Title:Neuroregenerative Activity of the Dipeptide Mimetic of Brain-derived Neurotrophic Factor GSB-106 Under Experimental Ischemic Stroke

VOLUME: 20 ISSUE: 10

Author(s):Tatiana A. Gudasheva*, Polina Y. Povarnina, Tatiana A. Antipova, Sergey V. Kruglov, Ilya O. Logvinov, Dmitry M. Nikiforov and Sergey B. Seredenin

Affiliation:Department of Medicinal Chemistry, V.V. Zakusov Research Institute of Pharmacology, ul. Baltijskaya, 8, 125315 Moscow, Department of Medicinal Chemistry, V.V. Zakusov Research Institute of Pharmacology, ul. Baltijskaya, 8, 125315 Moscow, Department of Pharmacogenetics, V.V. Zakusov Research Institute of Pharmacology, ul. Baltijskaya, 8, 125315 Moscow, Department of Pharmacogenetics, V.V. Zakusov Research Institute of Pharmacology, ul. Baltijskaya, 8, 125315 Moscow, Department of Pharmacogenetics, V.V. Zakusov Research Institute of Pharmacology, ul. Baltijskaya, 8, 125315 Moscow, Department of Medicinal Chemistry, V.V. Zakusov Research Institute of Pharmacology, ul. Baltijskaya, 8, 125315 Moscow, Department of Pharmacogenetics, V.V. Zakusov Research Institute of Pharmacology, ul. Baltijskaya, 8, 125315 Moscow

Keywords:Brain-derived neurotrophic factor (BDNF), dipeptide mimetic, ischemic stroke, neurogenesis, synaptogenesis, GSB-106.

Abstract:

Background: A dimeric dipeptide mimetic of the BDNF loop 4, bis(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide (GSB-106) activates TrkB, PI3K/AKT, MAPK/ ERK, and PLC-γ1, and was created at the V.V. Zakusov Research Institute of Pharmacology. GSB-106 showed neuroprotective activity in vitro and in vivo at systemic administration.

Objective: In this work, we studied the GSB-106 effect on the cerebral infarct volume, as well as on neurogenesis and synaptogenesis under the experimental ischemic stroke induced by intravascular occlusion of the middle cerebral artery in rats.

Methods: GSB-106 was administered i.p. in a dose of 0.1 mg/kg, 24 h after the surgery and then once a day, with the end of administration on day 6 after surgery. On day 7, brain samples were collected for morphometric and biochemical (Western-blot) analysis.

Results: It was established that GSB-106 reduced the brain damage volume by 24%, restored impaired neurogenesis and/or gliogenesis (by Ki-67) in the hippocampus and the striatum, and completely restored the reduced immunoreactivity to synaptic markers synaptophysin and PSD-95 in the striatum.

Conclusion: Thus, the dimer dipeptide BDNF mimetic GSB-106 exhibits neuroregenerative properties at a clinically relevant time window (24 h) in a model of ischemic stroke presumably due to the stimulation of neurogenesis (and/or gliogenesis) and synaptogenesis.