Abstract
Induction of BDNF-TrkB signaling is associated with the action mechanisms of conventional and fast-acting antidepressants. GSB-106, developed as a small dimeric dipeptide mimetic of BDNF, was previously shown to produce antidepressant-like effects in the mouse Porsolt test, tail suspension test, Nomura water wheel test, in the chronic social defeat stress model and in the inflammation-induced model of depression. In the present study, we evaluated the effect of chronic per os administration of GSB-106 to Balb/c mice under unpredictable chronic mild stress (UCMS). It was observed for the first time that long term GSB-106 treatment (1 mg/kg, 26 days) during ongoing UCMS procedure ameliorated the depressive-like behaviors in mice as indicated by the Porsolt test. In addition, chronic per os administration of GSB-106 resulted in an increase in BDNF levels, which were found to be decreased in the prefrontal cortex and hippocampus of mice after UCMS. Furthermore, prolonged GSB-106 treatment was accompanied by an increase in the content of pTrkB706/707 in the prefrontal cortex and by a pronounced increase in the level of pTrkB816 in both studied brain structures of mice subjected to UCMS procedure. In summary, the present data show that chronic GSB-106 treatment produces an antidepressant-like effect in the unpredictable chronic mild stress model, which is likely to be associated with the regulation of the BDNF-TrkB signaling.
Highlights
Magnetic resonance imaging (MRI) revealed smaller volumes of hippocampus, the inferior anterior cingulate, and the orbital prefrontal cortex in patients suffering from depression that are consistent with the post-mortem studies and the data on animal models of depression-like behavior [4]
Numerous basic research findings confirm that typical antidepressants increase the BDNF mRNA and protein expression as well as the TrkB activation in the hippocampus and the cortex [3,7,15], promoting the structural plastic changes associated with the antidepressant action mechanisms [8,16,17]
A rapidly developing and sustained antidepressant effect of ketamine which depends on the NMDA receptors inhibition, leads to the activation of mTORC1 complex followed by an increase in the translation and release of BDNF, an enhancement of BDNF/TrkB signaling, and a subsequent activation of the related cellular plasticity cascades [21]
Summary
Commonly referred to as clinical depression, is a severe mental chronic disease that has a high prevalence in almost all developed countries, with more than 280 million people affected worldwide (approximately 4.4% of the population), and is expected to become the leading cause of disease burden by 2030 [1]. Experimental studies have reported that the delayed onset of antidepressants action is associated with a slowly developed increase and rearrangements of synaptic strength in the depressionrelated circuits, requiring changes in the gene expression and protein translation that are dependent, to some extent, on the engagement of BDNF/TrkB pathways [13,14]. Numerous basic research findings confirm that typical antidepressants increase the BDNF mRNA and protein expression as well as the TrkB activation in the hippocampus and the cortex [3,7,15], promoting the structural plastic changes associated with the antidepressant action mechanisms [8,16,17]. A rapidly developing and sustained antidepressant effect of ketamine which depends on the NMDA receptors inhibition, leads to the activation of mTORC1 complex followed by an increase in the translation and release of BDNF, an enhancement of BDNF/TrkB signaling, and a subsequent activation of the related cellular plasticity cascades [21]. A number of previous observations as well as some more recent evidence emphasize the significance of TrkB as a valuable target for antidepressants [23,24] and reaffirm the critical role of BDNF/TrkB signaling in the pathophysiology of depression and in antidepressants action [7,25,26]
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