Novel antidepressant candidate RO-05 modulated glucocorticoid receptors activation and FKBP5 expression in chronic mild stress model in rats

Impaired Spinal Glucocorticoid Receptor Signaling Contributes to the Attenuating Effect of Depression on Mechanical Allodynia and Thermal Hyperalgesia in Rats with Neuropathic Pain

“…Lukic et al (2015) found that the accumulation of cytoplasmic GRs was related to the elevation of FKBP5 in the lymphocytes of depressed patients. Guidotti et al (2013) have observed that increased FKBP5 expression was associated with decreased GR translocation in the hippocampus of CMS-induced depressive-like rats, which was confirmed by Xing et al (2015). Maiaru et al (2016) discovered that intrathecal administration of the specific FKBP5 inhibitor SAFit2, global deletion FKBP5 by gene knockout, or local silencing with FKBP5 siRNA significantly attenuated the mechanical allodynia associated with CFA-induced chronic inflammatory pain via GR signaling.…”

“…Many studies on major depression patients or depressive-like animal models have reported abnormal GR expression and function in the pituitary or hippocampus, amygdala, prefrontal cortex and other brain areas, which was considered one of the important reasons for HPA axis hyperactivity and glucocorticoid resistance (Revollo and Cidlowski, 2009; Anacker et al, 2011a). Some studies have found that GR nuclear translocation in hippocampus and PFC was impaired in CMS-induced depressive-like rats, which could be reversed by chronic treatment with antidepressants (Guidotti et al, 2013; Xing et al, 2015). Studies in vitro reported that the tricyclic antidepressant desipramine facilitated GR nuclear translocation in mouse fibroblasts (Pariante et al, 1997), and SSRI antidepressant sertraline increased GR transactivation in human hippocampal progenitor cells (Anacker et al, 2011b).…”

“…Several studies have found that chronic stress-induced depressive-like behavior was associated with a reduction in GR and BDNF expression in the hippocampus, which is responsible for the alterations in hippocampal neural plasticity (Alboni et al, 2011; Xing et al, 2015). Antidepressants could protect hippocampal neurons and reverse these alterations (Anacker et al, 2011b; Tanti and Belzung, 2013).…”

“…Chronic stress-induced depressive-like behavior is associated with a reduction of GRs, BDNF expression and neuronal apoptosis in the hippocampus, which can be reversed by antidepressants (Numakawa et al, 2013; Xing et al, 2015). Local application of BDNF on the spinal dorsal horn induced long-time potentiation (LTP) of C-fiber evoked field potentials (Zhou et al, 2008) and the activation of p-SFKs and p-p38 MAPK signaling in microglia (Zhou et al, 2011) as well as TrkB signaling in neurons (Beggs and Salter, 2013; Khan and Smith, 2015), which is necessary for the central sensitization of neuropathic pain.…”

Icariin alters the expression of glucocorticoid receptor, FKBP5 and SGK1 in rat brains following exposure to chronic mild stress

“…FKBP5 also enhances the stability of the GR, potentially protecting it from proteolysis, and reduces GR sensitivity to GCs (7). It has been found that CMS or chronic dexamethasone treatment may increase the mRNA and/or protein expression of FKBP5 in the brain of rodents, particularly in the hippocampus and the prefrontal cortex (1,27,30,31). The upregulation of the mRNA and protein expression of FKBP5 in the frontal cortex has also been associated with the depression status (3).…”