Recent Research on Dimeric Dipeptide Mimetics of NGF and BDNF Are Promising Agents for Post- Stroke Therapy

The dimeric dipeptide mimetics of the brain derived neurotrophic factor (BDNF) loops 1, 2 and 4 and
nerve growth factor (NGF) loop 4 were designed and synthesized at the Zakusov Research Institute
of Pharmacology. All of the obtained compounds activated a corresponding specific NGF or BDNF
tyrosine kinase receptor (TrkA or TrkB), but had different postreceptor signaling patterns. GSB-106
activated the ERK and AKT, whereas GSB-214 and GK-2 only activated the AKT kinase. Here we
report a comparative analysis of neuroprotective activity of these dipeptides in a model of ischemic
stroke induced by transient middle cerebral artery occlusion (MCAO). In the experiment with BDNF
mimetics, GSB-106 reduced this volume by 66% and GSB-214 by 26%. NGF mimetic GK-2 reduced
the cerebral infarct volume by 45%. Thus, BDNF mimetic, which activated both the ERK and AKT,
and NGF mimetic, which selectively activated PI3K/AKT, showed high neuroprotective efficacy. In
addition, we studied neuroprotective effects of GK-2 at the beginning of the treatment 6, 8 and 24
hours after reperfusion. The neuroprotective effect of GK-2 persisted in all these conditions. The
effectiveness of GK-2 at a delayed start of administration suggests that the dipeptide has
neuroregenerative properties. The results obtained suggest a potential role for the dimeric dipeptide
NGF and BDNF mimetics as therapeutic agents useful in the treatment of a stroke.