Abstract
| Original language | English |
|---|---|
| Article number | 1139 |
| Journal | Cells |
| Volume | 8 |
| Issue number | 10 |
| DOIs | |
| Publication status | Published - 24 Sep 2019 |
Cite this
Ketamine increases proliferation of human iPSC-derived neuronal progenitor cells via insulin-like growth factor 2 and independent of the NMDA receptor. / Grossert, Alessandra; Mehrjardi, Narges Zare; Bailey, Sarah; Lindsay, Mark; Hescheler, Jurgen; Saric, Tomo; Teusch, Nicole.
In: Cells, Vol. 8, No. 10, 1139, 24.09.2019.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Ketamine increases proliferation of human iPSC-derived neuronal progenitor cells via insulin-like growth factor 2 and independent of the NMDA receptor
AU - Grossert, Alessandra
AU - Mehrjardi, Narges Zare
AU - Bailey, Sarah
AU - Lindsay, Mark
AU - Hescheler, Jurgen
AU - Saric, Tomo
AU - Teusch, Nicole
PY - 2019/9/24
Y1 - 2019/9/24
N2 - 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.
AB - 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.
U2 - 10.3390/cells8101139
DO - 10.3390/cells8101139
M3 - Article
VL - 8
JO - Cells
JF - Cells
SN - 2073-4409
IS - 10
M1 - 1139
ER -