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GHK- Anti-Pain (Analgesic) and Anti-Anxiety (Anxiolytic) Actions

1. Opiate peptides help with wound healing and pain control in rats. This appears to be mediated through the opioid mu1 recpetors and other receptors.

2. GHK possesses both strong wound healing and mild anti-pain activities. Based on Broad Institute data, GHK increases expression of the opioid mu1 gene OPRM1 by 13.9 fold. It also increases gene expression of the cannabinoid pain-reducing gene CNR1 by 2.7 fold (average of +3.1 and +2.3).

Gene, Gene Expression Fold Changes, and Gene Effects

OPRM1 +13.9 Opioi mu 1- High Affinity for enkephalins and beta-endorphins

CNR1 + +2.3 and3.1 - Cannabinoid receptor pain-reducing

AMPA3/GRIA3 +6.4 - glutamate receptor, retrograde endocannaboid signaling, nervous system

OPRL1 +3.5 - Receptor for neuropeptide nociceptin

PNOC - +2.5 - prepronociceptin, complex interactions with pain and anxiety induction

OPRK1 - 2.2 - decline, cocaine effects

OXT + 2.4 oxytocin, bonding protein - gene also increases human chorionic gonadotropin

SIGMAR1 +2.6 non-opioid receptor

CCKAR2 +2.9 cholecystokinin, affects satiety, release of beta-endorphin and dopamine

3. This anti-pain and wound healing effect of GHK is similar to the anti-pain and wound healing effects that were found by John Sorenson in DIPS-Copper (diisopropylsalicylate-copper). Sorenson's DIPS-copper was found to have a greater analgesic action than morphine.

4. The anti-anxiety action of GHK may be related to its anti-pain effects.

Anti-Pain (Analgesic) Actions of Opioid Peptides

Different expression of mu-opiate receptor in chronic and acute wounds and the effect of beta-endorphin on transforming growth factor beta type II receptor and cytokeratin 16 expression. Bigliardi PL1, Sumanovski LT, Büchner S, Rufli T, Bigliardi-Qi M.J Invest Dermatol. 2003 Jan;120(1):145-52.

There is evidence that neuropeptides, especially the opiate receptor agonists, are involved in wound healing. We have previously observed that beta-endorphin, the endogenous ligand for the mu-opiate receptor, stimulates the expression of cytokeratin 16 in a dose-dependent manner in human skin organ cultures. Cytokeratin 16 is expressed in hyperproliferative epidermis such as psoriasis and wound healing. Therefore we were interested to study whether epidermal mu-opiate receptor expression is changed at the wound margins in acute and chronic wounds. Using classical and confocal microscopy, we were able to compare the expression level of mu-opiate receptors and the influence of beta-endorphin on transforming growth factor beta type II receptor in organ culture. Our results show indeed a significantly decreased expression of mu-opiate receptors on keratinocytes close to the wound margin of chronic wounds compared to acute wounds. Additionally beta-endorphin upregulates the expression of transforming growth factor beta type II receptor in human skin organ cultures. These results suggest a crucial role of opioid peptides not only in pain control but also in wound healing. Opioid peptides have already been used in animal models in treatment of wounds; they induce fibroblast proliferation and growth of capillaries, and accelerate the maturation of granulation tissue and the epithelization of the defect. Furthermore opioid peptides may fine-tune pain and the inflammatory response while healing takes place. This new knowledge could potentially be used to design new locally applied drugs to improve the healing of painful chronic wounds.

GHK and Anti-Pain (Analgesic)

Application of peptide gly-his-lys for analgesic effect in pain caused by thermal irritation. RU patent 2421235.

SUBSTANCE: invention refers to medicine, namely physiology, pathophysiology and pharmacology, and may be used for an anxiolytic (antianxiety) effect. Substance of the invention consists in the use of peptide Gly-His-Lys of formula (NH2)Gly-His-Lys(COOH) for the anxiolytic effect. The experimental use of peptide Gly-His-Lys in single doses of 0.5 and 5 mcg/kg of body weight 12 minutes before the beginning of the examination causes the manifested anxiolytic effect.

EFFECT: invention allows applying known peptide Gly-His-Lys with manifested analgesic effect for a new purpose.

The invention relates to medicine, namely to the physiology and pathophysiology, and can be used for an analgesic effect in the pain caused by thermal stimulation.

In the literature, many authors described the properties of the peptide Gly-His-Lys. Known for its modulating effect in the regulation of cell growth and differentiation (Kato K., Kasai S., Onodera K. et al. Effect of hepatocyte growth factor on the proliferation of transplanted hepatocytes in the spleen. / / Transplant. Proc. - 1997. - Vol.29, № 4. - P.2029-2031; Sporn MB, Roberts AB Transforming growth factor-in: recent progress and new challenges. / / J. Cell Biol. - 1992. - Vol.119, № 5. - P.1017-1021). Several studies have confirmed the effect of the peptide as a stimulator of wound healing, as is known for its stimulating effect on collagen synthesis by fibroblasts (Maquart FX, Bellon G., Chaqour V. et al. In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L- histidyl-L-lysine-Cu2 + in rat experimental wounds. / / J. Clin. Invest. - 1993. - Vol.92, № 5. - P.2368-2376). It is shown that Gly-His-Lys promotes stimulation of physiological and reparative regeneration of the liver (Smakhtin MY, sewing IA, Hemp AA Bobyntsev II method for stimulating physiological and reparative regeneration of the liver. - Patent for invention number 2214269, of 20.10.2003). Known as a stimulating effect on hair growth peptide (Trackhy RE, Fors TD, Pickart L., Uno H. The hair follicle-stimulating properties of peptide copper complexes. Results in C3H mice / / Ann. N.-Y. Acad. Sci. - 1991. - Vol.642, № 10. - P.468-469) and anti-inflammatory effect associated with a decrease in iron release from ferritin in the damaged tissues (Miller DM, DeSilva D., Pickart L., Aust SD Effects of glycyl- histidyl-lysyl chelated Cu (II) on ferritin dependent lipid peroxidation / / Adv. Exp. Med. Biol. - 1990. - Vol.264. - P.79-84.).

The object of the invention is the use of a new purpose peptide Gly-His-Lys, having the formula: (NH 2) Gly-His-Lys (COOH), for an analgesic effect in the pain caused by thermal stimulation.

The task of the invention is achieved by applying the peptide Gly-His-Lys to an analgesic effect in the pain caused by thermal stimulation. Currently, as accurately known chemical formula of the peptide, it can be synthesized in any laboratory synthesis of peptides or purchased from companies engaged in the supply of biologically active compounds (Sigma, ICN, Merk, Bachim etc.). We used the drug, synthesized in the Institute of Chemistry at St. Petersburg State University. Dissolved in isotonic sodium chloride peptide Gly-His-Lys administered to experimental animals (mice), parenteral (i.p.) once daily doses of 0.5 and 5 mg / kg body weight 12 minutes before the onset of the pain stimulus.

Example of a specific implementation.

The experimental animals (male mice lines BALB / c) weighing 20-25 g were divided into groups of 10 animals each (Table). The animals were kept at a room temperature 22-24 C °, light regime: 12 hours - light, 12 hours - darkness and received standard pelleted food and water freely available.

In the experiment, the temperature sensitivity to pain can be estimated on the method of "hot plate" (Sernov LN Gatsura V. Elements of Experimental Pharmacology. - M., 2000. - 352.). In this method, an increase in the latent period of the reaction licking paws indicates the presence of an analgesic effect.

To examine sensitivity to pain during thermal exposure, mice were placed on a glass plate with excess cylinder heated to a temperature of 55 ° C. Test 4 was carried out for 1 minute at intervals of 1 min. Pain sensitivity was evaluated by the magnitude of the latent period (in seconds) reaction licking paws in the 2nd test.

The peptide Gly-His-Lys were dissolved in isotonic sodium chloride solution to obtain the required dose - 0.5 and 5 mg / kg animal body weight. Parenterally administered (i.p.) once the volume of experimental animals obtained the rate of 1 ml per 1 kg body weight (0.1 mL) for 12 minutes prior to a painful stimulus. Control animals received equivalent volume of saline (FR).

Thus, the results of experimental studies have shown that the use of the peptide Gly-His-Lys at doses of 0.5 and 5 mg / kg caused a pronounced analgesic effect in the pain provoked by thermal stimulation. This method is based on the use of regulatory peptides, belonging to the class of biologically active substances with a pronounced and polyfunctional modulatory effect is not tedious and does not require the use of complex equipment.

CLAIMS

Use of the peptide Gly-His-Lys, having the formula: (NH 2) Gly-His-Lys (COOH) for the analgesic effect in the pain caused by thermal stimulation.

Anti-Anxiety (Anxiolytic)

Biological sciences
PDF (2434 K)  |  p. 357-360
1
ВЛИЯНИЕ ТРИПЕПТИДА GLY-HIS-LYS НА ПОВЕДЕНИЕ КРЫС В ТЕСТЕ «ОТКРЫТОЕ ПОЛЕ»
Чернышёва О.И. 1, Бобынцев И.И. 1, Долгинцев М.Е. 1
1. ГБОУ ВПО «Курский государственный медицинский университет» Минздрава РФ

Резюме:

Ключевые слова: открытое поле, пептид Gly-His-Lys, тревожность, поведение, эмоциональность

2
THE TRIPEPTIDE GLY-HIS-LYS INFLUENCE ON BEHAVIOR OF RATS IN THE TEST «OPEN FIELD»
Chernysheva O.I. 1, Bobyntsev I.I. 1, Dolgintsev M.E. 1
1. Kursk State Medical University

Abstract:

The influence of the tripeptide Gly-His-Lys (hepatocyte growth factor, GHK) administered intraperitoneally 12 minutes before the start of the experiment at doses 0.5, 5 and 50 mkg / kg on male Wistar rats behavior in the test «open field» once with the exposure time 5 minutes has been analyzed. The peptide at all doses used caused a reduction of the manifestations of fear and anxiety manifested in increasing of the exploratory activity and decreasing of the immobility reaction in both the peripheral and in the central parts of the «open field». Emotionality indices (grooming and defecation) did not change significantly. The character of the received results suggests the presence of the peptide neurotropic effects, including anxiolytic.

Keywords: open field, the peptide Gly-His-Lys, anxiety, behavior, emotionality

...............................................................................................

Use of peptide gly-his-lys for anxiolytic effect. RU patent 2480232.

SUBSTANCE: invention refers to medicine, namely physiology, pathophysiology and pharmacology, and may be used for an anxiolytic (antianxiety) effect. Substance of the invention consists in the use of peptide Gly-His-Lys of formula (NH2)Gly-His-Lys(COOH) for the anxiolytic effect. The experimental use of peptide Gly-His-Lys in single doses of 0.5 and 5 mcg/kg of body weight 12 minutes before the beginning of the examination causes the manifested anxiolytic effect.

EFFECT: invention provides the use of peptide Gly-His-Lys by the new application, namely for anxiolytic action. The invention relates to medicine, namely to physiology, pathophysiology and pharmacology, and can be used for anxiolytic () effect. In the literature a number of researchers describes the properties of the peptide Gly-His-Lys. The modulatory effect of the regulation of processes of growth and differentiation of cells (Kato, K. Kasai S., Onodera K. et al. Effect of hepatocyte growth factor on the proliferation of transplanted hepatocytes in the spleen // Transplant. Proc. - 1997. - Vol.29, N 4. - P.2029-2031; Sporn M.B., Roberts A.B. Transforming growth factor-in: recent progress and new challenges // J. Cell Biol. - 1992. - Vol.119, N 5. - P.1017-1021). A number of studies have confirmed the influence of peptide as a stimulator of the wound healing, because it is known for its stimulating effect on the synthesis of collagen and fibroblasts (Maquart F.X., Bellon G., Chaqour Century et al. In vivo stimulation of connective tissue accumulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ in rat experimental wounds // J. Clin. Invest. - 1993. - Vol.92, N 5. - P.2368-2376). It is shown that Gly-His-Lys contributes to stimulation of physiological and reparative regeneration of the liver (Smakhtin M. et al Atlas, I.A., Hemp A.A., Б I.I. the Method of stimulation of physiological and reparative regeneration of the liver. - The patent for the invention №2214269, 20.10.2003,). Known to the stimulating effect of peptide on hair growth (Trackhy R.E., Fors T.D., Pickart L., Uno H. The hair follicle-stimulating properties of copper peptide complexes. Results in C3H mice // Ann. N. Y Acad. Sci. - 1991. - Vol.642, N 10. - P.468-469) and anti-inflammatory effect associated with a decrease in the allocation of iron of ferritin in the damaged tissues (Miller D.M., DeSilva D., Pickart L., Aust S.D. Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation // Adv. Exp. Med. Biol. - 1990. - Vol.264. - P.79-84). Also, set the analgesic effect of Gly-His-Lys with pain caused by temperature irritation ( of M.E. Ter-Minassian, Б I.I., Smakhtin M. et al Atlas and other Use of peptide Gly-His-Lys for analgesic effect with pain caused by temperature irritation. - The patent for the invention №2421235, 20.06.2011,). The technical result of the invention is new usage of peptide Gly-His-Lys with formula (NH2 )Gly-His-Lys(COOH), for the anxiolytic effect. The technical result of the invention is attained by application of peptide Gly-His-Lys for anxiolytic effect. Currently known as chemical formula of this peptide, it can be synthesized in a laboratory synthesis of peptides or bought from companies involved in the delivery of biologically active compounds (Sigma, ICN, Merk, Bachim and others). We used the drug first synthesized in Institute of chemistry of St. Petersburg state University. Dissolved in izotonicescom solution of sodium chloride peptide Gly-His-Lys impose experimental animals (rats) parenteral (injected) once in doses of 0.5 and 5 mg/kg body weight 12 minutes before the start of the study.

Specific example of the Experimental animals (rats-males Wistar) weighing 200-250 g were divided into groups of 10 animals each (table). Animals were kept at room temperature 22-24 C, light mode: 12 hours of light and 12 hours - darkness, and received a standard granulated food and water in the public domain. In the experiment, the anxiolytic effect of drugs commonly assessed by the method uplifted cruciform labyrinth (Voronin T.A., S.B. Seredenin Kiryukhina trankviliziruyuschego (anxiolytic) actions pharmacological substances // Hands-on experimental (pre-clinical) study of new pharmacological substances / Under the General Ed. Corr. Russian Academy of medical Sciences, Professor ... - M: Medicine, 2005. - S.257-258). In this method, the increase in the number of visits in the open (bright) sleeve maze and increase in the time spent there the animal without increasing the overall motion activity indicate the presence of the anxiolytic effect of the drug. To study anxiolytic activity of rats were placed on a unit consisting of the cross diverging from the Central platform of the right-angle 4 bags (two opposite, open, without walls and two closed, dark). Sleeve length - 50 cm, width - 14 cm, height of the walls closed sleeves - 30 cm, height of the Board of open sleeveless - 1 see the maze was installed on the cart with jammers, providing rise of the arena to a height of 50 cm above the floor level. Experiments were performed in normal lighting. Immediately before the start of the study of animals kept for 5 min in dark cells. Then the rat was placed in the elevated plus maze to the Central site head to the open sleeve and within 5 minutes we registered the time of stay of an animal in the public, private, sleeves, on the Central stage, the number of visits in open and closed sleeves. Anxiolytic effect was estimated to increase the number of visits in the open (bright) sleeve of the maze and increase the time spent there the animal (in seconds) with no increase in total physical activity. Peptide Gly-His-Lys was dissolved in izotonicescom solution of sodium chloride to obtain the necessary doses of 0.5 and 5 mg/kg body weight of the animal. Administered parenteral (injected) once experimental animal in the amount received at the rate of 1 ml per 1 kg of body weight (0.3 ml), 12 minutes before the start of the study. Control animals received an equivalent volume of a physiological solution (FR). When using peptide Gly-His-Lys in doses of 0.5 and 5 mcg/kg marked anxiolytic effect (table). Thus, the results of the experimental studies show that the use of peptide Gly-His-Lys in doses of 0.5 and 5 mg/kg caused a pronounced anxiolytic effect. This method is based on application of regulatory peptide belonging to class of biologically active substances with strong effect and , is not time consuming and requires the use of sophisticated machinery. Application of peptide Gly-His-Lys with formula (NH2 )Gly-His-Lys(COOH), for the anxiolytic effect.


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