Nerve Regeneration

When wound healing is inadequate, the healed area is often devoid of sensory abilities.

GHK tripeptide is suggested as a possible therapeutic agent against age-associated neurodegeneration and cognitive decline.

Oxid Med Cell Longev. 2012;2012:324832. Epub 2012 May 10.

The Human Tripeptide GHK-Cu in Prevention of Oxidative Stress and Degenerative Conditions of Aging: Implications for Cognitive Health.

Pickart L, Vasquez-Soltero JM, Margolina A.

Skin Biology, Research & Development Department, 4122 Factoria Boulevard SE-Suite No. 200, Bellevue, WA 98006, USA.

Abstract

Oxidative stress, disrupted copper homeostasis, and neuroinflammation due to overproduction of proinflammatory cytokines are considered leading causative factors in development of age-associated neurodegenerative conditions. Recently, a new mechanism of aging-detrimental epigenetic modifications-has emerged. Thus, compounds that possess antioxidant, anti-inflammatory activity as well as compounds capable of restoring copper balance and proper gene functioning may be able to prevent age-associated cognitive decline and ward off many common neurodegenerative conditions. The aim of this paper is to bring attention to a compound with a long history of safe use in wound healing and antiaging skin care. The human tripeptide GHK was discovered in 1973 as an activity in human albumin that caused old human liver tissue to synthesize proteins like younger tissue. It has high affinity for copper ions and easily forms a copper complex or GHK-Cu. In addition, GHK possesses a plethora of other regenerative and protective actions including antioxidant, anti-inflammatory, and wound healing properties. Recent studies revealed its ability to up- and downregulate a large number of human genes including those that are critical for neuronal development and maintenance. We propose GHK tripeptide as a possible therapeutic agent against age-associated neurodegeneration and cognitive decline.

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Studied the effect of GHK on nerve growth. Gly-His-Lys supported chick neuron differentiation and viability in cell culture and increased nerve outgrowth. The optimum concentrations of GHK for neuron function were 100-400 ng/ml. 

Neurobiology. 1975 Aug;5(4):207-13.

Effects of Synthetic Tripeptide on the Differentiation of Dissociated Cerebral Hemisphere Nerve Cells in Culturen

Sensenbrenner M, Jaros GG, Moonen G, Mandel P.

University of Strausbourg, France

Abstract
Dissociated cells from 7-day-old chick embryo cerebral hemispheres were cultivated on collagen in Falcon Petri dishes in the presence of various concentrations of fetal calf serum and of a chemically synthesized tripeptide Gly-His-Lys. Four different culture conditions were employed in the composition of the nutrient medium in which the cells were cultivated: a low serum concentration of 1, 2 or 5% (group A), a low serum concentration with 200 ng/ml tripeptide (group B), a serum concentration of 10 to 20% (group C) and a serum concentration of 10 or 20% with 200 ng/ml tripeptide (group D). Within the first 24 h of cultivation the cells settled on the collagen substrate and outgrowth of neuronal processes started in all four culture conditions. After 48 h in culture, differences between the groups became evident. In group A most isolated nerve cells had disappeared and glial cells proliferated from the remaining clumps. In group B the neurons had differentiated in absence of glial cells, the proliferation of which was greatly suppressed. In group C and D a differentiation of neurons occurred in a similar way to group B, but in addition the glial cells had proliferated. After 7-8 days in culture the cells in group A and B suddenly degenerated. In group C and D the nerve cells maintained for up to 3 weeks. The optimum concentrations of tripeptide in which the neuroblasts grew fibers and maintained in culture during 7-8 days were in the range of 100-400 ng/ml. The role of the tripeptide in the differentiation and maintenance of nerve cells is discussed.

Studied the effect of GHK on nerve growth. Gly-His-Lys supported chick neuron differentiation and viability in cell culture of various neurons -  chick embryo PNS (ganglion trigeminale) and from CNS of embryonal rats (hippocampus) and dissociated cells from chick embryo cerebral tissue.  The optimum concentrations of GHK for neuron outgrowth was 10 ng/ml. GHK increased the ratio of neurons to glial cell in culture. 

Z Mikrosk Anat Forsch. 1979;93(5):820-8.


Uber die Wirkung eines synthetischen Tripeptids auf  in vitro kultiviertes Nervengewebe [The effect of a synthetic tripeptide nervous tissue cultured in vitro].
[Article in German]

Lindner G, Grosse G, Halle W, Henklein P.

Abstract

Explants from chick embryo PNS (ganglion trigeminale) and from CNS of embryonal rats (hippocampus) and dissociated cells from chick embryo cerebral hemispheres were cultivated in maximow chambers in the presence of various concentrations of placental serum and of a chemically synthesized tripeptide Gly-His-Lys. 1. The presence of tripeptide in the nutrient medium with a low concentration of serum did not compensate the outgrowth of nerve fibers, that take place in the growth medium. 2. In the presence of tripeptide in the nutrient medium with low concentration of serum the index of growth area increased significantly. 3. Within the first days in cell cultures 0,01 microgram tripeptide pro ml medium stimulated the outgrowth of neuronal processes. 4. The experiments indicated, that the tripeptide did not replace the serum. The possible role of tripeptide as a system in controlling neuron-glial ratio in vitro is discussed.

Severed nerves are placed in a collagen tube impregnated with GHK. This caused an increase in the productino of Nerve Growth Factor and the neurotrophins NT-3 and NT-4..

J Peripher Nerv Syst. 2005 Mar;10(1):17-30.

Initial upregulation of growth factors and inflammatory mediators during nerve regeneration in the presence of cell adhesive peptide-incorporated collagen tubes.

Ahmed MR, Basha SH, Gopinath D, Muthusamy R, Jayakumar R.

Bio-organic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai, India.

Abstract

Neurotrophic factors play an important modulatory role in axonal sprouting during nerve regeneration involving the proliferation of hematogenous and Schwann cells in damaged tissue. We have exposed lesioned sciatic nerves to a collagen prosthesis with covalently bonded small cell adhesive peptides Arg-Gly-Asp-Ser (RGDS), Lys-Arg-Asp-Ser (KRDS), and Gly-His-Lys (GHK) to study local production of growth factors and cytokines in the regenerating tissues. Western/enzyme-linked immunosorbent assay (ELISA) studies were performed after 10 days of regeneration, when the tubular prosthesis is filled with fibrous matrix infiltrated by hematogenous cells and proliferating Schwann cells with growth factors produced locally. Regeneration was also analyzed by morphometrical methods after 30 days. The quantification of growth factors and proteins by ELISA revealed that there was an enhanced expression of the neurotrophic factors nerve growth factor (NGF) and neurotrophins (NT-3 and NT-4) in the regenerating tissues. This was further established by Western blot to qualitatively analyze the presence of the antigens in the regenerating tissues. Schwann cells were localized in the regenerating tissues using antibodies against S-100 protein. Other growth factors including growth-associated protein 43 (GAP-43), apolipoprotein E (Apo E), and pro-inflammatory cytokine like interleukin-1alpha (IL-1alpha) expression in the peptide groups were evaluated by ELISA and confirmed by Western blotting. Cell adhesive integrins in the proliferating cells were localized using integrin-alpha V. The combined results suggest that the early phase of regeneration of peripheral nerves in the presence of peptide-incorporated collagen tubes results in the enhanced production of trophic factors by the recruited hematogenous cells and Schwann cells, which in turn help in the secretion of certain vital trophic and tropic factors essential for early regeneration. Furthermore, hematogenous cells recruited within the first 10 days of regeneration help in the production of inflammatory mediators like interleukins that in turn stimulate Schwann cells to produce NGF for axonal growth.

 


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