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.
Highlights
Nerve growth factor (NGF) has gained much attention as a potential therapeutic agent for a number of disorders ranging from neurodegenerative diseases to inflammation, glaucoma and diabetes mellitus
We have examined possible neuroprotective and differentiative activity of GK-2 and ability of this dipeptide to induce the activation of TrkA receptors and PI3K/Akt and MAPK/Erk signaling pathways
It is known that the PI3K/Akt pathway activation is important for cell survival, whereas MAPK/Erk activation is associated with cell survival, and with cell differentiation and is involved in the induction of hyperalgesia [10]
Summary
Nerve growth factor (NGF) has gained much attention as a potential therapeutic agent for a number of disorders ranging from neurodegenerative diseases to inflammation, glaucoma and diabetes mellitus. Despite a success in a multitude of preclinical studies, the results of the majority of NGF clinical trials have been disappointing [1]. The pharmacological use of NGF is limited by its poor pharmacokinetics and undesirable side effects such as hyperalgesia and severe weight loss. A possible strategy to overcome these limitations is to develop low-molecular agents which would mimic the therapeutic effects of NGF during systemic administration while having no adverse effects. Several molecules mimicking specific neurotrophin signalings have been reported as potential therapeutic agents to overcome limitations of the native protein [2]-[6]
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