Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain-Derived Neurotrophic Factor

Abstract

Involvement of BDNF in the regulation of neuroplasticity and neurogenesis in the hippocampus, impairment of which underlies the pathophysiology of depression, makes this endogenous protein a promising object for the development of new-generation antidepressants with a neurophysiologically based mechanism of action. A low-molecular-weight BDNF mimetic, GSB-106 (a substituted dimeric dipeptide, bis-(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide), was designed and synthesized at the Zakusov Institute of Pharmacology. GSB-106 was found to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways MAPK/ERK and PI3K/AKT. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally. Because oral administration is preferable in the treatment of depression, which is associated with a prolonged duration and outpatient character of pharmacotherapy, we examined the antidepressant properties of GSB-106 administered orally as a pharmaceutical substance (PS) and in tablet dosage form (TDF). In the study, we used the Porsolt forced swim test in rats; a conventional antidepressant, Amitriptyline, was used as a reference drug. The antidepressant activity of GSB-106 was found to retain upon oral administration and to manifest at doses of 0.5–5.0 mg/kg for PS and 0.01–5.0 mg/kg for TDF. The effective dose of TDF was 50-fold lower than that of PS, and the efficacy of tableted GSB-106 exceeded that of Amitriptyline, the “gold standard” in antidepression care. Therefore, GSB-106, both as a substance and as a tablet dosage form, exhibits antidepressant activity when administered orally, which makes it a promising antidepressant agent, the first in the class of BDNF mimetics.

Low-Molecular Weight BDNF Mimetic, Dimeric Dipeptide GSB-106, Reverses Depressive Symptoms in Mouse Chronic Social Defeat Stress

“…Forced swimming test [ 20 ] was used to study the mechanism of GSB-106 antidepressant-like action. The test was carried out as described previously [ 11 , 21 ]. The apparatus setup consisted of 5 transparent plastic cylinders 10 cm in diameter and 30 cm in height, separated by black plastic opaque dividers to prevent visual contact of animals during the study.…”

“…GSB-106 antidepressant activity was revealed in the forced swimming test and tail suspension test in rats and mice at intraperitoneal (i.p.) (0.1–1.0 mg/kg) and oral (0.5–5.0 mg/kg) administration [ 10 , 11 ]. GSB-106 ability to stimulate hippocampal synapto- and neurogenesis was shown in experiments in mice [ 12 , 13 ].…”

Peptides Derived from Growth Factors to Treat Alzheimer’s Disease

“…For example, GSB-106 improves neurologic outcomes via PI3K/AKT and MAPK/ERK1/2 pathway activation in rat stroke model caused by transient middle cerebral artery occlusion [ 271 ]. Furthermore, GSB-106 administered intraperitoneally or orally exhibits antidepressant activity [ 270 , 272 , 273 ]. It also restores hippocampal neuroplasticity in a mice depression model induced by a chronic social defeat stress procedure ( Table 2 ) [ 238 ].…”

Low‐molecular mimetics of nerve growth factor and brain‐derived neurotrophic factor: Design and pharmacological properties

“…The antidepressant properties of GSB-106 were confirmed in outbred mice and rats at acute and subchronic administration ip in the Nomura water wheel test and in the tail suspension test. 132 The antidepressant activity persisted at oral administration in rats at doses of 0.5-5.0 mg/kg for substance 133 and at doses of 0.01-5.0 mg/kg for a tablet dosage form (RF Patent RU2697254 C2, 2019).…”