title: Mimetics of brain-derived neurotrophic factor loops 1 and 4 are active in a model of ischemic stroke in rats.
abstract: BACKGROUND
  Two dimeric dipeptides,bis-(N-monosuccinyl-l-seryl-l-lysine)hexamethylenediamide (GSB-106) andbis-(N-monosuccinyl-l-methionyl-l-serine) heptamethylenediamide (GSB-214), were designed based on the brain-derived neurotrophic factor (BDNF) loop 4 and loop 1 β-turn sequences, respectively. Earlier, both of these dipeptides were shown to exhibit neuroprotective activity in vitro (10-5-10-8M). The present study aimed to investigate the mechanisms of action of these peptides and their neuroprotective activity in an experimental stroke model.
  
  
  METHODS
  We used western blot and HT-22 hippocampal neuronal cell line to investigate whether these peptides induced phosphorylation of the TrkB receptor and the AKT and ERK kinases. Rat middle cerebral artery occlusion (MCAO) was used as a stroke model. GSB-106 and GSB-214 were administered intraperitoneally (0.1 mg (1.3×10-7mol)/kg) 4 hours after MCAO and daily for 7 days. The cerebral infarct volumes were measured with 2,3,5-triphenyltetrazolium chloride staining 21 days after MCAO.
  
  
  RESULTS
  Both compounds were shown to elevate the TrkB phosphorylation level while having different post-receptor signaling patterns. GSB-106 activated the PI3K/AKT and MAPK/ERK pathways simultaneously, whereas GSB-214 activated the PI3K/AKT only. In experimental stroke, the reduction of cerebral infarct volume by GSB-106 (∼66%) was significantly greater than that of GSB-214 (∼28% reduction), which could be explained by the fundamental role of the MAPK/ERK pathway in neurogenesis and neuroplasticity. Notably, between these two dipeptides, only GSB-106 exhibited antidepressant activity, as was found previously.
  
  
  CONCLUSIONS
  The results provided support for the beneficial pharmacological properties of BDNF loop 4 mimetic GSB-106, thereby suggesting a potential role for this dipeptide as a therapeutic agent.
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Gudasheva
authors.affiliation: Department of Medicinal Chemistry.
authors.forename: Polina
authors.initials: P
authors.lastname: Povarnina
authors.affiliation: Department of Neuroprotective Pharmacology.
authors.forename: Ilya O
authors.initials: IO
authors.lastname: Logvinov
authors.affiliation: Department of Neuroprotective Pharmacology.
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Antipova
authors.affiliation: Department of Pharmacogenetics, VV Zakusov Institute of Pharmacology, Moscow, Russia.
authors.forename: Sergey B
authors.initials: SB
authors.lastname: Seredenin
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western / Q000379:methods*; D002545:Brain Ischemia / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006624:Hippocampus / Q000502:physiology*; D008239:Lysine / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000737:chemistry* / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000473:pathology*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D004151:Dipeptides; C000618958:bis-(N-monosuccinyl-l-methionyl-l-serine)heptamethylenediamide; C000618956:bis-(N-monosuccinyl-l-seryl-l-lysine)hexamethylenediamide; D020813:Receptor, trkB; D008239:Lysine
keywords: MAPK/ERK; PI3K/AKT; brain-derived neurotrophic factor; ischemic stroke; mimetic