NGF Loop 4 Dimeric Dipeptide Mimetic Active on Animal Models of Parkinson's, Alzheimer's Diseases and Stroke

摘要

The ability of NGF to promote neuronal survival in pathological conditions makes this protein an attractive candidate for the treatment of neurodegenerative disorders. However, many problems are associated with its clinical use. The development of small molecule NGF mimetics is a promising approach to resolve the problems. To mimic NGF functions pharmacologically, we designed dimeric dipeptide named GK-2 (bis(N-succinyl-L-glutamyl-L-lysine)hexametylendiamide) on the basis of the most exposed to solvent beta-turn sequence Asp~(93)-Glu~(94)-Lys~(95) of loop4. The residue Asp~(93) was substituted by bioisostere, a succinic acid residue. Because NGF interacts with the TrkA receptor in the dimeric form, the agonistic activity was achieved by dimerizing the N-acyldipeptide by hexametylenediamine [1]. GK-2, like NGF, stimulated phosphorylation of TrkA, but not TrkB receptor and prevented glutamate-and H2O2-induced neuronal cell death at l0~(-9)M [2]. In the present study we investigated GK-2 ability to trigger phosphorylation of Akt and Erk proteins, which plays a key role in two major biochemical pathways mediated by TrkA receptor. In order to test the ability of GK-2 to mimic in vivo therapeutical properties of NGF we investigated the activity of the dipeptide on animal models of Parkinson's disease, Alzheimer's disease (AD) and brain ischemia.