Journal Menu
- About this Journal
- Abstracting and Indexing
- Aims and Scope
- Annual Issues
- Article Processing Charges
- Articles in Press
- Author Guidelines
- Bibliographic Information
- Citations to this Journal
- Contact Information
- Editorial Board
- Editorial Workflow
- Free eTOC Alerts
- Publication Ethics
- Reviewers Acknowledgment
- Submit a Manuscript
- Subscription Information
- Table of Contents
Oxidative Medicine and Cellular Longevity
Volume 2012 (2012), Article ID 324832, 8 pages
doi:10.1155/2012/324832
Review Article
The Human Tripeptide GHK-Cu in Prevention of Oxidative Stress and Degenerative Conditions of Aging: Implications for Cognitive Health
Skin Biology, Research & Development Department, 4122 Factoria Boulevard SE-Suite No. 200, Bellevue, WA 98006, USA
Received 13 January 2012; Accepted 27 February 2012
Academic Editor: Marcos Dias Pereira
Copyright © 2012 Loren Pickart et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Linked References
- V. Shukla, S. K. Mishra, and H. C. Pant, “Oxidative stress in neurodegeneration,” Advances Pharmacological Sciences, vol. 2011, Article ID 572634, 13 pages, 2011. View at Publisher · View at Google Scholar
- P. L. McGeer and E. G. McGeer, “Inflammation and the degenerative diseases of aging,” Annals of the New York Academy of Sciences, vol. 1035, pp. 104–116, 2004. View at Publisher · View at Google Scholar · View at Scopus
- S. Iraola-Guzmán, X. Estivill, and R. Rabionet, “DNA methylation in neurodegenerative disorders: a missing link between genome and environment?” Clinical Genetics, vol. 80, no. 1, pp. 1–14, 2011. View at Publisher · View at Google Scholar · View at Scopus
- B. Moosmann and C. Behl, “Antioxidants as treatment for neurodegenerative disorders,” Expert Opinion on Investigational Drugs, vol. 11, no. 10, pp. 1407–1435, 2002. View at Publisher · View at Google Scholar · View at Scopus
- C. D. Kamat, S. Gadal, M. Mhatre, K. S. Williamson, Q. N. Pye, and K. Hensley, “Antioxidants in central nervous system diseases: preclinical promise and translational challenges,” Journal of Alzheimer's Disease, vol. 15, no. 3, pp. 473–493, 2008. View at Scopus
- K. Jomova and M. Valko, “Importance of iron chelation in free radical-induced oxidative stress and human disease,” Current Pharmaceutical Design, vol. 17, no. 31, pp. 3460–3473, 2011.
- J. B. Kwok, “Role of epigenetics in Alzheimer's and Parkinson's disease,” Epigenomics, vol. 2, no. 5, pp. 671–682, 2010. View at Publisher · View at Google Scholar · View at Scopus
- L. Pickart, “The human tri-peptide GHK and tissue remodeling,” Journal of Biomaterials Science, Polymer Edition, vol. 19, no. 8, pp. 969–988, 2008. View at Publisher · View at Google Scholar · View at Scopus
- L. Pickart and F. Pickart, “A possible mechanism whereby skin remodeling may suppress cancer metastasis genes,” in Society for the Advancement of Wound Care and the Wound Healing Society, pp. A8–A62, Wound Repair and Regeneration, Dallas, Tex, USA, 2011.
- L. Pickart, A tripepeptide in human serum that promotes the growth of hepatoma cells and the survival of normal hepatocytes, Ph.D. thesis, University of California, San Francisco, Calif, USA, 1973.
- L. Pickart, J. H. Freedman, and W. J. Loker, “Growth-modulating plasma tripeptide may function by facilating copper uptake into cells,” Nature, vol. 288, no. 5792, pp. 715–717, 1980. View at Scopus
- C. M. Perkins, N. J. Rose, B. Weinstein, R. E. Stenkamp, L. H. Jensen, and L. Pickart, “The structure of a copper complex of the growth factor glycyl-L-histidyl-L-lysine at 1.1 Å resolution,” Inorganica Chimica Acta, vol. 82, no. 1, pp. 93–99, 1984. View at Scopus
- C. Hureau, H. Eury, R. Guillot et al., “X-ray and solution structures of Cu(II) GHK and Cu(II) DAHK complexes: influence on their redox properties,” Chemistry A, vol. 17, pp. 10151–10160, 2011.
- S. J. Lau and B. Sarkar, “The interaction of copper(II) and glycyl-L-histidyl-L-lysine, a growth-modulating tripeptide from plasma,” Biochemical Journal, vol. 199, no. 3, pp. 649–656, 1981. View at Scopus
- N. Kumar, J. B. Gross Jr., and J. E. Ahlskog, “Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration,” Neurology, vol. 63, no. 1, pp. 33–39, 2004. View at Scopus
- A. Kazemi, T. Frazier, and M. Cave, “Micronutrient-related neurologic complications following bariatric surgery,” Current Gastroenterology Reports, vol. 12, no. 4, pp. 288–295, 2010. View at Publisher · View at Google Scholar · View at Scopus
- R. T. Naismith, J. B. Shepherd, C. C. Weihl, N. T. Tutlam, and A. H. Cross, “Acute and bilateral blindness due to optic neuropathy associated with copper deficiency,” Archives of Neurology, vol. 66, no. 8, pp. 1025–1027, 2009. View at Publisher · View at Google Scholar · View at Scopus
- G. G. Zucconi, S. Cipriani, R. Scattoni, I. Balgkouranidou, D. P. Hawkins, and K. V. Ragnarsdottir, “Copper deficiency elicits glial and neuronal response typical of neurodegenerative disorders,” Neuropathology and Applied Neurobiology, vol. 33, no. 2, pp. 212–225, 2007. View at Publisher · View at Google Scholar · View at Scopus
- Y. H. Hung, A. I. Bush, and R. A. Cherny, “Copper in the brain and Alzheimer's disease,” Journal of Biological Inorganic Chemistry, vol. 15, no. 1, pp. 61–76, 2010. View at Publisher · View at Google Scholar · View at Scopus
- S. Bolognin, L. Messori, D. Drago, C. Gabbiani, L. Cendron, and P. Zatta, “Aluminum, copper, iron and zinc differentially alter amyloid-Aβ (1–42) aggregation and toxicity,” International Journal of Biochemistry and Cell Biology, vol. 43, no. 6, pp. 877–885, 2011. View at Publisher · View at Google Scholar · View at Scopus
- C. Exley, “Aluminium and iron, but neither copper nor zinc, are key to the precipitation of β-sheets of Aβ42 in senile plaque cores in Alzheimer's disease,” Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 173–177, 2006. View at Scopus
- M. Kawahara, H. Koyama, T. Nagata, and Y. Sadakane, “Zinc, copper, and carnosine attenuate neurotoxicity of prion fragment PrP106–126,” Metallomics, vol. 3, no. 7, pp. 726–734, 2011. View at Publisher · View at Google Scholar · View at Scopus
- G. M. Bishop and S. R. Robinson, “The amyloid paradox: Amyloid-β-metal complexes be neurotoxic and neuroprotective,” Brain Pathology, vol. 14, no. 4, pp. 448–452, 2004. View at Scopus
- M. Schrag, C. Mueller, U. Oyoyo, M. A. Smith, and W. M. Kirsch, “Iron, zinc and copper in the Alzheimer's disease brain: a quantitative meta-analysis. Some insight on the influence of citation bias on scientific opinion,” Progress in Neurobiology, vol. 94, no. 3, pp. 296–306, 2011. View at Publisher · View at Google Scholar · View at Scopus
- H. Kessler, F. G. Pajonk, P. Meisser et al., “Cerebrospinal fluid diagnostic markers correlate with lower plasma copper and ceruloplasmin in patients with Alzheimer's disease,” Journal of Neural Transmission, vol. 113, no. 11, pp. 1763–1769, 2006. View at Publisher · View at Google Scholar · View at Scopus
- P. M. Doraiswamy and A. E. Finefrock, “Metals in our minds: therapeutic implications for neurodegenerative disorders,” Lancet Neurology, vol. 3, no. 7, pp. 431–434, 2004. View at Publisher · View at Google Scholar · View at Scopus
- H. Akatsu, A. Hori, T. Yamamoto, et al., “Transition metal abnormalities in progressive dementias,” BioMetals, vol. 52, no. 2, pp. 337–350, 2012. View at Publisher · View at Google Scholar
- H. Kessler, F. G. Pajonk, D. Bach et al., “Effect of copper intake on CSF parameters in patients with mild Alzheimer's disease: a pilot phase 2 clinical trial,” Journal of Neural Transmission, vol. 115, no. 12, pp. 1651–1659, 2008. View at Publisher · View at Google Scholar · View at Scopus
- T. Borchardt, J. Camakaris, R. Cappai, C. L. Masters, K. Beyreuther, and G. Multhaup, “Copper inhibits β-amyloid production and stimulates the non-amyloidogenic pathway of amyloid-precursor-protein secretion,” Biochemical Journal, vol. 344, pp. 461–467, 1999. View at Publisher · View at Google Scholar · View at Scopus
- M. Narahara, M. Hamada-Kanazawa, M. Kouda, A. Odani, and M. Miyake, “Superoxide scavenging and xanthine oxidase inhibiting activities of copper-β-citryl-L-glutamate complex,” Biological and Pharmaceutical Bulletin, vol. 33, no. 12, pp. 1938–1943, 2010. View at Publisher · View at Google Scholar · View at Scopus
- M. Rózga and W. Bal, “The Cu(II)/Aβ/human serum albumin model of control mechanism for copper-related amyloid neurotoxicity,” Chemical Research in Toxicology, vol. 23, no. 2, pp. 298–308, 2010. View at Publisher · View at Google Scholar · View at Scopus
- L. Perrone, E. Mothes, M. Vignes et al., “Copper transfer from Cu-Aβ to human serum albumin inhibits aggregation, radical production and reduces Aβ toxicity,” ChemBioChem, vol. 11, no. 1, pp. 110–118, 2010. View at Publisher · View at Google Scholar · View at Scopus
- S. Lutsenko, A. Bhattacharjee, and A. L. Hubbard, “Copper handling machinery of the brain,” Metallomics, vol. 2, no. 9, pp. 596–608, 2010. View at Publisher · View at Google Scholar · View at Scopus
- S. N. Hawk, L. Lanoue, C. L. Keen, C. L. Kwik-Uribe, R. B. Rucker, and J. Y. Uriu-Adams, “Copper-deficient rat embryos are characterized by low superoxide dismutase activity and elevated superoxide anions,” Biology of Reproduction, vol. 68, no. 3, pp. 896–903, 2003. View at Publisher · View at Google Scholar · View at Scopus
- T. A. Bayer, S. Schäfer, A. Simons et al., “Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 24, pp. 14187–14192, 2003. View at Publisher · View at Google Scholar · View at Scopus
- V. Arul, D. Gopinath, K. Gomathi, and R. Jayakumar, “GHK peptide incorporated collagenous matrix: a novel biomaterial for dermal wound healing in rats,” Journal of Biomedical Materials Research, vol. 73, no. 2, pp. 383–391, 2005.
- D. M. Miller, D. DeSilva, L. Pickart, and S. D. Aust, “Effects of glycyl-histidyl-lysyl chelated Cu(II) on ferritin dependent lipid peroxidation,” Advances in Experimental Medicine and Biology, vol. 264, pp. 79–84, 1990. View at Scopus
- M. Alberghina, G. Lupo, G. La Spina et al., “Cytoprotective effect of copper(II) complexes against ethanol-induced damage to rat gastric mucosa,” Journal of Inorganic Biochemistry, vol. 45, no. 4, pp. 245–259, 1992. View at Publisher · View at Google Scholar · View at Scopus
- G. Beretta, R. Artali, L. Regazzoni, M. Panigati, and R. M. Facino, “Glycyl-histidyl-lysine (GHK) is a quencher of α,β-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,” Chemical Research in Toxicology, vol. 20, no. 9, pp. 1309–1314, 2007. View at Publisher · View at Google Scholar · View at Scopus
- G. Beretta, E. Arlandini, R. Artali, J. M. Anton, and R. Maffei Facino, “Acrolein sequestering ability of the endogenous tripeptide glycyl-histidyl-lysine (GHK): characterization of conjugation products by ESI-MSn and theoretical calculations,” Journal of Pharmaceutical and Biomedical Analysis, vol. 47, no. 3, pp. 596–602, 2008. View at Publisher · View at Google Scholar · View at Scopus
- P. Agostinho, R. A. Cunha, and C. Oliveira, “Neuroinflammation, oxidative stress and the pathogenesis of Alzheimer's disease,” Current Pharmaceutical Design, vol. 16, no. 25, pp. 2766–2778, 2010. View at Scopus
- M. C. McCormack, K. C. Nowak, and R. J. Koch, “The effect of copper tripeptide and tretinoin on growth factor production in a serum-free fibroblast model.,” Archives of Facial Plastic Surgery, vol. 3, no. 1, pp. 28–32, 2001. View at Scopus
- S. O. Canapp Jr., J. P. Farese, G. S. Schultz et al., “The effect of topical tripeptide-copper complex on healing of ischemic open wounds,” Veterinary Surgery, vol. 32, no. 6, pp. 515–523, 2003. View at Publisher · View at Google Scholar · View at Scopus
- R. N. Kalaria, “Vascular basis for brain degeneration: Faltering controls and risk factors for dementia,” Nutrition Reviews, vol. 68, supplement 2, pp. S74–S87, 2010. View at Publisher · View at Google Scholar · View at Scopus
- J. D. Pollard, S. Quan, T. Kang, and R. J. Koch, “Effects of copper tripeptide on the growth and expression of growth factors by normal and irradiated fibroblasts,” Archives of Facial Plastic Surgery, vol. 7, no. 1, pp. 27–31, 2005. View at Publisher · View at Google Scholar · View at Scopus
- T. F. Lane, M. L. Iruela-Arispe, R. S. Johnson, and E. H. Sage, “SPARC is a source of copper-binding peptides that stimulate angiogenesis,” Journal of Cell Biology, vol. 125, no. 4, pp. 929–943, 1994. View at Publisher · View at Google Scholar · View at Scopus
- T. Numakawa, T. Matsumoto, Y. Numakawa, et al., “Protective action of neurotrophic factors and estrogen against oxidative stress-mediated neurodegeneration,” Journal of Toxicology, vol. 2011, Article ID 405194, 12 pages, 2011. View at Publisher · View at Google Scholar
- M. Sensenbrenner, G. G. Jaros, G. Moonen, and B. J. Meyer, “Effect of conditioned media on nerve cell differentiation,” Experientia, vol. 36, no. 6, pp. 660–662, 1980. View at Scopus
- G. Lindner, G. Grosse, W. Halle, and P. Henklein, “The effect of a synthetic tripeptide nervous tissue cultured in vitro,” Zeitschrift für Mikroskopisch-Anatomische Forschung, vol. 93, no. 5, pp. 820–828, 1979 (German).
- M. R. Ahmed, S. H. Basha, D. Gopinath, R. Muthusamy, and R. Jayakumar, “Initial upregulation of growth factors and inflammatory mediators during nerve regeneration in the presence of cell adhesive peptide-incorporated collagen tubes,” Journal of the Peripheral Nervous System, vol. 10, no. 1, pp. 17–30, 2005. View at Publisher · View at Google Scholar · View at Scopus
- J. P. Spencer, K. Vafeiadou, R. J. Williams, and D. Vauzour, “Neuroinflammation: modulation by flavonoids and mechanisms of action,” Molecular Aspects of Medicine, vol. 33, no. 1, pp. 83–97, 2012.
- J. Y. Wang, L. L. Wen, Y. N. Huang, Y. T. Chen, and M. C. Ku, “Dual effects of antioxidants in neurodegeneration: direct neuroprotection against oxidative stress and indirect protection via suppression of glia-mediated inflammation,” Current Pharmaceutical Design, vol. 12, no. 27, pp. 3521–3533, 2006. View at Publisher · View at Google Scholar · View at Scopus
- L. Pickart, “Use of GHL-Cu as a wound-healing and anti-inflammatory agent,” United States Patent 4,760,051, July 1988.
- D. Downey, W. F. Larrabee, V. Voci, and L. Pickart, “Acceleration of wound healing using glycyl-histidyl-lysyl Cu(II),” Surgical Forum, vol. 36, pp. 573–575, 1985. View at Scopus
- F. X. Maquart, L. Pickart, M. Laurent, P. Gillery, J. C. Monboisse, and J. P. Borel, “Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycl-L-histidyl-L-lysine-Cu2+,” FEBS Letters, vol. 238, no. 2, pp. 343–346, 1988. View at Scopus
- Y. Wegrowski, F. X. Maquart, and J. P. Borel, “Stimulation of sulfated glycosaminoglycan synthesis by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+,” Life Sciences, vol. 51, no. 13, pp. 1049–1056, 1992. View at Scopus
- A. Siméon, H. Emonard, W. Hornebeck, and F. X. Maquart, “The tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+ stimulates matrix metalloproteinase-2 expression by fibroblast cultures,” Life Sciences, vol. 67, no. 18, pp. 2257–2265, 2000. View at Publisher · View at Google Scholar · View at Scopus
- A. Siméon, Y. Wegrowski, Y. Bontemps, and F. X. Maquart, “Expression of glycosaminoglycans and small proteoglycans in wounds: modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+,” Journal of Investigative Dermatology, vol. 115, no. 6, pp. 962–968, 2000. View at Publisher · View at Google Scholar · View at Scopus
- Y. A. Kang, H. R. Choi, J. I. Na et al., “Copper-GHK increases integrin expression and p63 positivity by keratinocytes,” Archives of Dermatological Research, vol. 301, no. 4, pp. 301–306, 2009. View at Publisher · View at Google Scholar · View at Scopus
- J. Lamb, “The Connectivity Map: a new tool for biomedical research,” Nature Reviews Cancer, vol. 7, no. 1, pp. 54–60, 2007. View at Publisher · View at Google Scholar · View at Scopus
- F. Iorio, R. Bosotti, E. Scacheri et al., “Discovery of drug mode of action and drug repositioning from transcriptional responses,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 33, pp. 14621–14626, 2010. View at Publisher · View at Google Scholar · View at Scopus
- Y. Hong, T. Downey, K. W. Eu, P. K. Koh, and P. Y. Cheah, “A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics,” Clinical and Experimental Metastasis, vol. 27, no. 2, pp. 83–90, 2010. View at Publisher · View at Google Scholar · View at Scopus
- P. Huang, S. Kishida, D. Cao et al., “The neuronal differentiation factor neuroD1 downregulates the neuronal repellent factor Slit2 expression and promotes cell motility and tumor formation of neuroblastoma,” Cancer Research, vol. 71, no. 8, pp. 2938–2948, 2011. View at Publisher · View at Google Scholar · View at Scopus
- C. M. Koch and W. Wagner, “Epigenetic-aging-signature to determine age in different tissues,” Aging, vol. 3, no. 10, pp. 1018–1027, 2011.
- A. Fischer, F. Sananbenesi, A. Mungenast, and L. H. Tsai, “Targeting the correct HDAC(s) to treat cognitive disorders,” Trends in Pharmacological Sciences, vol. 31, no. 12, pp. 605–617, 2010. View at Publisher · View at Google Scholar · View at Scopus
- J. J. Hostynek, F. Dreher, and H. I. Maibach, “Human skin retention and penetration of a copper tripeptide in vitro as function of skin layer towards anti-inflammatory therapy,” Inflammation Research, vol. 59, no. 11, pp. 983–988, 2010. View at Publisher · View at Google Scholar · View at Scopus
- J. J. Hostynek, F. Dreher, and H. I. Maibach, “Human skin penetration of a copper tripeptide in vitro as a function of skin layer,” Inflammation Research, vol. 60, no. 1, pp. 79–86, 2011. View at Publisher · View at Google Scholar · View at Scopus
- L. Pickart, “Method of using copper(II) containing compounds to accelerate wound healing,” United States Patent 5,164,367, November 1992.