Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis

Abstract

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

Analysis of the Selective Antagonist SAFit2 as a Chemical Probe for the FK506-Binding Protein 51

“…76, 77 Codagnone et al showed that in primary hippocampal cultures derived from C57BL/6 mice, SAFit2 could increase neurite length, neuronal ramification, and complexity; in rat hippocampal neuronal progenitor cells (NPCs) SAFit2 promoted neurogenesis, neurite outgrowth, and morphological maturation. 74 These results are in line with and further corroborate previous findings reported by Gaali et al, where incubation of human neuroblastoma cells (SH-SY5Y) and mouse neuroblastoma cells (N2a) with SAFit1 showed neurotrophic effects. 3 Overall, these initial studies confirmed the potential of selective FKBP51 inhibitors in the treatment of stress-related psychiatric disorders, even though the current PK properties of SAFit2 are not optimal.…”

“…There is mounting evidence that hippocampal neurogenesis is likely to play a protecting role against stress-related diseases as a mechanism of resilience. , Codagnone et al showed that in primary hippocampal cultures derived from C57BL/6 mice, SAFit2 could increase neurite length, neuronal ramification, and complexity; in rat hippocampal neuronal progenitor cells (NPCs) SAFit2 promoted neurogenesis, neurite outgrowth, and morphological maturation . These results are in line with and further corroborate previous findings reported by Gaali et al, where incubation of human neuroblastoma cells (SH-SY5Y) and mouse neuroblastoma cells (N2a) with SAFit1 showed neurotrophic effects …”

“…Very recently, Codagnone et al showed that the acute treatment with SAFit2 of C57BL/6N mice reduced immobility during the FST. However, chronic administration of SAFit2 could not reproduce these effects, as no changes on immobility could be observed …”

“…When compared to fluoxetine, another common SSRI, the chronic administration of SAFit2 was more effective in increasing the distance traveled by the mice in the center of the OFT and had anxiolytic effects in a model of stress-induced social aversion. Interestingly, and opposite to fluoxetine, SAFit2 had no effects on anhedonia in the female urine sniffing test (FUST) . Some of these differences in results may be due to different administration routes and formulations of SAFit2, ultimately leading to varying plasma concentrations of the drug, that were not always assessed in the different studies.…”

“…However, chronic administration of SAFit2 could not reproduce these effects, as no changes on immobility could be observed. 74 When compared to fluoxetine, another common SSRI, the chronic administration of SAFit2 was more effective in increasing the distance traveled by the mice in the center of the OFT and had anxiolytic effects in a model of stress-induced social aversion. Interestingly, and opposite to fluoxetine, SAFit2 had no effects on anhedonia in the female urine sniffing test (FUST).…”