Hippocampal PPARα Plays a Role in the Pharmacological Mechanism of Vortioxetine, a Multimodal-Acting Antidepressant

Abstract

As a well-known multimodal-acting antidepressant, vortioxetine is thought to aim at several serotonin (5-HT) receptors and the 5-HT transporter. However, recently more and more proteins besides 5-HT are being reported to participate in the antidepressant mechanism of vortioxetine. As a widely known nuclear hormone receptor, peroxisome proliferator activated receptor α (PPARα) possesses transcriptional activity and is very important in the brain. Several reports have suggested that hippocampal PPARα is implicated in antidepressant responses. Here we speculate that hippocampal PPARα may participate in the antidepressant mechanism of vortioxetine. In this study, chronic unpredictable mild stress (CUMS), chronic social defeat stress (CSDS), behavioral tests, the western blotting and adenovirus associated virus (AAV)-mediated gene knockdown methods were used together. It was found that vortioxetine administration significantly reversed the inhibitory actions of both CUMS and CSDS on the hippocampal PPARα expression. Pharmacological blockade of PPARα notably prevented the antidepressant actions of vortioxetine in the CUMS and CSDS models. Moreover, genetic knockdown of PPARα in the hippocampus also significantly blocked the protecting effects of vortioxetine against both CUMS and CSDS. Therefore, the antidepressant effects of vortioxetine in mice require hippocampal PPARα.

Activation of mTORC1 Signaling Cascade in Hippocampus and Medial Prefrontal Cortex Is Required for Antidepressant Actions of Vortioxetine in Mice

“…For each experiment, the mice were subjected to stratified randomization according to body weight, and all groups of mice were subjected to behavioral tests carried out during the light phase. The sample sizes were determined according to G. power analysis and our previous studies ( Jiang et al, 2019 ; Wang et al, 2020a , 2020b , 2021 ; Guan et al, 2021 ).…”

“…The procedures for CUMS were performed according to our previous studies ( Xu et al, 2018 ; Jiang et al, 2019 ; Wang et al, 2020b , 2021 ). Except for the vehicle-treated control group, the mice were individually subjected to various stressors for a period of 8 weeks.…”

“…The paradigm of CSDS was performed as we have frequently reported ( Xu et al, 2018 ; Jiang et al, 2019 ; Wang et al, 2020a , 2020b , 2021 ; Guan et al, 2021 ). Before CSDS, adequate amounts of CD1 aggressors were selected from the retired male CD1 mice according to the experimental design.…”

“…It has been demonstrated that vortioxetine functions as a blocker for serotonin (5-HT) transporter, an antagonist for 5-HT 3 , 5-HT 7 , and 5-HT 1D receptors, and also an agonist for 5-HT 1A and 5-HT 1B receptors ( Pehrson et al, 2016 ). Recently, more pharmacological targets beyond 5-HT have been reported to participate in the antidepressant mechanism of vortioxetine, such as peroxisome proliferator activated receptor α (PPARα), F3/Contactin, the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) system, and so on ( Yu et al, 2017 ; Lu et al, 2018 ; Sun et al, 2020 ; Wang et al, 2020a , 2021 ). Interestingly, in 2016, du Jardin et al reported that a single dose of vortioxetine significantly enhanced the expression of several plasticity-related genes (mammalian target of rapamycin complex 1 [mTORC1], Mglur-1, PKCα, Homer-3, Spinophilin, and Synapsin-3) in the frontal cortex of rats ( du Jardin et al, 2016 ).…”

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“…Along the aforementioned, other mechanisms could be at play; vortioxetine showed antioxidative and anti-inflammatory activity on human monocytes and macrophages [ 27 ], and this matches the neuroinflammation hypothesis of depression. There is a recent hypothesis describing that vortioxetine induces antidepressant effects in mice models of depression by significantly promoting the hippocampal peroxisome proliferator activated receptor a (PPARα) expression, that is known to be involved in antidepressant response [ 28 ].…”