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

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

  • Mol Neurobiol. 2024 Jul;61(7):4102-4115. doi: 10.1007/s12035-023-03832-8.
Yuhan Wu 1,  Zhanpeng Zhu 1,  Tian Lan 1,  Shuhan Li 1,  Ye Li 1,  Changmin Wang 1,  Yabo Feng 2,  Xueqin Mao 3,  Shuyan Yu 4 5
Affiliations

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.
  • 2 Department of Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, 250021, People's Republic of China.
  • 3 Department of Psychology, Qilu Hospital of Shandong University, 107 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China. m_xqin@126.com.
  • 4 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. shuyanyu@sdu.edu.cn.
  • 5 Shandong Provincial Key Laboratory of Mental Disorders, School of Basic Medical Sciences, 44 Wenhuaxilu Road, Jinan, Shandong Province, 250012, People's Republic of China. shuyanyu@sdu.edu.cn.
PMID: 38057644 DOI: 10.1007/s12035-023-03832-8
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.

Keywords

BDNF; Depression; Levomilnacipran; Neuroinflammation; Synaptic plasticity.

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