Сhronically Administered BDNF Dipeptide Mimetic GSB-106 Prevents the Depressive-like Behavior and Memory Impairments after Transient Middle Cerebral Artery Occlusion in Rats.

Abstract

A dipeptide mimetic of the BDNF loop 4, bis (N-monosuccinyl-L-seryl-L-lysine) hexamethylenediamide, GSB-106, was designed and synthesized by V.V. Zakusov Research Institute of Pharmacology. The compound activated in vitro TrkB, MAPK/ERK, PI3K/AKT, and PLCγ, like full-length BDNF. In vivo, GSB-106 exhibited antidepressant-like, neuroprotective and neuroregenerative properties. The aim of this work was to study the effects of GSB-106 on depressive-like behavior, cognitive impairments, as well as on hippocampal neuroplasticity in an experimental model of ischemic stroke. Male Wistar rats were subjected to 60 minutes of transient middle cerebral artery occlusion (MCAO). Dipeptide GSB-106 was administered intraperitoneally at a dose of 0.1 mg/kg/day for 21 days after surgery. 30-40 days after MCAO, the depressive-like state in the forced swimming test and memory impairment in the novel object recognition test were assessed. Then, the content of CREB, as a neuroplasticity marker, was assessed in the ipsilateral hippocampus. Rats in MCAO group showed depression-like behavior (increase in immobility time in the forced swimming test by 22% compared to sham group), impairments in short-term and long-term memory (decrease in the discrimination index in the novel object recognition test by 70% and 50%, respectively), and a decrease in immunoreactivity to CREB (cAMP response element-binding protein) in the hippocampus by 36% as compared with the sham group. GSB-106 completely prevented the behavior impairments and counteracted the reduction of immunoreactivity to CREB in the hippocampus. The BDNF dipeptide mimetic GSB-106 is promising for further development as a drug for the treatment of poststroke neuropsychiatric disorders.