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.