title: Ketamine affects the neurogenesis of rat fetal neural stem progenitor cells via the PI3K/Akt-p27 signaling pathway.
abstract: Ketamine is widely used as an anesthetic, analgesic, or sedative in pediatric patients. We reported that ketamine alters the normal neurogenesis of rat fetal neural stem progenitor cells (NSPCs) in the developing brain, but the underlying mechanisms remain unknown. The PI3K-PKB/Akt (phosphatidylinositide 3-kinase/protein kinase B) signaling pathway plays many important roles in cell survival, apoptosis, and proliferation. We hypothesized that PI3K-PKB/Akt signaling may be involved in ketamine-altered neurogenesis of cultured NSPCs in vitro. NSPCs were isolated from Sprague-Dawley rat fetuses on gestational day 17. 5-bromo-2'-deoxyuridine (BrdU) incorporation, Ki67 staining, and differentiation tests were utilized to identify primary cultured NSPCs. Immunofluorescent staining was used to detect Akt expression, whereas Western blots measured phosphorylated Akt and p27 expression in NSPCs exposed to different treatments. We report that cultured NSPCs had properties of neurogenesis: proliferation and neural differentiation. PKB/Akt was expressed in cultured rat fetal cortical NSPCs. Ketamine inhibited the phosphorylation of Akt and further enhanced p27 expression in cultured NSPCs. All ketamine-induced PI3K/Akt signaling changes could be recovered by N-methyl-d-aspartate (NMDA) receptor agonist, NMDA. These data suggest that the inhibition of PI3K/Akt-p27 signaling may be involved in ketamine-induced neurotoxicity in the developing brain, whereas excitatory NMDA receptor activation may reverse these effects.
authors.affiliation: Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Anatomy and Neurobiology, Neuroscience Institute, University of Tennessee Health Science Center, Memphis, Tennessee.
authors.forename: Chaoxuan
authors.initials: C
authors.lastname: Dong
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Rovnaghi
authors.forename: Kanwaljeet J S
authors.initials: KJ
authors.lastname: Anand
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000196:embryology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D016202:N-Methylaspartate / Q000494:pharmacology; D058953:Neural Stem Cells / Q000166:cytology*; D055495:Neurogenesis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists
chemical_list: D000700:Analgesics; C493962:Cdkn1b protein, rat; D016194:Receptors, N-Methyl-D-Aspartate; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016202:N-Methylaspartate; D007649:Ketamine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: embryogenesis; embryonic/fetal physiology; pharmaceuticals; safety assessment; signal transduction