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Levomilnacipran Improves Lipopolysaccharide-Induced Dysregulation of Synaptic Plasticity and Depression-Like Behaviors via Activating BDNF/TrkB Mediated PI3K/Akt/mTOR Signaling Pathway

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Abstract

Depression is a common psychological disease with high morbidity and mortality. Recently, the involvement of synaptic plasticity in the pathogenesis of depression has shed light on the direction of developing novel antidepressants. Levomilnacipran is a newly approved medication for the treatment of adult major depressive disorder. However, the detailed mechanisms underlying its antidepressant-like effects have yet to be illuminated. In this study, we aimed to investigate the role of levomilnacipran in regulating synaptic plasticity and explore the possible molecular mechanisms of its antidepressant effects using a rat model of depression induced by lipopolysaccharide (LPS). The results demonstrated that levomilnacipran (30 mg/kg, i.p.) significantly ameliorated depression-like behaviors in rats, alleviated the dysregulation of synaptic plasticity, and suppressed neuroinflammation within hippocampus induced by LPS-treatment. Levomilnacipran increased the expression of postsynaptic dense 95 (PSD-95) and synaptophysin (Syn) and reversed the imbalance between pro- and anti-inflammatory cytokines within hippocampus of depressed rats. Additionally, levomilnacipran elevated expression level of brain-derived neurotrophic factor (BDNF), accompanied by increased tyrosine kinase B (TrkB), phosphorylated phosphatidylinositol 3-kinase (PI3K), phosphorylated protein kinase B (p-Akt), and phosphorylated mammalian target of rapamycin (p-mTOR). Taken together, these results suggest that levomilnacipran may exert antidepressant effects via upregulating BDNF/TrkB mediated PI3K/Akt/mTOR signaling pathway to improve synaptic plasticity. These findings reveal potential mechanisms for the antidepressant effects of levomilnacipran and offer new insights into the treatments for depression.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

LTP:

Long-term potentiation

LTD:

Long-term depression

AMPAR:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

NMDAR:

N-methyl-D-aspartate receptor

SNRI:

Serotonin and norepinephrine reuptake inhibitor

LPS:

Lipopolysaccharide

SPT:

Sucrose preference test

FST:

Forced swim test

OFT:

Open field test

TEM:

Transmission electron microscopy

ANOVA:

Analysis of variance

PSD-95:

Postsynaptic density protein 95

Syn:

Synaptophysin

BDNF:

Brain-derived neurotrophic factor

TrkB:

Tyrosine kinase B

PI3K:

Phosphatidylinositol 3-kinase

Akt:

Protein kinase B

mTOR:

Mammalian target of rapamycin

CREB:

CAMP-responsive element binding protein

GAPDH:

Glyceraldehyde-phosphate dehydrogenase

IL:

Interleukin

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Acknowledgements

We thank Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.

Funding

This study was supported by grants to Shu Yan Yu from the National Natural Science Foundation of China (82071513; 82271566) and the Natural Science Foundation of Shandong Province of China (ZR2021MH151; ZR2020MH152).

Author information

Authors and Affiliations

  1. Department of Physiology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People’s Republic of China

    Yuhan Wu, Zhanpeng Zhu, Tian Lan, Shuhan Li, Ye Li, Changmin Wang & Shuyan Yu

  2. Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, 250021, People’s Republic of China

    Yabo Feng

  3. Department of Psychology, Qilu Hospital of Shandong University, 107 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People’s Republic of China

    Xueqin Mao

  4. Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People’s Republic of China

    Shuyan Yu

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  1. Yuhan Wu
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Contributions

Conceptualization: SYY, YW, and TL; methodology: YW, ZZ, and TL; investigation: YW, TL, SL, YL, and CW; funding acquisition: SYY; writing: YW, TL, and SYY; supervision: YF, XM, and SYY.

Corresponding authors

Correspondence to Xueqin Mao or Shuyan Yu.

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Ethics Approval and Consent to Participate

The Ethics Committee at Shandong University Animal Care and Use Committee (Jinan, China) approved the protocols of this study. All experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). All authors declare that they consent to participate and approve for the publication of this article.

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Highlights

1. Levomilnacipran ameliorated anxiety- and depression-like behaviors in rats.

2. Levomilnacipran alleviated LPS-induced dysregulation of synaptic plasticity.

3. Levomilnacipran ameliorated LPS-induced neuroinflammation.

4. Levomilnacipran activated the BDNF/TrkB mediated PI3K/Akt/mTOR pathway.

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Wu, Y., Zhu, Z., Lan, T. et al. Levomilnacipran Improves Lipopolysaccharide-Induced Dysregulation of Synaptic Plasticity and Depression-Like Behaviors via Activating BDNF/TrkB Mediated PI3K/Akt/mTOR Signaling Pathway. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03832-8

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