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

has been cited by the following article:

• TITLE: 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

  AUTHORS: T. A. Gudasheva, P. Yu. Povarnina, T. A. Antipova, S. B. Seredenin

  KEYWORDS: Nerve Growth Factor, Mimetic, Dipeptide, GK-2, TrkA, PI3K/Akt, MAPK/Erk, Alzheimer’s Disease, Parkinson’s Disease, Stroke, Diabetes

  JOURNAL NAME: Neuroscience and Medicine, Vol.5 No.2, April 30, 2014

  ABSTRACT: 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.