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Article

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

1
Bio-Pharmaceutical Chemistry and Molecular Pharmacology, Faculty of Applied Natural Sciences, Technische Hochschule Köln, 51373 Leverkusen, Germany
2
Center for Physiology and Pathophysiology, Institute for Neurophysiology, Medical Faculty, University of Cologne, 50931 Cologne, Germany
3
Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK
4
Department of Biomedical Sciences, Faculty of Human Sciences, University of Osnabrück, 49076 Osnabrück, Germany
*
Author to whom correspondence should be addressed.
Cells 2019, 8(10), 1139; https://doi.org/10.3390/cells8101139
Received: 25 July 2019 / Revised: 19 September 2019 / Accepted: 20 September 2019 / Published: 24 September 2019
(This article belongs to the Special Issue iPS Cells for Disease Modeling)
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. View Full-Text
Keywords: human iPSC-derived NPCs; depression; neurogenesis; ketamine; IGF2; cAMP; p11 human iPSC-derived NPCs; depression; neurogenesis; ketamine; IGF2; cAMP; p11
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MDPI and ACS Style

Grossert, A.; Mehrjardi, N.Z.; Bailey, S.J.; Lindsay, M.A.; Hescheler, J.; Šarić, T.; Teusch, N. Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor. Cells 2019, 8, 1139. https://doi.org/10.3390/cells8101139

AMA Style

Grossert A, Mehrjardi NZ, Bailey SJ, Lindsay MA, Hescheler J, Šarić T, Teusch N. Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor. Cells. 2019; 8(10):1139. https://doi.org/10.3390/cells8101139

Chicago/Turabian Style

Grossert, Alessandra; Mehrjardi, Narges Z.; Bailey, Sarah J.; Lindsay, Mark A.; Hescheler, Jürgen; Šarić, Tomo; Teusch, Nicole. 2019. "Ketamine Increases Proliferation of Human iPSC-Derived Neuronal Progenitor Cells via Insulin-Like Growth Factor 2 and Independent of the NMDA Receptor" Cells 8, no. 10: 1139. https://doi.org/10.3390/cells8101139

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