A Novel Dimeric Dipeptide Mimetic of the Nerve Growth Factor Exhibits Pharmacological Effects upon Systemic Administration and Has No Side Effects Accompanying the Neurotrophin Treatment


The development of small molecule nerve growth factor (NGF) mimetics is a promising approach to overcome limitations in the use of the neurotrophin as a drug, which are poor pharmacokinetics and undesirable side effects. We designed dimeric dipeptide called GK-2 (bis(N-succinyl-L-glutamyl-L-lysine)hexametylendiamide) on the base of beta-turn sequence of NGF loop4 which most exposed to solvent and hence can play the major role in the interaction of NGF with the receptor. It was shown, that GK-2 stimulates phosphorylation of TrkA receptor, selectively activates PI3K/Akt signaling cascade that is important for cell survival, and does not activate MAPK/Erk pathway, associated not only with cell survival but also with cell differentiation. According to these data, GK-2 in vitro prevented H2O2- or MPTP- or glutamate-induced neuronal cell death at nanomolar concentrations, but did not provoke neurite outgrowth in PC12 cells. In vivo GK-2 exhibits therapeutic effects in models of Parkinson’s disease, Alzheimer’s disease, brain ischemia and diabetes mellitus. GK-2 shows activity in doses 0.01 - 5 mg/kg intraperitoneally and retains the activity after oral administration in dose 10 mg/kg. GK-2 has no side effects accompanying NGF treatment namely hyperalgesia and weight loss. Thus, the designed dimeric substituted dipeptide provides promising drug candidate and a molecular tool for investigating the possibility of divergence in NGF therapeutic and adverse effects.

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Gudasheva, T. , Povarnina, P. , Antipova, T. and Seredenin, S. (2014) A Novel Dimeric Dipeptide Mimetic of the Nerve Growth Factor Exhibits Pharmacological Effects upon Systemic Administration and Has No Side Effects Accompanying the Neurotrophin Treatment. Neuroscience and Medicine, 5, 101-108. doi: 10.4236/nm.2014.52013.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Aloe, L., Rocco, M.L., Bianchi, P. and Manni, L. (2012) Nerve Growth Factor: From the Early Discoveries to the Potential Clinical Use. Journal of Translational Medicine, 10, 239-252. http://dx.doi.org/10.1186/1479-5876-10-239
[2] Longo, F.M., Manthorpe, M., Xie, Y.M. and Varon, S. (1997) Synthetic NGF Peptide Derivatives Prevent Neuronal Death via a P75 Receptor-Dependent Mechanism. Synthetic NGF Peptide Derivatives Prevent Neuronal Death via a P75 Receptor-Dependent Mechanism. Journal of Neuroscience Research, 48, 1-17.
[3] Peleshok, J. and Saragovi, H.U. (2006) Functional Mimetics of Neurotrophins and Their Receptors. Biochemical Society Transaction, 34, 612-617. http://dx.doi.org/10.1042/BST0340612
[4] Massa, S.M., Yang, T., Xie, Y., Shi, J., Bilgen, M., Joyce, J.N., Nehama, D., Rajadas, J. and Longo, F.M. (2010) Small Molecule BDNF Mimetics Activate TrkB Signaling and Prevent Neuronal Degeneration in Rodents. The Journal of clinical investigation, 120, 1775-1785. http://dx.doi.org/10.1172/JCI41356
[5] Colangelo, A.M., Bianco, M.R., Vitagliano, L., Cavaliere, C., Cirillo, G., De Gioia, L., Diana, D., Colombo, D., Redaelli, C., Zaccaro, L., Morelli, G., Papa, M., Sarmientos, P., Alberghina, L. and Martegani, E. (2008) A New Nerve Growth Factor-Mimetic Peptide Active on Neuropathic Pain in Rats. The Journal of Neuroscience, 10, 2698-2709.
[6] Scarpi, D., Cirelli, D., Matrone, C., Castronovo, G., Rosini, P., Occhiato, E.G., Romano, F., Bartali, L., Clemente, A.M., Bottegoni, G., Cavalli, A., De Chiara, G., Bonini, P., Calissano, P., Palamara, A.T., Garaci, E., Torcia, M.G., Guarna, A. and Cozzolino, F. (2012) Low Molecular Weight, Non-Peptidic Agonists of TrkA Receptor with NGF-Mimetic Activity. Cell Death and Disease, 3, 389-402. http://dx.doi.org/10.1038/cddis.2012.80
[7] Gudasheva, T.A., Antipova, T.A. and Seredenin, S.B. (2010) Novel Low-Molecular-Weight Mimetics of the Nerve Growth Factor. Doklady Biochemistry and Biophysics, 434, 262-265. http://dx.doi.org/10.1134/S160767291005011X
[8] Seredenin, S.B. and Gudasheva, T.A. (2011) Dipeptide Mimetics of NGF and BDNF Neurotrophins. US Patent, Application No. US 2011/0312895 A1.
[9] Reichardt, L.F. (2006) Neurotrophin-Regulated Signalling Pathways. Philosophical Transactions of the Royal Society of London, Series B: Biological Sciences, 361, 1545-1564. http://dx.doi.org/10.1098/rstb.2006.1894
[10] Obata, K. and Noguchi, K. (2004) MAPK Activation in Nociceptive Neurons and Pain Hypersensitivity. Life Sciences, 74, 2643-5263. http://dx.doi.org/10.1016/j.lfs.2004.01.007
[11] Antipova, T.A., Gudasheva, T.A. and Seredenin, S.B. (2011) In Vitro Study of Neuroprotective Properties of GK-2, a New Original Nerve Growth Factor Mimetic. Bulletin of Experimental Biology and Medicine, 150, 607-609.
[12] Gudasheva, T., Antipova, T., Povarnina, P. and Seredenin, S. (2013) NGF Loop 4 Dimeric Dipeptide Mimetic Active on Animal Models of Parkinson’s, Alzheimer’s Diseases and Stroke. Proceedings of the 23rd American and the 6th International Peptide Symposium, Big Island, 22-27 June 2013, 194-195.
[13] Mogi, M., Togari, A., Kondo, T., Mizuno, Y., Komure, O., Kuno, S., Ichinose, H. and Nagatsu, T. (1999) Brain-Derived Growth Factor and Nerve Growth Factor Concentrations are Decreased in the Substantia Nigra in Parkinson’s Disease. Neuroscience Letters, 270, 45-48. http://dx.doi.org/10.1016/S0304-3940(99)00463-2
[14] Chaturvedi, R.K., Shukla, S., Seth, K. and Agrawal, A.K. (2006) Nerve Growth Factor Increases Survival of Dopaminergic Graft, Rescue Nigral Dopaminergic Neurons and Restores Functional Deficits in Rat Model of Parkinson’s Disease. Neuroscience Letters, 398, 44-49. http://dx.doi.org/10.1016/j.neulet.2005.12.042
[15] Kurakhmaeva, K.B., Voronina, T.A., Kapica, I.G., Kreuter, J., Nerobkova, L.N., Seredenin, S.B., Balabanian, V.Y. and Alyautdin R.N. (2008) Antiparkinsonian Effect of Nerve Growth Factor Adsorbed on Polybutylcyanoacrylate Nanoparticles Coated With Polysorbate-80. Bulletin of Experimental Biology and Medicine, 145, 259-262.
[16] Povarnina, P.Y., Gudasheva, T.A., Vorontsova, O.N., Bondarenko, N.A. and Seredenin, S.B. (2011) Antiparkinsonian Properties of a Nerve Growth Factor Dipeptide Mimetic GK-2 in in Vivo Experiments. Bulletin of Experimental Biology and Medicine, 151, 690-693. http://dx.doi.org/10.1007/s10517-011-1417-6
[17] Lindvall, O., Ernfors, P., Bengzon, J., Kokaia, Z., Smith, M.L., Siesjö, B.K. and Persson, H. (1992) Differential Regulation of mRNAs for Nerve Growth Factor, Brain-Derived Neurotrophic Factor, and Neurotrophin 3 in the Adult Rat Brain Following Cerebral Ischemia and Hypoglycemic Coma. Proceedings of National Academy of Sciences of the United States of America, 89, 648-652. http://dx.doi.org/10.1073/pnas.89.2.648
[18] Guégan, C., Onténiente, B., Makiura, Y., Merad-Boudia, M., Ceballos-Picot, I. and Sola, B. (1998) Reduction of Cortical Infarction and Impairment of Apoptosis in NGF-Transgenic Mice Subjected to Permanent Focal Ischemia. Molecular Brain Research, 55, 133-140. http://dx.doi.org/10.1016/S0169-328X(97)00372-0
[19] Gusev, E.I. and Skvortsova, V.I. (2001) Brain Ischemia. Medicine, Moscow.
[20] Yang, JP. Liu, H.J., Yang, H. and Fenq, P.Y. (2011) Therapeutic Time Window for the Neuroprotective Effects of NGF When Administered after Focal Cerebral Ischemia. Neurological Sciences, 32, 433-441.
[21] Shigeno, T., Mima, T., Takakura, K., Graham, D., Kato, G., Hashimoto, Y. and Furukawa, S. (1991) Amelioration of Delayed Neuronal Death in the Hippocampus by Nerve Growth Factor. The Journal of Neuroscience, 11, 2914-2919.
[22] Zhu, W., Cheng, S., Xu, G., Ma, M., Zhou, Z., Liu, D. and Liu, X. (2011) Intranasal Nerve Growth Factor Enhances Striatal Neurogenesis in Adult Rats with Focal Cerebral Ischemia. Drug Delivery, 18, 338-343.
[23] Seredenin, S.B., Romanova, G.A., Gudasheva, T.A., Shakova, F.M., Barskov, I.V., Stelmashuk, E.V. and Antipova, T.A. (2011) Neuroprotective and Antiamnestic Effect of Nerve Growth Factor Dipeptide Mimetic GK-2 in Experimental Ischemic Infarction of Brain Cortex. Bulletin of Experimental Biology and Medicine, 150, 432-435.
[24] Seredenin, S.B., Silachev, D.N., Gudasheva, T.A., Pirogov, Y.A. and Isaev, N.K. (2011) Neuroprotective Effect of GK-2, a Dipeptide Mimetic of Nerve Growth Factor, During Experimental Focal Ischemia in Middle Cerebral Artery Basin. Bulletin of Experimental Biology and Medicine, 151, 584-587. http://dx.doi.org/10.1007/s10517-011-1388-7
[25] Robinet, P.M., Rowlett, J.K. and Bardo, M.T. (1998) Individual Differences in Novelty-Induced Activity and the Rewarding Effects of Novelty and Amphetamine in Rats. Behavioural Processess, 44, 1-9.
[26] Povarnina, P.Y., Gudasheva, T.A., Vorontsova, O.N., Nikolaev, S.V., Antipova, T.A., Ostrovskaia, R.U. and Seredenin, S.B. (2012) Neuroprotective Effects of a Dipeptide Mimetic of the GK-2 Nerve Growth Factor in Model of Permanent Common Carotid Artery Occlusion in Rats. Eksperimental’naia i klinicheskaia farmakologiia, 75, 15-20.
[27] Avrushchenko, M.S., Zarzhetsky, Y.V., Moroz, V.V., Ostrova, I.V., Gudasheva, T.A. and Seredenin, S.B. (2012) Effect of Nerve Growth Factor Mimetic GK-2 on Brain Structural and Functional State in the Early Postresuccination Period. General Reanimatology, 8, 19-23.
[28] Cattaneo, A., Capsoni, S. and Paoletti, F. (2008) Towards Non Invasive Nerve Growth Factor Therapies for Alzheimer’s Disease. Journal of Alzheimer’s Disease, 15, 255-283.
[29] Gu, H., Long, D., Song, C. and Li, X. (2009) Recombinant Human NGF-Loaded Microspheres Promote Survival of Basal Forebrain Cholinergic Neurons and Improve Memory Impairments of Spatial Learning in the Rat Model of Alzheimer’s Disease with Fimbria-Fornix Lesion. Neuroscience Letters, 453, 204-209.
[30] Koliatsos, V.E., Nauta, H.J., Clatterbuck, R.E., Holtzman, D.M., Mobley, W.C. and Price, D.L. (1990) Mouse Nerve Growth Factor Prevents Degeneration of Axotomized Basal Forebrain Cholinergic Neurons in the Monkey. The Journal of Neuroscience, 10, 3801-3813.
[31] Smith, D.E., Roberts, J., Gage, F.H. and Tuszynski, M.H. (1999) Age-Associated Neuronal Atrophy Occurs in the Primate Brain and is Reversible by Growth Factor Gene Therapy. Proceedings of National Academy of Sciences of the United States of America, 96, 10893-10898. http://dx.doi.org/10.1073/pnas.96.19.10893
[32] Winkler, J. and Thal, L.J. (1995) Effects of Nerve Growth Factor Treatment on Rats Witch Lesions of the Nucleus Basalis Magnocellularis Produced by Ibotenic Acid, Quisqualic Acid, and AMPA. Experimental Neurology, 136, 234-250.
[33] Povarnina, P.Y., Vorontsova, O.N., Gudasheva, T.A., Ostrovskaya, R.U. and Seredenin, S.B. (2013) Original Nerve Growth Factor Mimetic Dipeptide GK-2 Restores Impaired Cognitive Functions in Rat Models of Alzheimer’s Disease. Acta Naturae, 5, 84-91.
[34] Polak, M., Scharfmann, R., Seilheimer, B., Eisenbarth, G., Dressler, D., Verma, I.M. and Potter, H. (1993) Nerve Growth Factor Induces Neuron-Like Differentiation of an Insulin-Secreting Pancreatic Beta Cell Line. Proceedings of National Academy of Sciences of the United States of America, 90, 5781-5781.
[35] Rosenbaum, T., Sanches-Soto, M.C. and Hiriart, M. (2001) Nerve Growth Factor Increases Sodium Current in Pancreatic Beta-Cells. Diabetes, 50, 1755-1762. http://dx.doi.org/10.2337/diabetes.50.8.1755
[36] Nielsen, J.H., Galsgaard, E.D., Møldrup, A., Friedrichsen, B.N., Billestrup, N., Hansen, J.A., Lee, Y.C. and Carlsson, C. (2001) Regulation of Beta-Cell Mass by Hormones and Growth Factors. Diabetes, 50, S25-S29.
[37] Hathway, G.J. and Fitzgerald, M. (2006) Time Course and Dose-Dependence of Nerve Growth Factor-Induced Secondary Hyperalgesia in the Mouse. The Journal of Pain, 7, 57-61. http://dx.doi.org/10.1016/j.jpain.2005.08.003

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