Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor

Cells

Alessandra Grossert¹  Nicole Teusch¹  NargesZare Mehrjardi²  Jürgen Hescheler²  Tomo Šarić²  MarkA. Lindsay³  SarahJ. Bailey³ 

[1] Bio-Pharmaceutical Chemistry and Molecular Pharmacology, Faculty of Applied Natural Sciences, Technische Hochschule Köln, 51373 Leverkusen, Germany;Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, 50931 Cologne, Germany;Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK;

关键词: human iPSC-derived NPCs;    depression;    neurogenesis;    ketamine;    IGF2;    cAMP;    p11;   

DOI  :  10.3390/cells8101139

来源: DOAJ

【 摘 要 】

The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine offers promising perspectives for the treatment of major depressive disorder. Although ketamine demonstrates rapid and long-lasting effects, even in treatment-resistant patients, to date, the underlying mode of action remains elusive. Thus, the aim of our study was to investigate the molecular mechanism of ketamine at clinically relevant concentrations by establishing an in vitro model based on human induced pluripotent stem cells (iPSCs)-derived neural progenitor cells (NPCs). Notably, ketamine increased the proliferation of NPCs independent of the NMDA receptor, while transcriptome analysis revealed significant upregulation of insulin-like growth factor 2 (IGF2) and p11, a member of the S100 EF-hand protein family, which are both implicated in the pathophysiology of depression, 24 h after ketamine treatment. Ketamine (1 µM) was able to increase cyclic adenosine monophosphate (cAMP) signaling in NPCs within 15 min and cell proliferation, while ketamine-induced IGF2 expression was reduced after PKA inhibition with cAMPS-Rp. Furthermore, 24 h post-administration of ketamine (15 mg/kg) in vivo confirmed phosphorylation of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the subgranular zone (SGZ) of the hippocampus in C57BL/6 mice. In conclusion, ketamine promotes the proliferation of NPCs presumably by involving cAMP-IGF2 signaling.

【 授权许可】

Unknown