Comparison of Therapeutic Effects of TREK1 Blockers and Fluoxetine on Chronic Unpredicted Mild Stress Sensitive Rats

Abstract

The animal model for depressive behavior due to chronic unpredicted mild stress (CUMS) is commonly used to evaluate antidepressant treatments. The CUMS model has faced some criticism because of the heterogeneity of behavioral effects. Spadin and SID1900 are TREK1 blockers with a quick antidepressant effect. However, to date, their effectiveness and the long-term therapeutic mechanisms are not known. We hypothesize that early intervention with TREK1 blockers can fully reverse depressive-like behaviors, that the chronic administration of TREK1 blockers has a more pronounced effect than the SSRI fluoxetine, and that its long-term therapeutic effects may be mediated by improvement of impaired neurogenesis. Furthermore, we optimized the use of the CUMS model for increased homogeneity by screening the rats after the CUMS induction procedure. Depressive-like behavior was assessed by a forced swimming test, sucrose preference, and open field tests. To evaluate neurogenesis, cell proliferation and newly generated cell apoptosis were measured in the hippocampal dentate gyrus. Of 32 rats that underwent the CUMS procedure, 26 rats that exhibited depressive-like behaviors were grouped as CUMS sensitive rats (CUMSS), while six that did not were grouped as CUMS resistant ones (CUMSR). The CUMSR rats exhibited minor neurogenesis impairments, while the CUMSS rats had a more pronounced effect. Treatment with TREK1 blockers could reverse depressive-like behaviors at least 1 week earlier than that of fluoxetine. Chronic administration of both the TREK1 blockers and fluoxetine could restore neurogenesis impairments. This study underlines the importance of model validation by determination of CUMS sensitivity. The TREK1 blockers were found to have an effect that was more rapid and more pronounced than that of fluoxetine. Therapeutic benefits after chronic administration were associated with a restoration of impaired neurogenesis.

Ocimum basilicum (Basil) Modulates Apoptosis and Neurogenesis in Olfactory Pulp of Mice Exposed to Chronic Unpredictable Mild Stress

“…In this study, increased neuronal apoptosis, evidenced by increase number of caspase-3 positive cells as well as upregulation of caspase-3 gene expression was detected in MOB of mice exposed to CUMS. In agreement with this (54), and Meyer, Glaser (4) reported marked increase of apoptosis in rat and mice olfactory bulbs in models of experimentally induced neurodegeneration as well as in the hippocampus of CUMSexposed mice (48). In the present study, O. basilicum reduced caspase-3 positive cells population via downregulated caspase-3 gene expression.…”

“…Similar results were recorded by (46) and (47) in the MOB of chronic stressed rats using the cell proliferation markers; PSA-NCAM, DCX, and BrdU. In addition, previous studies reported a significant suppression of neurogenesis in hippocampal regions in mice model of depression (12,48). This effect might be attributed to increased plasma levels of corticosterone in CUMS-exposed rats, recorded in this study as well as many other studies which concluded that chronic exposure to corticosterone, or stressors that increase its secretion, has powerful suppressor effect on proliferation process (10,49,50).…”

Musk (Moschus moschiferus) Attenuates Changes in Main Olfactory Bulb of Depressed Mice: Behavioral, Biochemical, and Histopathological Evidence

“…Yang et al (2011a) and Siopi et al (2016) reported similar results in MOB using different cell proliferation markers as PSANCAM, DCX, and BrdU. Marked inhibition of neurogenesis has also been reported in the hippocampus of mice model of depression (Ayuob et al, 2018;Qi et al, 2018). This observation might be caused by elevation of plasma corticosterone in CUMS mice, which has antiproliferative effects (Ali et al, 2017;Tong et al, 2019).…”

The Involvement of Sortilin/NTSR3 in Depression as the Progenitor of Spadin and Its Role in the Membrane Expression of TREK-1

“…Although most of the research works with spadin have been performed in our laboratory, the « spadin concept » targeting TREK-1 has been validated by several other international laboratories in the field of depression, anxiety and stress (Bista et al, 2012; Zhang et al, 2015; Lengyel et al, 2016; Vallee et al, 2016; Qi et al, 2018).…”