Anti-Inflammatory Actions: Damaged Tissue
The anti-oxidant actions of GHK and GHK-Cu that help to protect injured tissue appear to have multiple actions. These are (1) a direct anti-inflammatory of the copper-peptide complex, (2) an activity that blocks the release of free iron from ferritin molecules, (3) an ability to block tissue damage caused by interleukin-1 at a GHK-Cu concentration of about 10exp(-10) M, and (4) an ability to block the oxidation of low density lipoproteins (LDL) by free copper.
Study |
Result |
Reference |
Development of tissue protective analogs of GHK-Cu |
GHK-Cu and analogs were tested for anti-oxidant and tissue protective properties GHK-Cu and analogs were found to enhance or restore resistance to oxidative or inflammatory damage. Certain analogs were 100-fold more effective than GHK-Cu. |
US Patent 5,118,665 New anti oxidative and anti-inflammatory metal peptide complexes - containing glycine, histidine and lysine residues used to enhance or restore resistance to oxidative or inflammatory damage. Pickart |
Blocking of iron oxidation |
A study of whether some of the wound healing properties of GHK-Cu are due to an affect on iron metabolism. The presence of iron complexes in damaged tissues is detrimental to wound healing, due to local inflammation, as well as microbial infection mediated by iron. The effects of GHK:Cu(II) on iron catalyzed lipid peroxidation. GHK:Cu(II) inhibited lipid peroxidation if the iron source was ferritin. Whereas GHK:Cu(II) inhibited ferritin iron release it did not exhibit significant superoxide dismutase-like or ceruloplasmin activity. It appears that GHK-Cu binds to the channels of ferritin involved in iron release and physically prevents the release of fee). Thus, a biological effect of GHK:Cu(II), related to wound healing, may be the inhibition of ferritin iron release in damaged tissues, preventing inflammation and microbial infections. |
Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation. Miller, DeSilva, Pickart, Aust. Pickart and Aust (Biotechnology Center, Utah State University, Logan, UT, USA) Adv. Exp Med Biol 1990;264:79-84 |
Finding of superoxide dismutase and catalase-like activities in GHK Nickel complexes |
The reactions between nickel ions and GHK and similar oligopeptides were characterized by spin trapping experiments. GHK-Cu possessed superoxide dismutase and catalase-like activities. |
Redox chemistry of complexes of nickel) with some biologically important peptides in the presence of reduced oxygen species. Coterie N; Tremolieres E; Berliner JCL; Cattier JP; Henichart JP (INSERM, Ill, France) J Internat BioPharm 1992 Apr;46(1):7-15 |
Cytoprotective actions against oxygen free radicals |
GHK-Cu markedly inhibited intestinal mucosal tissue from lipid peroxidation by oxygen-derived free radicals. |
Alberghina M, Lupo G, La Spina G, Mangiameli A, Gulisano M, Sciotto D, Rizzarelli E, Cytoprotective effect of copper(II) complexes against ethanol-induced damage to rat gastric mucosa, J Inorg Biochem. 1992 Mar;45(4):245-59. |
Anti-oxidant protection of insulin secreting cells after injury. Interleukin beta (IL-1 beta) is released during injuries and after tissue damage. IL-1 inhibits insulin release by pancreatic cells. |
The study tested whether GHK-Cu would block the IL-1 damage to insulin secreting pancreatic cells. Rat pancreatic islet cells were incubated with or without 50 U/ml IL-1 beta, in the presence or absence of various concentrations of Cu(II)-GHK or CuSO4 (1-1000 ng/ml). After incubation, insulin secretion was evaluated in the presence of either 2.8 mmol/l (basal insulin secretion) or 16.7 mmol/l glucose (glucose-induced release). In control islets, basal insulin secretion was 92 +/- 11 ( pg/islet) and glucose-induced release was 2824 +/- 249. In islets pre-exposed to 50 U/ml IL-1 beta, basal insulin release was not significantly affected but glucose- induced insulin release was greatly reduced (841 +/- 76 ). In islets incubated with IL-1 beta and Cu-GHK (0.4 mumol/l, maximal effect) basal secretion was 119.0 +/- 13 and glucose-induced release was 2797 +/- 242. CuSO4 was without protective actions. |
Copper addition prevents the inhibitory effects of interleukin 1-beta on rat pancreatic islets, Vinci, Caltabiano, Santoro, Rabuazzo, Buscema, Purrello, Rizzarelli, Vigneri and Purrello (University of Catania Medical Endocrinology, University of Catania Medical School, Italy) Diabetologia 1995 38(1):39-45 |
Effect of GHK on blocking oxidative damage that produces Alzheimer's disease |
Loosely bound copper(II) can produce oxidation of amyloid protein of Alzheimer's disease and cause neurodegeneration Loosely bound copper(II) can produce oxidation of amyloid protein of Alzheimer's disease and cause neurodegeneration |
The amyloid precursor protein of Alzheimer's disease in the reduction of copper(II) to copper(I). Multhaup; Schlicksupp Hesse; Beher; Ruppert Masters; Beyreuther ( ZMBH-Center for Molecular Biology University of Heidelberg, Germany) Science 1996 Mar 8;271(5254):1406-9 |
Increase superoxide dismutase in wounds |
Biotin was attached to GHK then bound to collagen films. This gave increased wound contraction, increased cell proliferation, and produced a high expression of the antioxidant superoxide dismutase. Tissue copper levels were increased 9-fold. |
Arul V, Gopinath D, Gomathi K, Jayakumar R. Biotinylated GHK peptide incorporated collagenous matrix: A novel biomaterial for dermal wound healing in rats. Biomed Mater Res B Appl Biomater. 2005 May;73(2):383-91 |
GHK detoxifies 4-hydroxy-2-nonenal, a toxic mlecule |
GHK blocks the toxic actions of 4-hydroxy-2-nonenal (HNE), a fatty acid decomposition product felt to be causative in the development of diabetes, nephropathy, retinopathy, and neurodegenaerative diseases. |
Beretta G, Artali R, Regazzoni L, Panigati M, Facino RM, Glycyl-histidyl-lysine (GHK) is a quencher of alpha,beta-4-hydroxy-trans-2-nonenal: a comparison with carnosine. insights into the mechanism of reaction by electrospray ionization mass spectrometry, 1H NMR, and computational techniques. |
GHK blocks block acrolein production |
Acrolein is a toxin created by carbonyl radicals from polyunsaturated fatty acids. GHK detoxifies acrolein. The authors suggest that GHK may be of value in prevention of atherosclerosis, diabetes, neuropathy, and Alzheimer disease. |
Beretta G, Arlandini E, Artali R, Anton JM, Maffei Facino R. Acrolein sequestering ability of the endogenous tripeptide glycyl-histidyl-lysine (GHK): Characterization of conjugation products by ESI-MS(n) and theoretical calculations. |
Anti-Inflammatory Actions: General
Blocking the oxidation of low density lipoproteins GHK tested on effecting the extent of in vitro Cu(2+)-dependent oxidation of low density lipoproteins (LDL)
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GHK blocked the extent of in vitro Cu(2+)-dependent oxidation of low density lipoproteins (LDL). Treatment of LDL with 5 microM of copper (+2) for 18 h in either phosphate buffered saline (PBS) or Ham's F-10 medium resulted in extensive oxidation as determined by the content of thiobarbituric acid reactive substances (TABORS). In PBS, oxidation was entirely blocked by gly-his-lys (GHK). In comparison , superoxide dismutase (SOD) provided only 20% protection.
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The influence of medium components on Cu(2+) dependent oxidation of low- density lipoproteins and its sensitivity to superoxide dismutase. Thomas (Marion Merle Dow Research Institute, Cincinnati, Ohio, USA) Biochem Biophys Acta 1992 1128(1):50-7
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Angiotensin II appears to incite inflammatory processes that accelerated atheroma development. GHK interacts with the angiotensin II AT1 receptor.
The effect of GHK on phosphorylase A was determined. Binding competition experiments using the radioligand [125I][Sar1-Ile8] angiotensin II measured the interaction of GHK with AT1 receptors. |
GHK stimulated in dose-dependent fashion the activity of phosphorylase A in isolated rat hepatocytes. This effect was associated with increases in both IP3 production and [Ca++]. These effects of GHK were antagonized by losartan, a nonpeptide angiotensin II receptor antagonist (AT1 selective), which suggested that these receptors were involved in its effect. Binding competition experiments clearly indicated that GHK interacts with AT1 receptors. |
Glycyl-histidyl-lysine interacts with the angiotensin II AT1 receptor. Garcia-Sainz JA; Olivares-Reyes JA (Departamento de Bioenergetica, Universidad Nacional Autonoma de Mexico, Mexico D. F). Peptides 1995;16(7):1203-7 |
GHK-Cu inhibits platelet aggregation |
GHK-Cu inhibits platelet aggregation at 10exp (-7) M |
Unpublished studies. Savage, Pickart, et al, Hope Heart Institute, Seattle, Washington, USA |
GHK-Cu inhibits thromboxane production |
Significant inhibition at 10exp (-7) M |
Unpublished studies. Savage, Pickart, et al, Hope Heart Institute, Seattle, Washington, USA |
Anti-Oxidant and Anti-Inflammatory Actions of GHK and GHK-Cu
Human NSAIDs
GHK and GHK-Cu may function as the circulating human non-steroidal anti-inflammatories (NSAIDs). In human plasma there is about 200 nanograms per milliliters of GHK and GHK-Cu at age 20. This declines to about 80 nanograms per milliliter at age 60 but these levels are highly variable. Given the respective binding constants for copper(+2) between GHK and albumin in human plasma, it is likely that only about 10% of circulating GHK is chelated with copper(+2). In areas of tissue damage, this ratio could be higher because of lowered albumin concentrations. There are very close similarities between the three dimensional chemical structures of GHK-Cu and H2-Receptor antagonists used as anti-ulcer medicines such as cimetidine, ranitidine, famotidine and nizatidine. Since GHK-Cu is a normal component of saliva present at about 40 nanograms/milliliter, it may function a natural protector of gastrointestinal linings. Also, most common anti-ulcer drugs are potent binders of ionic copper (II).There are also similarities, though less obvious, between most Non-Steroidal Anti-Inflammatory Drugs (NAISDs) and GHK. Virtually all NSAIDs avidly bind copper(+2).
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