Diterpene Ginkgolides Exert an Antidepressant Effect Through the NT3-TrkA and Ras-MAPK Pathways

Drug Des Devel Ther. 2020 Mar 31:14:1279-1294. doi: 10.2147/DDDT.S229145. eCollection 2020.

Abstract

Background: Depression is a highly prevalent mental illness that severely impacts the quality of life of affected individuals. Our recent studies demonstrated that diterpene ginkgolides (DG) have antidepressant effects in mice. However, the underlying molecular mechanisms remained much unclear.

Methods: In this study, we assessed the antidepressant effects of chronic DG therapy in rats by evaluating depression-related behaviors, we also examined potential side effects using biochemical indicators. Furthermore, we performed an in-depth molecular network analysis of gene-protein-metabolite interactions on the basis of metabolomics.

Results: Chronic DG treatment significantly ameliorated the depressive-like behavioral phenotype. Furthermore, the neurotrophin signaling-related NT3-TrkA and Ras-MAPK pathways may play an important role in the antidepressant effect of DG in the hippocampus.

Conclusion: These findings provide novel insight into the mechanisms underlying the antidepressant action of DG, and should help advance the development of new therapeutic strategies for depression.

Keywords: NT3-TrkA and Ras-MAPK pathways; antidepressant; diterpene ginkgolides; hippocampus; neurotrophin.

MeSH terms

  • Animals
  • Antidepressive Agents / administration & dosage
  • Antidepressive Agents / pharmacology*
  • Behavior, Animal / drug effects*
  • Depression / drug therapy*
  • Diterpenes / administration & dosage
  • Diterpenes / pharmacology*
  • Ginkgolides / administration & dosage
  • Ginkgolides / pharmacology*
  • Hippocampus / drug effects
  • Injections, Intraperitoneal
  • Male
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurotrophin 3 / genetics
  • Neurotrophin 3 / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / drug effects*

Substances

  • Antidepressive Agents
  • Diterpenes
  • Ginkgolides
  • Neurotrophin 3
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases
  • Proto-Oncogene Proteins p21(ras)