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-Lglutamyl-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 * Corresponding author. T. A. Gudasheva et al. 102 provides promising drug candidate and a molecular tool for investigating the possibility of divergence in NGF therapeutic and adverse effects.
The effects of endogenous dipeptide cycloprolyl-glycine on learning and memory in the model of postconvulsive retrograde amnesia of passive avoidance response in rats depended on the administration schedule. The dipeptide prevented retrograde amnesia, when injected prior to learning, had no effect after postlearning administration, and aggravated amnesia, when injected immediately before retrieval. These data suggest that cycloprolyl-glycine is similar to the standard nootropic piracetam by its mnemotropic activity.
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