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Ifenprodil rapidly ameliorates depressive-like behaviors, activates mTOR signaling and modulates proinflammatory cytokines in the hippocampus of CUMS rats

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Abstract

Rationale

The rapid-onset and long-lasting antidepressant properties of ketamine have prompted investigations into a variety of agents that target N-methyl-D-aspartate receptors (NMDARs) for the treatment of major depressive disorder (MDD). According to the literature, ifenprodil (a GluN2B-containing NMDAR antagonist) can potentiate the antidepressant-like effects of certain antidepressant drugs in mice. Here, we report that a single injection of ifenprodil (3 mg/kg, intraperitoneally (i.p.)) was sufficient to provoke rapid antidepressant-like effects in chronic unpredictable mild stress (CUMS) rats. Moreover, ifenprodil activated mTOR signaling and reversed the CUMS-induced elevation of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, in our study, ifenprodil had no influence on corticosterone levels in the plasma. Our data indicate that ifenprodil per se might exert antidepressant-like effects by modulating neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors.

Objectives

To explore the potential rapid antidepressant-like effects and mechanisms of ifenprodil, a GluN2B subunit-selective NMDAR antagonist.

Methods

Male Sprague-Dawley rats were used in 3 separate experiments. In experiment 1, we used the forced swim test (FST) and sucrose preference test (SPT) to identify the rapid antidepressant-like effects of ifenprodil in chronic unpredictable mild stress (CUMS) rats after acute administration. In experiment 2, we assessed neurochemical changes involved in synaptic plasticity within the hippocampus of CUMS rats. In experiment 3, we assessed the levels of corticosterone in the plasma and proinflammatory cytokines in the hippocampus in CUMS rats after ifenprodil treatment.

Results

Ifenprodil rapidly ameliorated depressive-like behaviors in the FST and SPT, activated mTOR signaling, dephosphorylated eukaryotic elongation factor 2, enhanced BDNF expression, and promoted the synthesis of the synaptic protein GluA1 synthesis after acute administration. Moreover, ifenprodil reversed the CUMS-induced elevation of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the hippocampus after acute administration. Unfortunately, ifenprodil had no influence on corticosterone levels in the plasma in our study.

Conclusions

Our data indicate that ifenprodil per se might exert antidepressant-like effects through its effects on neuroplasticity and inflammatory processes rather than the typical hormonal factors affected by stressors.

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Funding

The work was supported by the National Key Research and Development Program of China (2016YFC1307100), the National Natural Science Foundation of China (81771465, 81930033), the National Key Technologies R&D Program of China (2012BAI01B04); the Sanming Project of Medicine in Shenzhen (SZSM201612006), Youth project of Shanghai Municipal Health and Planning Commission (20154Y0045) and Shanghai Mental Health Center Medical Youth Talents “Flying Plan” (2018-FX-03), and also supported by the Innovative Research Team of High-level Local Universities in Shanghai.

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  1. Ya-min Yao, Pei-jun Ju and Hong-mei Liu contributed equally to this work.

Authors and Affiliations

  1. Clinical Research Center & Division of Mood Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yamin Yao, Hongmei Liu, Xiaohui Wu, Zhiang Niu, Yuncheng Zhu & Yiru Fang

  2. Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China

    Peijun Ju, Chen Zhang & Yiru Fang

  3. CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai, China

    Yiru Fang

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  1. Yamin Yao
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Yao, Y., Ju, P., Liu, H. et al. Ifenprodil rapidly ameliorates depressive-like behaviors, activates mTOR signaling and modulates proinflammatory cytokines in the hippocampus of CUMS rats. Psychopharmacology 237, 1421–1433 (2020). https://doi.org/10.1007/s00213-020-05469-0

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