleted food and water freely available in compliance with all regulations and International recommendations of the European Convention for the protection of vertebrate animals used in experimental research (1997), "Manual on experimental (preclinical) study of new pharmacological substances" (Moscow, 2005). At the time of the experiments the animals were healthy, changes in behavior, appetite, sleep and wakefulness are not detected.

Dissolved in isotonic sodium chloride to obtain the necessary doses of 5 and 50 mg/kg of body weight peptide ACTH (4-7)-PCP was administered to the experimental animal parenteral (intraperitoneal) once a day for 5 days. Control group animals received equivalent volumes of saline.

On the 5th day of the animals taken out of the experiment by exsanguination under ether anesthesia. A portion of liver was placed in cold saline and homogenized, followed by freezing at -20°C.

The functional state of the element of the antioxidant enzyme system of the liver was assessed by the content of superoxide dismutase (SOD) (Kostyuk V.A., A.N. Potapov, Kovalev IV // the honey. chemistry. 1990. No. 2. P.88-91) and catalase (Korolyuk M.A., Ivanova L.I., Mayorova I.G., Tokarev V.E. // lab. case. 1988. No. 1. P.16-19).

Statistical processing of results was made using t-student criterion and criterion of Mann-Whitney.

The experiments showed that after injection of peptide ACTH (4-7)-PCP at doses of 5 and 50 mg/kg activated element of the antioxidant enzyme system of the liver, indicating the hepatoprotective effect (table).

Table
The status element of the antioxidant enzyme system of the liver in norm and in the conditions of introduction of the peptide ACTH (4-7)-GWP.
Indicator
The group of animals
Control animalsIntroduction ACTH 4-7-PCP at a dose of 5 ág/kgIntroduction ACTH 4-7-PCP at a dose of 50 mg/kg
SOD, srvc. ed2,3±0,12,6±0,1*2,7±0,1*
Catalase, mkat/l4,8±0,25,8±0,3*5,6±0,3*
Note: * - p<0,05 in comparison with displaying the firs control group...

Thus, the results of experimental studies show that the use of the peptide ACTH (4-7)-PCP at doses of 5 and 50 mg/kg causes a hepatoprotective effect in animals in good condition. This method is based on application of regulatory peptide belonging to the class of biologically active substances with a strong modulatory effect and multifunctional, is not time consuming and does not require sophisticated equipment.

The use of peptide ACTH (4-7)-GWP having the formula Met-Glu-His-Phe-Pro-Gly-Pro, for the hepatoprotective effects.



 

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